Endothelial cell signaling and ventilator-induced lung injury: Molecular mechanisms, genomic analyses, and therapeutic targets

American Journal of Physiology - Lung Cellular and Molecular Physiology

Volumn 312, Issue 4, 2017, Pages L452-L476

  Wang, Ting ^a   Gross, Christine ^b   Desai, Ankit A ^a   Zemskov, Evgeny ^a   Wu, Xiaomin ^a   Garcia, Alexander N ^c   Jacobson, Jeffrey R ^c   Yuan, Jason X J ^a   Garcia, Joe G N ^a   Black, Stephen M ^a  

^a UNIVERSITY OF ARIZONA   (United States)

^b MEDICAL COLLEGE OF GEORGIA   (United States)

^c UNIVERSITY OF ILLINOIS AT CHICAGO   (United States)

Author keywords

Acute lung injury; ARDS; Endothelial cell barrier dysfunction; Inflammation; Mechanical forces; Transcriptional regulation; VILI

Indexed keywords

TRANSCRIPTION FACTOR;

ADULT RESPIRATORY DISTRESS SYNDROME; ARTIFICIAL VENTILATION; ENDOTHELIUM CELL; ENDOTHELIUM INJURY; EPIGENETICS; GENE CONTROL; GENE TARGETING; GENETIC REGULATION; GENOME ANALYSIS; HUMAN; LUNG BLOOD VESSEL; MECHANICAL STRESS; MECHANICAL VENTILATOR; MECHANOTRANSDUCTION; MOLECULAR BIOLOGY; NONHUMAN; PATHOGENESIS; PRIORITY JOURNAL; PROTEIN PROCESSING; REVIEW; STRESS FIBER; VENTILATOR INDUCED LUNG INJURY; ANIMAL; BIOLOGICAL MODEL; GENETICS; GENOMICS; METABOLISM; MOLECULARLY TARGETED THERAPY; SIGNAL TRANSDUCTION; VENTILATOR-INDUCED LUNG INJURY;

ANIMALS; ENDOTHELIAL CELLS; GENOMICS; HUMANS; MODELS, BIOLOGICAL; MOLECULAR TARGETED THERAPY; SIGNAL TRANSDUCTION; STRESS, MECHANICAL; VENTILATOR-INDUCED LUNG INJURY;

EID: 85017016877     PISSN: 10400605     EISSN: 15221504     Source Type: Journal    
DOI: 10.1152/ajplung.00231.2016     Document Type: Review

References (387)

1. Abdulnour RE, Peng X, Finigan JH, Han EJ, Hasan EJ, Birukov KG, Reddy SP, Watkins JE III, Kayyali US, Garcia JG, Tuder RM, Hassoun PM. Mechanical stress activates xanthine oxidoreductase through MAP kinase-dependent pathways. Am J Physiol Lung Cell Mol Physiol 291: L345-L353, 2006. doi:10.1152/ajplung.00453.2005.
2. Abiko H, Fujiwara S, Ohashi K, Hiatari R, Mashiko T, Sakamoto N, Sato M, Mizuno K. Rho guanine nucleotide exchange factors involved in cyclic-stretch-induced reorientation of vascular endothelial cells. J Cell Sci 128: 1683-1695, 2015. doi:10.1242/jcs.157503.
3. Aboab J, Jonson B, Kouatchet A, Taille S, Niklason L, Brochard L. Effect of inspired oxygen fraction on alveolar derecruitment in acute respiratory distress syndrome. Intensive Care Med 32: 1979-1986, 2006. doi:10.1007/s00134-006-0382-4.
4. Acosta-Herrera M, Pino-Yanes M, Ma SF, Barreto-Luis A, Corrales A, Cumplido J, Pérez-Rodríguez E, Campo P, Eng C, García-Robaina JC, Quintela I, Villar J, Blanca M, Carracedo A, Carrillo T, Garcia JG, Burchard EG, Flores C. Fine mapping of the myosin light chain kinase (MYLK) gene replicates the association with asthma in populations of Spanish descent. J Allergy Clin Immunol 136: 1116-1118.e9, 2015. doi:10.1016/j.jaci.2015.04.025.
5. Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 342: 1301-1308, 2000. doi:10.1056/NEJM200005043421801.
6. Adyshev DM, Elangovan VR, Moldobaeva N, Mapes B, Sun X, Garcia JG. Mechanical stress induces pre-B-cell colony-enhancing factor/ NAMPT expression via epigenetic regulation by miR-374a and miR-568 in human lung endothelium. Am J Respir Cell Mol Biol 50: 409-418, 2014. doi:10.1165/rcmb.2013-0292OC.
7. Aggarwal S, Dimitropoulou C, Lu Q, Black SM, Sharma S. Glutathione supplementation attenuates lipopolysaccharide-induced mitochondrial dysfunction and apoptosis in a mouse model of acute lung injury. Front Physiol 3: 161, 2012. doi:10.3389/fphys.2012.00161.
8. Agrawal A, Mabalirajan U. Rejuvenating cellular respiration for optimizing respiratory function: targeting mitochondria. Am J Physiol Lung Cell Mol Physiol 310: L103-L113, 2016. doi:10.1152/ajplung.00320.2015.
9. Ali MH, Mungai PT, Schumacker PT. Stretch-induced phosphorylation of focal adhesion kinase in endothelial cells: role of mitochondrial oxidants. Am J Physiol Lung Cell Mol Physiol 291: L38-L45, 2006. doi:10.1152/ajplung.00287.2004.
10. Ali MH, Pearlstein DP, Mathieu CE, Schumacker PT. Mitochondrial requirement for endothelial responses to cyclic strain: implications for mechanotransduction. Am J Physiol Lung Cell Mol Physiol 287: L486-L496, 2004. doi:10.1152/ajplung.00389.2003.
11. American Thoracic Society. International consensus conferences in intensive care medicine: Ventilator-associated Lung Injury in ARDS. Am J Respir Crit Care Med 160: 2118-2124, 1999.
12. Ando-Akatsuka Y, Yonemura S, Itoh M, Furuse M, Tsukita S. Differential behavior of E-cadherin and occludin in their colocalization with ZO-1 during the establishment of epithelial cell polarity. J Cell Physiol 179: 115-125, 1999. doi:10.1002/(SICI)1097-4652(199905)179:2_115::AID-JCP1_3.0.CO;2-T.
13. Argaw AT, Gurfein BT, Zhang Y, Zameer A, John GR. VEGFmediated disruption of endothelial CLN-5 promotes blood-brain barrier breakdown. Proc Natl Acad Sci USA 106: 1977-1982, 2009. doi:10.1073/pnas.0808698106.
14. Armstrong HK, Koay YC, Irani S, Das R, Nassar ZD; Australian Prostate Cancer BioResource, Selth LA, Centenera MM, McAlpine SR, Butler LM. A novel class of Hsp90 C-terminal modulators have pre-clinical efficacy in prostate tumor cells without induction of a heat shock response. Prostate 76: 1546-1559, 2016. doi:10.1002/pros.23239.
15. Aslam M, Ahmad N, Srivastava R, Hemmer B. TNF-alpha induced NF_B signaling and p65 (RelA) overexpression repress Cldn5 promoter in mouse brain endothelial cells. Cytokine 57: 269-275, 2012. doi:10.1016/j.cyto.2011.10.016.
16. Awolesi MA, Sessa WC, Sumpio BE. Cyclic strain upregulates nitric oxide synthase in cultured bovine aortic endothelial cells. J Clin Invest 96: 1449-1454, 1995. doi:10.1172/JCI118181.
17. Bae S, Kim SY, Jung JH, Yoon Y, Cha HJ, Lee H, Kim K, Kim J, An IS, Kim J, Um HD, Park IC, Lee SJ, Nam SY, Jin YW, Lee JH, An S. Akt is negatively regulated by the MULAN E3 ligase. Cell Res 22: 873-885, 2012. doi:10.1038/cr.2012.38.
18. Bajwa EK, Yu CL, Gong MN, Thompson BT, Christiani DC. Pre-Bcell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome. Crit Care Med 35: 1290-1295, 2007. doi:10.1097/01.CCM.0000260243.22758.4F.
19. Balda MS, Anderson JM, Matter K. The SH3 domain of the tight junction protein ZO-1 binds to a serine protein kinase that phosphorylates a region C-terminal to this domain. FEBS Lett 399: 326-332, 1996. doi:10.1016/S0014-5793(96)01352-X.
20. Balda MS, Gonzalez-Mariscal L, Matter K, Cereijido M, Anderson JM. Assembly of the tight junction: the role of diacylglycerol. J Cell Biol 123: 293-302, 1993. doi:10.1083/jcb.123.2.293.
21. Banerji U, Judson I, Workman P. The clinical applications of heat shock protein inhibitors in cancer-present and future. Curr Cancer Drug Targets 3: 385-390, 2003. doi:10.2174/1568009033481813.
22. Banes AJ, Gilbert J, Taylor D, Monbureau O. A new vacuumoperated stress-providing instrument that applies static or variable duration cyclic tension or compression to cells in vitro. J Cell Sci 75: 35-42, 1985.
23. Barabutis N, Handa V, Dimitropoulou C, Rafikov R, Snead C, Kumar S, Joshi A, Thangjam G, Fulton D, Black SM, Patel V, Catravas JD. LPS induces pp60c-src-mediated tyrosine phosphorylation of Hsp90 in lung vascular endothelial cells and mouse lung. Am J Physiol Lung Cell Mol Physiol 304: L883-L893, 2013. doi:10.1152/ajplung.00419.2012.
24. Barron V, Brougham C, Coghlan K, McLucas E, O’Mahoney D, Stenson-Cox C, McHugh PE. The effect of physiological cyclic stretch on the cell morphology, cell orientation and protein expression of endothelial cells. J Mater Sci Mater Med 18: 1973-1981, 2007. doi:10.1007/s10856-007-3125-3.
25. Bazzoni G. The JAM family of junctional adhesion molecules. Curr Opin Cell Biol 15: 525-530, 2003. doi:10.1016/S0955-0674(03)00104-2.
26. Beasley MB. The pathologist’s approach to acute lung injury. Arch Pathol Lab Med 134: 719-727, 2010.
27. Belperio JA, Keane MP, Lynch JP III, Strieter RM. The role of cytokines during the pathogenesis of ventilator-associated and ventilatorinduced lung injury. Semin Respir Crit Care Med 27: 350-364, 2006. doi:10.1055/s-2006-948289.
28. Berardi DE, Tarbell JM. Stretch and shear interactions affect intercellular junction protein expression and turnover in endothelial cells. Cell Mol Bioeng 2: 320-331, 2009. doi:10.1007/s12195-009-0073-7.
29. Berlanga J, Lodos J, López-Saura P. Attenuation of internal organ damages by exogenously administered epidermal growth factor (EGF) in burned rodents. Burns 28: 435-442, 2002. doi:10.1016/S0305-4179(02)00023-2.
30. Bertok S, Wilson MR, Morley PJ, de Wildt R, Bayliffe A, Takata M. Selective inhibition of intra-alveolar p55 TNF receptor attenuates ventilator-induced lung injury. Thorax 67: 244-251, 2012. doi:10.1136/thoraxjnl-2011-200590.
31. Biehl M, Kashiouris MG, Gajic O. Ventilator-induced lung injury: minimizing its impact in patients with or at risk for ARDS. Respir Care 58: 927-937, 2013. doi:10.4187/respcare.02347.
32. Bierman A, Yerrapureddy A, Reddy NM, Hassoun PM, Reddy SP. Epidermal growth factor receptor (EGFR) regulates mechanical ventilation-induced lung injury in mice. Transl Res 152: 265-272, 2008. doi:10.1016/j.trsl.2008.10.004.
33. Bijli KM, Fazal F, Slavin SA, Leonard A, Grose V, Alexander WB, Smrcka AV, Rahman A. Phospholipase C-ε signaling mediates endothelial cell inflammation and barrier disruption in acute lung injury. Am J Physiol Lung Cell Mol Physiol 311: L517-L524, 2016. doi:10.1152/ajplung.00069.2016.
34. Birukov K. Ventilator-induced mechanical stress and lung vascular dysfunction. In: Textbook of Pulmonary Vascular Disease, edited by Yuan JX-J. New York: Springer, 2011, p. 913-934.
35. Birukov KG. Cyclic stretch, reactive oxygen species, and vascular remodeling. Antioxid Redox Signal 11: 1651-1667, 2009. doi:10.1089/ars.2008.2390.
36. Birukov KG. Small GTPases in mechanosensitive regulation of endothelial barrier. Microvasc Res 77: 46-52, 2009. doi:10.1016/j.mvr.2008.09.006.
37. Birukov KG, Jacobson JR, Flores AA, Ye SQ, Birukova AA, Verin AD, Garcia JG. Magnitude-dependent regulation of pulmonary endothelial cell barrier function by cyclic stretch. Am J Physiol Lung Cell Mol Physiol 285: L785-L797, 2003. doi:10.1152/ajplung.00336.2002.
38. Birukova AA, Chatchavalvanich S, Rios A, Kawkitinarong K, Garcia JG, Birukov KG. Differential regulation of pulmonary endothelial monolayer integrity by varying degrees of cyclic stretch. Am J Pathol 168: 1749-1761, 2006. doi:10.2353/ajpath.2006.050431.
39. Birukova AA, Moldobaeva N, Xing J, Birukov KG. Magnitudedependent effects of cyclic stretch on HGF-and VEGF-induced pulmonary endothelial remodeling and barrier regulation. Am J Physiol Lung Cell Mol Physiol 295: L612-L623, 2008. doi:10.1152/ajplung.90236.2008.
40. Blasig IE, Winkler L, Lassowski B, Mueller SL, Zuleger N, Krause E, Krause G, Gast K, Kolbe M, Piontek J. On the self-association potential of transmembrane tight junction proteins. Cell Mol Life Sci 63: 505-514, 2006. doi:10.1007/s00018-005-5472-x.
41. Boitano S, Safdar Z, Welsh DG, Bhattacharya J, Koval M. Cell-cell interactions in regulating lung function. Am J Physiol Lung Cell Mol Physiol 287: L455-L459, 2004. doi:10.1152/ajplung.00172.2004.
42. Braga VM. Cell-cell adhesion and signalling. Curr Opin Cell Biol 14: 546-556, 2002. doi:10.1016/S0955-0674(02)00373-3.
43. Briel M, Meade M, Mercat A, Brower RG, Talmor D, Walter SD, Slutsky AS, Pullenayegum E, Zhou Q, Cook D, Brochard L, Richard JC, Lamontagne F, Bhatnagar N, Stewart TE, Guyatt G. Higher vs lower positive end-expiratory pressure in patients with acute lung injury and acute respiratory distress syndrome: systematic review and metaanalysis. JAMA 303: 865-873, 2010. doi:10.1001/jama.2010.218.
44. Brower RG, Lanken PN, MacIntyre N, Matthay MA, Morris A, Ancukiewicz M, Schoenfeld D, Thompson BT; National Heart, Lung, and Blood Institute ARDS Clinical Trials Network. Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome. N Engl J Med 351: 327-336, 2004. doi:10.1056/NEJMoa032193.
45. Brown LM, Kallet RH, Matthay MA, Dicker RA. The influence of race on the development of acute lung injury in trauma patients. Am J Surg 201: 486-491, 2011. doi:10.1016/j.amjsurg.2010.02.003.
46. Brown M, Adyshev D, Bindokas V, Moitra J, Garcia JG, Dudek SM. Quantitative distribution and colocalization of non-muscle myosin light chain kinase isoforms and cortactin in human lung endothelium. Microvasc Res 80: 75-88, 2010. doi:10.1016/j.mvr.2009.12.010.
47. Brown MD, Sacks DB. IQGAP1 in cellular signaling: bridging the GAP. Trends Cell Biol 16: 242-249, 2006. doi:10.1016/j.tcb.2006.03.002.
48. Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376: 599-602, 1995. doi:10.1038/376599a0.
49. Campos R, Shimizu MH, Volpini RA, de Bragança AC, Andrade L, Lopes FD, Olivo C, Canale D, Seguro AC. N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 302: L640-L650, 2012. doi:10.1152/ajplung.00097.2011.
50. Chacon-Cabrera A, Rojas Y, Martínez-Caro L, Vila-Ubach M, Nin N, Ferruelo A, Esteban A, Lorente JA, Barreiro E. Influence of mechanical ventilation and sepsis on redox balance in diaphragm, myocardium, limb muscles, and lungs. Transl Res 164: 477-495, 2014. doi:10.1016/j.trsl.2014.07.003.
51. Chan CH, Jo U, Kohrman A, Rezaeian AH, Chou PC, Logothetis C, Lin HK. Posttranslational regulation of Akt in human cancer. Cell Biosci 4: 59, 2014. doi:10.1186/2045-3701-4-59.
52. Chang AL, Ulrich A, Suliman HB, Piantadosi CA. Redox regulation of mitophagy in the lung during murine Staphylococcus aureus sepsis. Free Radic Biol Med 78: 179-189, 2015. doi:10.1016/j.freeradbiomed.2014.10.582.
53. Chatterjee A, Snead C, Yetik-Anacak G, Antonova G, Zeng J, Catravas JD. Heat shock protein 90 inhibitors attenuate LPS-induced endothelial hyperpermeability. Am J Physiol Lung Cell Mol Physiol 294: L755-L763, 2008. doi:10.1152/ajplung.00350.2007.
54. Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol 49: 2379-2393, 2007. doi:10.1016/j.jacc.2007.02.059.
55. +-toxins. PLoS One 9: e99823, 2014. doi:10.1371/journal.pone.0099823.
56. Chen L, Zhao L, Zhang C, Lan Z. Protective effect of p-cymene on lipopolysaccharide-induced acute lung injury in mice. Inflammation 37: 358-364, 2014. doi:10.1007/s10753-013-9747-3.
57. Chen W, Epshtein Y, Ni X, Dull RO, Cress AE, Garcia JG, Jacobson JR. Role of integrin β4 in lung endothelial cell inflammatory responses to mechanical stress. Sci Rep 5: 16529, 2015. doi:10.1038/srep16529.
58. Chian CF, Chiang CH, Chuang CH, Liu SL, Tsai CL. SN50, a cell-permeable inhibitor of nuclear factor-κB, attenuates ventilator-induced lung injury in an isolated and perfused rat lung model. Shock 46: 194-201, 2016. doi:10.1097/SHK.0000000000000563.
59. Chiu YJ, Kusano K, Thomas TN, Fujiwara K. Endothelial cell-cell adhesion and mechanosignal transduction. Endothelium 11: 59-73, 2004. doi:10.1080/10623320490432489.
60. Christie JD, Ma SF, Aplenc R, Li M, Lanken PN, Shah CV, Fuchs B, Albelda SM, Flores C, Garcia JG. Variation in the myosin light chain kinase gene is associated with development of acute lung injury after major trauma. Crit Care Med 36: 2794-2800, 2008. doi:10.1097/CCM.0b013e318186b843.
61. Clarke H, Soler AP, Mullin JM. Protein kinase C activation leads to dephosphorylation of occludin and tight junction permeability increase in LLC-PK1 epithelial cell sheets. J Cell Sci 113: 3187-3196, 2000.
62. Collins NT, Cummins PM, Colgan OC, Ferguson G, Birney YA, Murphy RP, Meade G, Cahill PA. Cyclic strain-mediated regulation of vascular endothelial occludin and ZO-1: influence on intercellular tight junction assembly and function. Arterioscler Thromb Vasc Biol 26: 62-68, 2006. doi:10.1161/01.ATV.0000194097.92824.b3.
63. Copland IB, Martinez F, Kavanagh BP, Engelberts D, McKerlie C, Belik J, Post M. High tidal volume ventilation causes different inflammatory responses in newborn versus adult lung. Am J Respir Crit Care Med 169: 739-748, 2004. doi:10.1164/rccm.200310-1417OC.
64. Correa-Meyer E, Pesce L, Guerrero C, Sznajder JI. Cyclic stretch activates ERK1/2 via G proteins and EGFR in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 282: L883-L891, 2002. doi:10.1152/ajplung.00203.2001.
65. Cummins PM. Occludin: one protein, many forms. Mol Cell Biol 32: 242-250, 2012. doi:10.1128/MCB.06029-11.
66. Cummins PM, von Offenberg Sweeney N, Killeen MT, Birney YA, Redmond EM, Cahill PA. Cyclic strain-mediated matrix metalloproteinase regulation within the vascular endothelium: a force to be reckoned with. Am J Physiol Heart Circ Physiol 292: H28-H42, 2007. doi:10.1152/ajpheart.00304.2006.
67. D’Alessio FR, Craig JM, Singer BD, Files DC, Mock JR, Garibaldi BT, Fallica J, Tripathi A, Mandke P, Gans JH, Limjunyawong N, Sidhaye VK, Heller NM, Mitzner W, King LS, Aggarwal NR. Enhanced resolution of experimental ARDS through IL-4-mediated lung macrophage reprogramming. Am J Physiol Lung Cell Mol Physiol 310: L733-L746, 2016. doi:10.1152/ajplung.00419.2015.
68. D’Atri F, Nadalutti F, Citi S. Evidence for a functional interaction between cingulin and ZO-1 in cultured cells. J Biol Chem 277: 27757-27764, 2002. doi:10.1074/jbc.M203717200.
69. Davidovich N, DiPaolo BC, Lawrence GG, Chhour P, Yehya N, Margulies SS. Cyclic stretch-induced oxidative stress increases pulmonary alveolar epithelial permeability. Am J Respir Cell Mol Biol 49: 156-164, 2013. doi:10.1165/rcmb.2012-0252OC.
70. Davidson BA, Vethanayagam RR, Grimm MJ, Mullan BA, Raghavendran K, Blackwell TS, Freeman ML, Ayyasamy V, Singh KK, Sporn MB, Itagaki K, Hauser CJ, Knight PR, Segal BH. NADPH oxidase and Nrf2 regulate gastric aspiration-induced inflammation and acute lung injury. J Immunol 190: 1714-1724, 2013. doi:10.4049/jimmunol.1202410.
71. Davies PF. Flow-mediated endothelial mechanotransduction. Physiol Rev 75: 519-560, 1995.
72. Dejana E. Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 5: 261-270, 2004. doi:10.1038/nrm1357.
73. Del Sorbo L, Goffi A, Ranieri VM. Mechanical ventilation during acute lung injury: current recommendations and new concepts. Presse Med 40: e569-e583, 2011. doi:10.1016/j.lpm.2011.05.028.
74. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med 36: 296-327, 2008. doi:10.1097/01.CCM.0000298158.12101.41.
75. Determann RM, Royakkers A, Wolthuis EK, Vlaar AP, Choi G, Paulus F, Hofstra JJ, de Graaff MJ, Korevaar JC, Schultz MJ. Ventilation with lower tidal volumes as compared with conventional tidal volumes for patients without acute lung injury: a preventive randomized controlled trial. Crit Care 14: R1, 2010. doi:10.1186/cc8230.
76. Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies. Am J Respir Crit Care Med 157: 294-323, 1998. doi:10.1164/ajrccm.157.1.9604014.
77. Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am Rev Respir Dis 137: 1159-1164, 1988. doi:10.1164/ajrccm/137.5.1159.
78. Du Q, Wang C, Zhang N, Li G, Zhang M, Li L, Zhang Q, Zhang J. In vivo study of the effects of exogenous hydrogen sulfide on lung mitochondria in acute lung injury in rats. BMC Anesthesiol 14: 117, 2014. doi:10.1186/1471-2253-14-117.
79. Dubeykovskaya Z, Dubeykovskiy A, Solal-Cohen J, Wang TC. Secreted trefoil factor 2 activates the CXCR4 receptor in epithelial and lymphocytic cancer cell lines. J Biol Chem 284: 3650-3662, 2009. doi:10.1074/jbc.M804935200.
80. Dudek SM, Birukov KG, Zhan X, Garcia JG. Novel interaction of cortactin with endothelial cell myosin light chain kinase. Biochem Biophys Res Commun 298: 511-519, 2002. doi:10.1016/S0006-291X(02)02492-0.
81. Dudek SM, Chiang ET, Camp SM, Guo Y, Zhao J, Brown ME, Singleton PA, Wang L, Desai A, Arce FT, Lal R, Van Eyk JE, Imam SZ, Garcia JG. Abl tyrosine kinase phosphorylates nonmuscle Myosin light chain kinase to regulate endothelial barrier function. Mol Biol Cell 21: 4042-4056, 2010. doi:10.1091/mbc.E09-10-0876.
82. Dudek SM, Garcia JG. Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol (1985) 91: 1487-1500, 2001.
83. Dudek SM, Jacobson JR, Chiang ET, Birukov KG, Wang P, Zhan X, Garcia JG. Pulmonary endothelial cell barrier enhancement by sphingosine 1-phosphate: roles for cortactin and myosin light chain kinase. J Biol Chem 279: 24692-24700, 2004. doi:10.1074/jbc.M313969200.
84. Duggan M, McNamara PJ, Engelberts D, Pace-Asciak C, Babyn P, Post M, Kavanagh BP. Oxygen attenuates atelectasis-induced injury in the in vivo rat lung. Anesthesiology 103: 522-531, 2005. doi:10.1097/00000542-200509000-00015.
85. Ebnet K, Schulz CU, Meyer Zu Brickwedde MK, Pendl GG, Vestweber D. Junctional adhesion molecule interacts with the PDZ domaincontaining proteins AF-6 and ZO-1. J Biol Chem 275: 27979-27988, 2000.
86. Exley AR, Cohen J, Buurman W, Owen R, Lumley J, Hanson G, Aulakh JM, Bodmer M, Stephens S, Riddell A, Perry M. Monoclonal antibody to TNF in severe septic shock. Lancet 335: 1275-1277, 1990. doi:10.1016/0140-6736(90)91337-A.
87. Fanning AS, Jameson BJ, Jesaitis LA, Anderson JM. The tight junction protein ZO-1 establishes a link between the transmembrane protein occludin and the actin cytoskeleton. J Biol Chem 273: 29745-29753, 1998. doi:10.1074/jbc.273.45.29745.
88. Farquhar MG, Palade GE. Junctional complexes in various epithelia. J Cell Biol 17: 375-412, 1963. doi:10.1083/jcb.17.2.375.
89. Finigan JH, Boueiz A, Wilkinson E, Damico R, Skirball J, Pae HH, Damarla M, Hasan E, Pearse DB, Reddy SP, Grigoryev DN, Cheadle C, Esmon CT, Garcia JG, Hassoun PM. Activated protein C protects against ventilator-induced pulmonary capillary leak. Am J Physiol Lung Cell Mol Physiol 296: L1002-L1011, 2009. doi:10.1152/ajplung.90555.2008.
90. Fletcher ME, Boshier PR, Wakabayashi K, Keun HC, Smolenski RT, Kirkham PA, Adcock IM, Barton PJ, Takata M, Marczin N. Influence of glutathione-S-transferase (GST) inhibition on lung epithelial cell injury: role of oxidative stress and metabolism. Am J Physiol Lung Cell Mol Physiol 308: L1274-L1285, 2015. doi:10.1152/ajplung.00220.2014.
91. Flores C, Ma SF, Maresso K, Ober C, Garcia JG. A variant of the myosin light chain kinase gene is associated with severe asthma in African Americans. Genet Epidemiol 31: 296-305, 2007. doi:10.1002/gepi.20210.
92. Fontijn RD, Volger OL, Fledderus JO, Reijerkerk A, de Vries HE, Horrevoets AJ. SOX-18 controls endothelial-specific claudin-5 gene expression and barrier function. Am J Physiol Heart Circ Physiol 294: H891-H900, 2008. doi:10.1152/ajpheart.01248.2007.
93. Frank JA, Pittet JF, Wray C, Matthay MA. Protection from experimental ventilator-induced acute lung injury by IL-1 receptor blockade. Thorax 63: 147-153, 2008. doi:10.1136/thx.2007.079608.
94. Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR, Tsichlis PN. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81: 727-736, 1995. doi:10.1016/0092-8674(95)90534-0.
95. Frye SR, Yee A, Eskin SG, Guerra R, Cong X, McIntire LV. cDNA microarray analysis of endothelial cells subjected to cyclic mechanical strain: importance of motion control. Physiol Genomics 21: 124-130, 2005. doi:10.1152/physiolgenomics.00029.2003.
96. Fu P, Usatyuk PV, Jacobson J, Cress AE, Garcia JG, Salgia R, Natarajan V. Role played by paxillin and paxillin tyrosine phosphorylation in hepatocyte growth factor/sphingosine-1-phosphate-mediated reactive oxygen species generation, lamellipodia formation, and endothelial barrier function. Pulm Circ 5: 619-630, 2015. doi:10.1086/683693.
97. Fu P, Usatyuk PV, Lele A, Harijith A, Gregorio CC, Garcia JG, Salgia R, Natarajan V. c-Abl mediated tyrosine phosphorylation of paxillin regulates LPS-induced endothelial dysfunction and lung injury. Am J Physiol Lung Cell Mol Physiol 308: L1025-L1038, 2015. doi:10.1152/ajplung.00306.2014.
98. Fu Z, Costello ML, Tsukimoto K, Prediletto R, Elliott AR, Mathieu-Costello O, West JB. High lung volume increases stress failure in pulmonary capillaries. J Appl Physiol (1985) 73: 123-133, 1992.
99. Furuse M, Furuse K, Sasaki H, Tsukita S. Conversion of zonulae occludentes from tight to leaky strand type by introducing claudin-2 into Madin-Darby canine kidney I cells. J Cell Biol 153: 263-272, 2001. doi:10.1083/jcb.153.2.263.
100. Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol 123: 1777-1788, 1993. doi:10.1083/jcb.123.6.1777.
101. Furuse M, Itoh M, Hirase T, Nagafuchi A, Yonemura S, Tsukita S, Tsukita S. Direct association of occludin with ZO-1 and its possible involvement in the localization of occludin at tight junctions. J Cell Biol 127: 1617-1626, 1994. doi:10.1083/jcb.127.6.1617.
102. Furuse M, Sasaki H, Fujimoto K, Tsukita S. A single gene product, claudin-1 or-2, reconstitutes tight junction strands and recruits occludin in fibroblasts. J Cell Biol 143: 391-401, 1998. doi:10.1083/jcb.143.2.391.
103. Furuse M, Sasaki H, Tsukita S. Manner of interaction of heterogeneous claudin species within and between tight junction strands. J Cell Biol 147: 891-903, 1999. doi:10.1083/jcb.147.4.891.
104. Gajic O, Dara SI, Mendez JL, Adesanya AO, Festic E, Caples SM, Rana R, St Sauver JL, Lymp JF, Afessa B, Hubmayr RD. Ventilatorassociated lung injury in patients without acute lung injury at the onset of mechanical ventilation. Crit Care Med 32: 1817-1824, 2004. doi:10.1097/01.CCM.0000133019.52531.30.
105. Gajic O, Frutos-Vivar F, Esteban A, Hubmayr RD, Anzueto A. Ventilator settings as a risk factor for acute respiratory distress syndrome in mechanically ventilated patients. Intensive Care Med 31: 922-926, 2005. doi:10.1007/s00134-005-2625-1.
106. Gao J, Huang T, Zhou LJ, Ge YL, Lin SY, Dai Y. Preconditioning effects of physiological cyclic stretch on pathologically mechanical stretch-induced alveolar epithelial cell apoptosis and barrier dysfunction. Biochem Biophys Res Commun 448: 342-348, 2014. doi:10.1016/j.bbrc.2014.03.063.
107. Gao L, Grant A, Halder I, Brower R, Sevransky J, Maloney JP, Moss M, Shanholtz C, Yates CR, Meduri GU, Shriver MD, Ingersoll R, Scott AF, Beaty TH, Moitra J, Ma SF, Ye SQ, Barnes KC, Garcia JG. Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury. Am J Respir Cell Mol Biol 34: 487-495, 2006. doi:10.1165/rcmb.2005-0404OC.
108. Gao L, Grant AV, Rafaels N, Stockton-Porter M, Watkins T, Gao P, Chi P, Muñoz M, Watson H, Dunston G, Togias A, Hansel N, Sevransky J, Maloney JP, Moss M, Shanholtz C, Brower R, Garcia JG, Grigoryev DN, Cheadle C, Beaty TH, Mathias RA, Barnes KC. Polymorphisms in the myosin light chain kinase gene that confer risk of severe sepsis are associated with a lower risk of asthma. J Allergy Clin Immunol 119: 1111-1118, 2007. doi:10.1016/j.jaci.2007.03.019.
109. Gao R, Ma Z, Ma M, Yu J, Chen J, Li Z, Shetty S, Fu J. Deletion of Src family kinase Lyn aggravates endotoxin-induced lung inflammation. Am J Physiol Lung Cell Mol Physiol 309: L1376-L1381, 2015. doi:10.1152/ajplung.00219.2015.
110. Garcia CS, Prota LF, Morales MM, Romero PV, Zin WA, Rocco PR. Understanding the mechanisms of lung mechanical stress. Braz J Med Biol Res 39: 697-706, 2006. doi:10.1590/S0100-879X2006000600001.
111. Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA, Gerthoffer WT, Bamberg JR, English D. Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J Clin Invest 108: 689-701, 2001. doi:10.1172/JCI12450.
112. Garcia JG, Sznajder JI. Healthcare disparities in patients with acute respiratory distress syndrome. Toward equity. Am J Respir Crit Care Med 188: 631-632, 2013. doi:10.1164/rccm.201307-1394ED.
113. Gattinoni L, Bombino M, Pelosi P, Lissoni A, Pesenti A, Fumagalli R, Tagliabue M. Lung structure and function in different stages of severe adult respiratory distress syndrome. JAMA 271: 1772-1779, 1994. doi:10.1001/jama.1994.03510460064035.
114. Gavard J, Gutkind JS. VE-cadherin and claudin-5: it takes two to tango. Nat Cell Biol 10: 883-885, 2008. doi:10.1038/ncb0808-883.
115. Glavan BJ, Holden TD, Goss CH, Black RA, Neff MJ, Nathens AB, Martin TR, Wurfel MM; ARDSnet Investigators. Genetic variation in the FAS gene and associations with acute lung injury. Am J Respir Crit Care Med 183: 356-363, 2011. doi:10.1164/rccm.201003-0351OC.
116. Goldenberg NM, Ravindran K, Kuebler WM. TRPV4: physiological role and therapeutic potential in respiratory diseases. Naunyn Schmiedebergs Arch Pharmacol 388: 421-436, 2015. doi:10.1007/s00210-014-1058-1.
117. Gotsch U, Borges E, Bosse R, Böggemeyer E, Simon M, Mossmann H, Vestweber D. VE-cadherin antibody accelerates neutrophil recruitment in vivo. J Cell Sci 110: 583-588, 1997.
118. Gray KD, MacMillan-Crow LA, Simovic MO, Stain SC, May AK. Pulmonary MnSOD is nitrated following hepatic ischemia-reperfusion. Surg Infect (Larchmt) 5: 166-173, 2004. doi:10.1089/sur.2004.5.166.
119. Grigoryev DN, Ma SF, Irizarry RA, Ye SQ, Quackenbush J, Garcia JG. Orthologous gene-expression profiling in multi-species models: search for candidate genes. Genome Biol 5: R34, 2004. doi:10.1186/gb-2004-5-5-r34.
120. Grobe AC, Wells SM, Benavidez E, Oishi P, Azakie A, Fineman JR, Black SM. Increased oxidative stress in lambs with increased pulmonary blood flow and pulmonary hypertension: role of NADPH oxidase and endothelial NO synthase. Am J Physiol Lung Cell Mol Physiol 290: L1069-L1077, 2006. doi:10.1152/ajplung.00408.2005.
121. Gross CM, Aggarwal S, Kumar S, Tian J, Kasa A, Bogatcheva N, Datar SA, Verin AD, Fineman JR, Black SM. Sox18 preserves the pulmonary endothelial barrier under conditions of increased shear stress. J Cell Physiol 229: 1802-1816, 2014. doi:10.1002/jcp.24633.
122. Gross CM, Rafikov R, Kumar S, Aggarwal S, Ham PB III, Meadows ML, Cherian-Shaw M, Kangath A, Sridhar S, Lucas R, Black SM. Endothelial nitric oxide synthase deficient mice are protected from lipopolysaccharide induced acute lung injury. PLoS One 10: e0119918, 2015. doi:10.1371/journal.pone.0119918.
123. Grote K, Flach I, Luchtefeld M, Akin E, Holland SM, Drexler H, Schieffer B. Mechanical stretch enhances mRNA expression and proenzyme release of matrix metalloproteinase-2 (MMP-2) via NAD(P)H oxidase-derived reactive oxygen species. Circ Res 92: e80-e86, 2003. doi:10.1161/01.RES.0000077044.60138.7C.
124. Gu C, Liu M, Zhao T, Wang D, Wang Y. Protective role of p120-catenin in maintaining the integrity of adherens and tight junctions in ventilator-induced lung injury. Respir Res 16: 58, 2015. doi:10.1186/s12931-015-0217-3.
125. Gunaydin H, Houk KN. Mechanisms of peroxynitrite-mediated nitration of tyrosine. Chem Res Toxicol 22: 894-898, 2009. doi:10.1021/tx800463y.
126. Gundersen GG. Microtubule capture: IQGAP and CLIP-170 expand the repertoire. Curr Biol 12: R645-R647, 2002. doi:10.1016/S0960-9822(02)01156-9.
127. Hamanaka K, Jian MY, Townsley MI, King JA, Liedtke W, Weber DS, Eyal FG, Clapp MM, Parker JC. TRPV4 channels augment macrophage activation and ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 299: L353-L362, 2010. doi:10.1152/ajplung.00315.2009.
128. Hamanaka K, Jian MY, Weber DS, Alvarez DF, Townsley MI, Al-Mehdi AB, King JA, Liedtke W, Parker JC. TRPV4 initiates the acute calcium-dependent permeability increase during ventilator-induced lung injury in isolated mouse lungs. Am J Physiol Lung Cell Mol Physiol 293: L923-L932, 2007. doi:10.1152/ajplung.00221.2007.
129. Haorah J, Heilman D, Knipe B, Chrastil J, Leibhart J, Ghorpade A, Miller DW, Persidsky Y. Ethanol-induced activation of myosin light chain kinase leads to dysfunction of tight junctions and blood-brain barrier compromise. Alcohol Clin Exp Res 29: 999-1009, 2005. doi:10.1097/01.ALC.0000166944.79914.0A.
130. Harris TJ, Tepass U. Adherens junctions: from molecules to morphogenesis. Nat Rev Mol Cell Biol 11: 502-514, 2010. doi:10.1038/nrm2927.
131. Hassoun PM, Mouthon L, Barberà JA, Eddahibi S, Flores SC, Grimminger F, Jones PL, Maitland ML, Michelakis ED, Morrell NW, Newman JH, Rabinovitch M, Schermuly R, Stenmark KR, Voelkel NF, Yuan JX, Humbert M. Inflammation, growth factors, and pulmonary vascular remodeling. J Am Coll Cardiol 54, Suppl: S10-S19, 2009. doi:10.1016/j.jacc.2009.04.006.
132. Hassoun PM, Yu FS, Cote CG, Zulueta JJ, Sawhney R, Skinner KA, Skinner HB, Parks DA, Lanzillo JJ. Upregulation of xanthine oxidase by lipopolysaccharide, interleukin-1, and hypoxia. Role in acute lung injury. Am J Respir Crit Care Med 158: 299-305, 1998. doi:10.1164/ajrccm.158.1.9709116.
133. Hegeman MA, Hemmes SN, Kuipers MT, Bos LD, Jongsma G, Roelofs JJ, van der Sluijs KF, Juffermans NP, Vroom MB, Schultz MJ. The extent of ventilator-induced lung injury in mice partly depends on duration of mechanical ventilation. Crit Care Res Pract 2013: 435236, 2013. doi:10.1155/2013/435236.
134. 2+/calmodulin and Cdc42 signaling. J Biol Chem 274: 464-470, 1999. doi:10.1074/jbc.274.1.464.
135. Hoegl S, Bachmann M, Scheiermann P, Goren I, Hofstetter C, Pfeilschifter J, Zwissler B, Muhl H. Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury. Am J Respir Cell Mol Biol 44: 369-376, 2011. doi:10.1165/rcmb.2009-0440OC.
136. Hoegl S, Boost KA, Czerwonka H, Dolfen A, Scheiermann P, Muhl H, Zwissler B, Hofstetter C. Inhaled IL-10 reduces biotrauma and mortality in a model of ventilator-induced lung injury. Respir Med 103: 463-470, 2009. doi:10.1016/j.rmed.2008.09.020.
137. Honda M, Nakagawa S, Hayashi K, Kitagawa N, Tsutsumi K, Nagata I, Niwa M. Adrenomedullin improves the blood-brain barrier function through the expression of claudin-5. Cell Mol Neurobiol 26: 109-118, 2006. doi:10.1007/s10571-006-9028-x.
138. Hong DS, Banerji U, Tavana B, George GC, Aaron J, Kurzrock R. Targeting the molecular chaperone heat shock protein 90 (HSP90): lessons learned and future directions. Cancer Treat Rev 39: 375-387, 2013. doi:10.1016/j.ctrv.2012.10.001.
139. Hong SB, Huang Y, Moreno-Vinasco L, Sammani S, Moitra J, Barnard JW, Ma SF, Mirzapoiazova T, Evenoski C, Reeves RR, Chiang ET, Lang GD, Husain AN, Dudek SM, Jacobson JR, Ye SQ, Lussier YA, Garcia JG. Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury. Am J Respir Crit Care Med 178: 605-617, 2008. doi:10.1164/rccm.200712-1822OC.
140. Hou Y, Liu M, Husted C, Chen C, Thiagarajan K, Johns JL, Rao SP, Alvira CM. Activation of the nuclear factor-κB pathway during postnatal lung inflammation preserves alveolarization by suppressing macrophage inflammatory protein-2. Am J Physiol Lung Cell Mol Physiol 309: L593-L604, 2015. doi:10.1152/ajplung.00029.2015.
141. How Kit A, Nielsen HM, Tost J. DNA methylation based biomarkers: practical considerations and applications. Biochimie 94: 2314-2337, 2012. doi:10.1016/j.biochi.2012.07.014.
142. Howard MD, Greineder CF, Hood ED, Muzykantov VR. Endothelial targeting of liposomes encapsulating SOD/catalase mimetic EUK-134 alleviates acute pulmonary inflammation. J Control Release 177: 34-41, 2014. doi:10.1016/j.jconrel.2013.12.035.
143. Hu Z, Gu Z, Sun M, Zhang K, Gao P, Yang Q, Yuan Y. Ursolic acid improves survival and attenuates lung injury in septic rats induced by cecal ligation and puncture. J Surg Res 194: 528-536, 2015. doi:10.1016/j.jss.2014.10.027.
144. Husari A, Khayat A, Bitar H, Hashem Y, Rizkallah A, Zaatari G, El Sabban M. Antioxidant activity of pomegranate juice reduces acute lung injury secondary to hyperoxia in an animal model. BMC Res Notes 7: 664, 2014. doi:10.1186/1756-0500-7-664.
145. Iba T, Shin T, Sonoda T, Rosales O, Sumpio BE. Stimulation of endothelial secretion of tissue-type plasminogen activator by repetitive stretch. J Surg Res 50: 457-460, 1991. doi:10.1016/0022-4804(91)90024-G.
146. Ichimura H, Parthasarathi K, Quadri S, Issekutz AC, Bhattacharya J. Mechano-oxidative coupling by mitochondria induces proinflammatory responses in lung venular capillaries. J Clin Invest 111: 691-699, 2003. doi:10.1172/JCI17271.
147. Inai T, Kobayashi J, Shibata Y. Claudin-1 contributes to the epithelial barrier function in MDCK cells. Eur J Cell Biol 78: 849-855, 1999. doi:10.1016/S0171-9335(99)80086-7.
148. Infusino GA, Sammani S, Siegler J, Letsiou E, Wang T, Huey B, Dudek SM, Garcia JG. Trefoil factor 2 regulates lung endothelial and epithelial response to injury. Am J Respir Crit Care Med 187: A251, 2013.
149. Ishizaki T, Chiba H, Kojima T, Fujibe M, Soma T, Miyajima H, Nagasawa K, Wada I, Sawada N. Cyclic AMP induces phosphorylation of claudin-5 immunoprecipitates and expression of claudin-5 gene in blood-brain-barrier endothelial cells via protein kinase A-dependent and-independent pathways. Exp Cell Res 290: 275-288, 2003. doi:10.1016/S0014-4827(03)00354-9.
150. Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J Cell Biol 147: 1351-1363, 1999. doi:10.1083/jcb.147.6.1351.
151. Itoh M, Morita K, Tsukita S. Characterization of ZO-2 as a MAGUK family member associated with tight as well as adherens junctions with a binding affinity to occludin and alpha catenin. J Biol Chem 274: 5981-5986, 1999. doi:10.1074/jbc.274.9.5981.
152. Jacquemet G, Green DM, Bridgewater RE, von Kriegsheim A, Humphries MJ, Norman JC, Caswell PT. RCP-driven α5β1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1-IQGAP1 complex. J Cell Biol 202: 917-935, 2013. doi:10.1083/jcb.201302041.
153. Jacquemet G, Humphries MJ. IQGAP1 is a key node within the small GTPase network. Small GTPases 4: 199-207, 2013. doi:10.4161/sgtp.27451.
154. Jacquemet G, Morgan MR, Byron A, Humphries JD, Choi CK, Chen CS, Caswell PT, Humphries MJ. Rac1 is deactivated at integrin activation sites through an IQGAP1-filamin-A-RacGAP1 pathway. J Cell Sci 126: 4121-4135, 2013. doi:10.1242/jcs.121988.
155. Jaecklin T, Otulakowski G, Kavanagh BP. Do soluble mediators cause ventilator-induced lung injury and multi-organ failure? Intensive Care Med 36: 750-757, 2010. doi:10.1007/s00134-010-1850-4.
156. Jesaitis LA, Goodenough DA. Molecular characterization and tissue distribution of ZO-2, a tight junction protein homologous to ZO-1 and the Drosophila discs-large tumor suppressor protein. J Cell Biol 124: 949-961, 1994. doi:10.1083/jcb.124.6.949.
157. Jian MY, King JA, Al-Mehdi AB, Liedtke W, Townsley MI. High vascular pressure-induced lung injury requires P450 epoxygenase-dependent activation of TRPV4. Am J Respir Cell Mol Biol 38: 386-392, 2008. doi:10.1165/rcmb.2007-0192OC.
158. Jiang WG, Martin TA, Matsumoto K, Nakamura T, Mansel RE. Hepatocyte growth factor/scatter factor decreases the expression of occludin and transendothelial resistance (TER) and increases paracellular permeability in human vascular endothelial cells. J Cell Physiol 181: 319-329, 1999. doi:10.1002/(SICI)1097-4652(199911)181:2_319::AID-JCP14_3.0.CO;2-S.
159. Joshi AD, Barabutis N, Birmpas C, Dimitropoulou C, Thangjam G, Cherian-Shaw M, Dennison J, Catravas JD. Histone deacetylase inhibitors prevent pulmonary endothelial hyperpermeability and acute lung injury by regulating heat shock protein 90 function. Am J Physiol Lung Cell Mol Physiol 309: L1410-L1419, 2015. doi:10.1152/ajplung.00180.2015.
160. Ju YN, Yu KJ, Wang GN. Budesonide ameliorates lung injury induced by large volume ventilation. BMC Pulm Med 16: 90, 2016. doi:10.1186/s12890-016-0251-z.
161. Kaestle SM, Reich CA, Yin N, Habazettl H, Weimann J, Kuebler WM. Nitric oxide-dependent inhibition of alveolar fluid clearance in hydrostatic lung edema. Am J Physiol Lung Cell Mol Physiol 293: L859-L869, 2007. doi:10.1152/ajplung.00008.2007.
162. Kage H, Flodby P, Gao D, Kim YH, Marconett CN, DeMaio L, Kim KJ, Crandall ED, Borok Z. Claudin 4 knockout mice: normal physiological phenotype with increased susceptibility to lung injury. Am J Physiol Lung Cell Mol Physiol 307: L524-L536, 2014. doi:10.1152/ajplung.00077.2014.
163. Kandasamy K, Escue R, Manna J, Adebiyi A, Parthasarathi K. Changes in endothelial connexin 43 expression inversely correlate with microvessel permeability and VE-cadherin expression in endotoxinchallenged lungs. Am J Physiol Lung Cell Mol Physiol 309: L584-L592, 2015. doi:10.1152/ajplung.00211.2014.
164. Kangelaris KN, Prakash A, Liu KD, Aouizerat B, Woodruff PG, Erle DJ, Rogers A, Seeley EJ, Chu J, Liu T, Osterberg-Deiss T, Zhuo H, Matthay MA, Calfee CS. Increased expression of neutrophil-related genes in patients with early sepsis-induced ARDS. Am J Physiol Lung Cell Mol Physiol 308: L1102-L1113, 2015. doi:10.1152/ajplung.00380.2014.
165. Kangelaris KN, Sapru A, Calfee CS, Liu KD, Pawlikowska L, Witte JS, Vittinghoff E, Zhuo H, Auerbach AD, Ziv E, Matthay MA; National Heart, Lung, and Blood Institute ARDS Network. The association between a Darc gene polymorphism and clinical outcomes in African American patients with acute lung injury. Chest 141: 1160-1169, 2012. doi:10.1378/chest.11-1766.
166. Katsuno T, Umeda K, Matsui T, Hata M, Tamura A, Itoh M, Takeuchi K, Fujimori T, Nabeshima Y, Noda T, Tsukita S, Tsukita S. Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. Mol Biol Cell 19: 2465-2475, 2008. doi:10.1091/mbc.E07-12-1215.
167. Kausalya PJ, Phua DC, Hunziker W. Association of ARVCF with zonula occludens (ZO)-1 and ZO-2: binding to PDZ-domain proteins and cell-cell adhesion regulate plasma membrane and nuclear localization of ARVCF. Mol Biol Cell 15: 5503-5515, 2004. doi:10.1091/mbc.E04-04-0350.
168. Kluger MS, Clark PR, Tellides G, Gerke V, Pober JS. Claudin-5 controls intercellular barriers of human dermal microvascular but not human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 33: 489-500, 2013. doi:10.1161/ATVBAHA.112.300893.
169. Koay YC, McConnell JR, Wang Y, Kim SJ, Buckton LK, Mansour F, McAlpine SR. Chemically accessible hsp90 inhibitor that does not induce a heat shock response. ACS Med Chem Lett 5: 771-776, 2014. doi:10.1021/ml500114p.
170. Komarova Y, Malik AB. Regulation of endothelial permeability via paracellular and transcellular transport pathways. Annu Rev Physiol 72: 463-493, 2010. doi:10.1146/annurev-physiol-021909-135833.
171. Kovacs EM, Yap AS. Cell-cell contact: cooperating clusters of actin and cadherin. Curr Biol 18: R667-R669, 2008. doi:10.1016/j.cub.2008.06.024.
172. Kuethe DO, Filipczak PT, Hix JM, Gigliotti AP, Estépar RS, Washko GR, Baron RM, Fredenburgh LE. Magnetic resonance imaging provides sensitive in vivo assessment of experimental ventilatorinduced lung injury. Am J Physiol Lung Cell Mol Physiol 311: L208-L218, 2016. doi:10.1152/ajplung.00459.2015.
173. Kuroda S, Fukata M, Nakagawa M, Fujii K, Nakamura T, Ookubo T, Izawa I, Nagase T, Nomura N, Tani H, Shoji I, Matsuura Y, Yonehara S, Kaibuchi K. Role of IQGAP1, a target of the small GTPases Cdc42 and Rac1, in regulation of E-cadherin-mediated cell-cell adhesion. Science 281: 832-835, 1998. doi:10.1126/science.281.5378.832.
174. Lazar V, Garcia JG. A single human myosin light chain kinase gene (MLCK; MYLK) transcribes multiple nonmuscle isoforms. Genomics 57: 256-267, 1999. doi:10.1006/geno.1999.5774.
175. Le NP, Channabasappa S, Hossain M, Liu L, Singh B. Leukocytespecific protein 1 regulates neutrophil recruitment in acute lung inflammation. Am J Physiol Lung Cell Mol Physiol 309: L995-L1008, 2015. doi:10.1152/ajplung.00068.2014.
176. Lee H, Cha S, Lee MS, Cho GJ, Choi WS, Suk K. Role of antiproliferative B cell translocation gene-1 as an apoptotic sensitizer in activation-induced cell death of brain microglia. J Immunol 171: 5802-5811, 2003. doi:10.4049/jimmunol.171.11.5802.
177. Lee I, Dodia C, Chatterjee S, Zagorski J, Mesaros C, Blair IA, Feinstein SI, Jain M, Fisher AB. A novel nontoxic inhibitor of the activation of NADPH oxidase reduces reactive oxygen species production in mouse lung. J Pharmacol Exp Ther 345: 284-296, 2013. doi:10.1124/jpet.112.201079.
178. Letsiou E, Rizzo AN, Sammani S, Naureckas P, Jacobson JR, Garcia JG, Dudek SM. Differential and opposing effects of imatinib on LPSand ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 308: L259-L269, 2015. doi:10.1152/ajplung.00323.2014.
179. Letsiou E, Sammani S, Zhang W, Zhou T, Quijada H, Moreno-Vinasco L, Dudek SM, Garcia JG. Pathologic mechanical stress and endotoxin exposure increases lung endothelial microparticle shedding. Am J Respir Cell Mol Biol 52: 193-204, 2015. doi:10.1165/rcmb.2013-0347OC.
180. Li X, Stankovic M, Lee BP, Aurrand-Lions M, Hahn CN, Lu Y, Imhof BA, Vadas MA, Gamble JR. JAM-C induces endothelial cell permeability through its association and regulation of beta3 integrins. Arterioscler Thromb Vasc Biol 29: 1200-1206, 2009. doi:10.1161/ATVBAHA.109.189217.
181. Li Y, Fanning AS, Anderson JM, Lavie A. Structure of the conserved cytoplasmic C-terminal domain of occludin: identification of the ZO-1 binding surface. J Mol Biol 352: 151-164, 2005. doi:10.1016/j.jmb.2005.07.017.
182. Lindsay CD. Novel therapeutic strategies for acute lung injury induced by lung damaging agents: the potential role of growth factors as treatment options. Hum Exp Toxicol 30: 701-724, 2011. doi:10.1177/0960327110376982.
183. Lingaraju MC, Pathak NN, Begum J, Balaganur V, Bhat RA, Ram M, Kumar D, Kumar D, Tandan SK. Betulinic acid negates oxidative lung injury in surgical sepsis model. J Surg Res 193: 856-867, 2015. doi:10.1016/j.jss.2014.09.008.
184. Liu Y, Wada R, Yamashita T, Mi Y, Deng CX, Hobson JP, Rosenfeldt HM, Nava VE, Chae SS, Lee MJ, Liu CH, Hla T, Spiegel S, Proia RL. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 106: 951-961, 2000. doi:10.1172/JCI10905.
185. Lutmer J, Watkins D, Chen CL, Velten M, Besner G. Heparinbinding epidermal growth factor-like growth factor attenuates acute lung injury and multiorgan dysfunction after scald burn. J Surg Res 185: 329-337, 2013. doi:10.1016/j.jss.2013.05.064.
186. Ma J, Wang P, Liu Y, Zhao L, Li Z, Xue Y. Krüppel-like factor 4 regulates blood-tumor barrier permeability via ZO-1, occludin and claudin-5. J Cell Physiol 229: 916-926, 2014. doi:10.1002/jcp.24523.
187. Ma SF, Grigoryev DN, Taylor AD, Nonas S, Sammani S, Ye SQ, Garcia JG. Bioinformatic identification of novel early stress response genes in rodent models of lung injury. Am J Physiol Lung Cell Mol Physiol 289: L468-L477, 2005. doi:10.1152/ajplung.00109.2005.
188. Ma W, Sun Y, Han D, Chu W, Lin D, Chen D. Cytoskeletal response of microvessel endothelial cells to an applied stress force at the submicrometer scale studied by atomic force microscopy. Microsc Res Tech 69: 784-793, 2006. doi:10.1002/jemt.20346.
189. Macarthur H, Warner TD, Wood EG, Corder R, Vane JR. Endothelin-1 release from endothelial cells in culture is elevated both acutely and chronically by short periods of mechanical stretch. Biochem Biophys Res Commun 200: 395-400, 1994. doi:10.1006/bbrc.1994.1462.
190. Machado JC, Nogueira AM, Carneiro F, Reis CA, Sobrinho-Simões M. Gastric carcinoma exhibits distinct types of cell differentiation: an immunohistochemical study of trefoil peptides (TFF1 and TFF2) and mucins (MUC1, MUC2, MUC5AC, and MUC6). J Pathol 190: 437-443, 2000. doi:10.1002/(SICI)1096-9896(200003)190:4_437::AID-PATH547_3.0.CO;2-1.
191. Mahajan K, Mahajan NP. PI3K-independent AKT activation in cancers: a treasure trove for novel therapeutics. J Cell Physiol 227: 3178-3184, 2012. doi:10.1002/jcp.24065.
192. Maitra U, Singh N, Gan L, Ringwood L, Li L. IRAK-1 contributes to lipopolysaccharide-induced reactive oxygen species generation in macrophages by inducing NOX-1 transcription and Rac1 activation and suppressing the expression of antioxidative enzymes. J Biol Chem 284: 35403-35411, 2009. doi:10.1074/jbc.M109.059501.
193. Martìn-Padura I, Lostaglio S, Schneemann M, Williams L, Romano M, Fruscella P, Panzeri C, Stoppacciaro A, Ruco L, Villa A, Simmons D, Dejana E. Junctional adhesion molecule, a novel member of the immunoglobulin superfamily that distributes at intercellular junctions and modulates monocyte transmigration. J Cell Biol 142: 117-127, 1998. doi:10.1083/jcb.142.1.117.
194. Martínez-Caro L, Lorente JA, Marín-Corral J, Sánchez-Rodríguez C, Sánchez-Ferrer A, Nin N, Ferruelo A, de Paula M, Fernández-Segoviano P, Barreiro E, Esteban A. Role of free radicals in vascular dysfunction induced by high tidal volume ventilation. Intensive Care Med 35: 1110-1119, 2009. doi:10.1007/s00134-009-1469-5.
195. Martínez-Caro L, Nin N, Sánchez-Rodríguez C, Ferruelo A, El Assar M, de Paula M, Fernández-Segoviano P, Esteban A, Lorente JA. Inhibition of nitro-oxidative stress attenuates pulmonary and systemic injury induced by high-tidal volume mechanical ventilation. Shock 44: 36-43, 2015. doi:10.1097/SHK.0000000000000381.
196. Mathew B, Takekoshi D, Sammani S, Epshtein Y, Sharma R, Smith BD, Mitra S, Desai AA, Weichselbaum RR, Garcia JG, Jacobson JR. Role of GADD45a in murine models of radiation-and bleomycininduced lung injury. Am J Physiol Lung Cell Mol Physiol 309: L1420-L1429, 2015. doi:10.1152/ajplung.00146.2014.
197. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 122: 2731-2740, 2012. doi:10.1172/JCI60331.
198. McConnell JR, Buckton LK, McAlpine SR. Regulating the master regulator: Controlling heat shock factor 1 as a chemotherapy approach. Bioorg Med Chem Lett 25: 3409-3414, 2015. doi:10.1016/j.bmcl.2015.06.052.
199. McVerry BJ, Garcia JG. Endothelial cell barrier regulation by sphingosine 1-phosphate. J Cell Biochem 92: 1075-1085, 2004. doi:10.1002/jcb.20088.
200. Meade MO, Cook DJ, Guyatt GH, Slutsky AS, Arabi YM, Cooper DJ, Davies AR, Hand LE, Zhou Q, Thabane L, Austin P, Lapinsky S, Baxter A, Russell J, Skrobik Y, Ronco JJ, Stewart TE; Lung Open Ventilation Study Investigators. Ventilation strategy using low tidal volumes, recruitment maneuvers, and high positive end-expiratory pressure for acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299: 637-645, 2008. doi:10.1001/jama.299.6.637.
201. Medina R, Rahner C, Mitic LL, Anderson JM, Van Itallie CM. Occludin localization at the tight junction requires the second extracellular loop. J Membr Biol 178: 235-247, 2000. doi:10.1007/s002320010031.
202. Meens MJ, Pfenniger A, Kwak BR, Delmar M. Regulation of cardiovascular connexins by mechanical forces and junctions. Cardiovasc Res 99: 304-314, 2013. doi:10.1093/cvr/cvt095.
203. Mehta D, Tiruppathi C, Sandoval R, Minshall RD, Holinstat M, Malik AB. Modulatory role of focal adhesion kinase in regulating human pulmonary arterial endothelial barrier function. J Physiol 539: 779-789, 2002. doi:10.1113/jphysiol.2001.013289.
204. Mercat A, Richard JC, Vielle B, Jaber S, Osman D, Diehl JL, Lefrant JY, Prat G, Richecoeur J, Nieszkowska A, Gervais C, Baudot J, Bouadma L, Brochard L; Expiratory Pressure (Express) Study Group. Positive end-expiratory pressure setting in adults with acute lung injury and acute respiratory distress syndrome: a randomized controlled trial. JAMA 299: 646-655, 2008. doi:10.1001/jama.299.6.646.
205. Meyer NJ, Christie JD. Genetic heterogeneity and risk of acute respiratory distress syndrome. Semin Respir Crit Care Med 34: 459-474, 2013. doi:10.1055/s-0033-1351121.
206. Meyer NJ, Garcia JG. Wading into the genomic pool to unravel acute lung injury genetics. Proc Am Thorac Soc 4: 69-76, 2007. doi:10.1513/pats.200609-157JG.
207. Meyer NJ, Huang Y, Singleton PA, Sammani S, Moitra J, Evenoski CL, Husain AN, Mitra S, Moreno-Vinasco L, Jacobson JR, Lussier YA, Garcia JG. GADD45a is a novel candidate gene in inflammatory lung injury via influences on Akt signaling. FASEB J 23: 1325-1337, 2009. doi:10.1096/fj.08-119073.
208. Meyer TN, Schwesinger C, Denker BM. Zonula occludens-1 is a scaffolding protein for signaling molecules. Galpha(12) directly binds to the Src homology 3 domain and regulates paracellular permeability in epithelial cells. J Biol Chem 277: 24855-24858, 2002. doi:10.1074/jbc.C200240200.
209. Mineta K, Yamamoto Y, Yamazaki Y, Tanaka H, Tada Y, Saito K, Tamura A, Igarashi M, Endo T, Takeuchi K, Tsukita S. Predicted expansion of the claudin multigene family. FEBS Lett 585: 606-612, 2011. doi:10.1016/j.febslet.2011.01.028.
210. Mirzapoiazova T, Moitra J, Moreno-Vinasco L, Sammani S, Turner JR, Chiang ET, Evenoski C, Wang T, Singleton PA, Huang Y, Lussier YA, Watterson DM, Dudek SM, Garcia JG. Non-muscle myosin light chain kinase isoform is a viable molecular target in acute inflammatory lung injury. Am J Respir Cell Mol Biol 44: 40-52, 2011. doi:10.1165/rcmb.2009-0197OC.
211. Mitra S, Sammani S, Wang T, Boone DL, Meyer NJ, Dudek SM, Moreno-Vinasco L, Garcia JG, Jacobson JR. Role of growth arrest and DNA damage-inducible α in Akt phosphorylation and ubiquitination after mechanical stress-induced vascular injury. Am J Respir Crit Care Med 184: 1030-1040, 2011. doi:10.1164/rccm.201103-0447OC.
212. Mitra S, Wade MS, Sun X, Moldobaeva N, Flores C, Ma SF, Zhang W, Garcia JG, Jacobson JR. GADD45a promoter regulation by a functional genetic variant associated with acute lung injury. PLoS One 9: e100169, 2014. doi:10.1371/journal.pone.0100169.
213. Morita K, Furuse M, Fujimoto K, Tsukita S. Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc Natl Acad Sci USA 96: 511-516, 1999. doi:10.1073/pnas.96.2.511.
214. Morita K, Sasaki H, Furuse M, Tsukita S. Endothelial claudin: claudin-5/TMVCF constitutes tight junction strands in endothelial cells. J Cell Biol 147: 185-194, 1999. doi:10.1083/jcb.147.1.185.
215. Morrow CM, Tyagi G, Simon L, Carnes K, Murphy KM, Cooke PS, Hofmann MC, Hess RA. Claudin 5 expression in mouse seminiferous epithelium is dependent upon the transcription factor Ets variant 5 and contributes to blood-testis barrier function. Biol Reprod 81: 871-879, 2009. doi:10.1095/biolreprod.109.077040.
216. Moss M, Mannino DM. Race and gender differences in acute respiratory distress syndrome deaths in the United States: an analysis of multiplecause mortality data (1979-1996). Crit Care Med 30: 1679-1685, 2002. doi:10.1097/00003246-200208000-00001.
217. Müller SL, Portwich M, Schmidt A, Utepbergenov DI, Huber O, Blasig IE, Krause G. The tight junction protein occludin and the adherens junction protein alpha-catenin share a common interaction mechanism with ZO-1. J Biol Chem 280: 3747-3756, 2005. doi:10.1074/jbc.M411365200.
218. Murakami K, Enkhbaatar P, Yu YM, Traber LD, Cox RA, Hawkins HK, Tompkins RG, Herndon D, Traber DL. L-arginine attenuates acute lung injury after smoke inhalation and burn injury in sheep. Shock 28: 477-483, 2007. doi:10.1097/shk.0b013e31804a59bd.
219. Narimanbekov IO, Rozycki HJ. Effect of IL-1 blockade on inflammatory manifestations of acute ventilator-induced lung injury in a rabbit model. Exp Lung Res 21: 239-254, 1995. doi:10.3109/01902149509068830.
220. Natale DR, Watson AJ. Rac-1 and IQGAP are potential regulators of E-cadherin-catenin interactions during murine preimplantation development. Mech Dev 119, Suppl 1: S21-S26, 2002. doi:10.1016/S0925-4773(03)00086-8.
221. Natarajan V, Dudek SM, Jacobson JR, Moreno-Vinasco L, Huang LS, Abassi T, Mathew B, Zhao Y, Wang L, Bittman R, Weichselbaum R, Berdyshev E, Garcia JG. Sphingosine-1-phosphate, FTY720, and sphingosine-1-phosphate receptors in the pathobiology of acute lung injury. Am J Respir Cell Mol Biol 49: 6-17, 2013. doi:10.1165/rcmb.2012-0411TR.
222. Nickles HT, Sumkauskaite M, Wang X, Wegner I, Puderbach M, Kuebler WM. Mechanical ventilation causes airway distension with proinflammatory sequelae in mice. Am J Physiol Lung Cell Mol Physiol 307: L27-L37, 2014. doi:10.1152/ajplung.00288.2013.
223. Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, Furuse M, Tsukita S. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol 161: 653-660, 2003. doi:10.1083/jcb.200302070.
224. O’Donnell JJ III, Birukova AA, Beyer EC, Birukov KG. Gap junction protein connexin43 exacerbates lung vascular permeability. PLoS One 9: e100931, 2014. doi:10.1371/journal.pone.0100931.
225. Okamoto T, Akita N, Hayashi T, Shimaoka M, Suzuki K. Endothelial connexin 32 regulates tissue factor expression induced by inflammatory stimulation and direct cell-cell interaction with activated cells. Atherosclerosis 236: 430-437, 2014. doi:10.1016/j.atherosclerosis.2014.07.025.
226. Okamoto T, Akita N, Kawamoto E, Hayashi T, Suzuki K, Shimaoka M. Endothelial connexin32 enhances angiogenesis by positively regulating tube formation and cell migration. Exp Cell Res 321: 133-141, 2014. doi:10.1016/j.yexcr.2013.12.002.
227. Okamoto T, Akiyama M, Takeda M, Akita N, Yoshida K, Hayashi T, Suzuki K. Connexin32 protects against vascular inflammation by modulating inflammatory cytokine expression by endothelial cells. Exp Cell Res 317: 348-355, 2011. doi:10.1016/j.yexcr.2010.10.018.
228. Ooshio T, Kobayashi R, Ikeda W, Miyata M, Fukumoto Y, Matsuzawa N, Ogita H, Takai Y. Involvement of the interaction of afadin with ZO-1 in the formation of tight junctions in Madin-Darby canine kidney cells. J Biol Chem 285: 5003-5012, 2010. doi:10.1074/jbc.M109.043760.
229. Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF, Sadoff JC, Slotman GJ, Levy H, Balk RA, Shelly MP, Pribble JP, LaBrecque JF, Lookabaugh J, Donovan H, Dubin H, Baughman R, Norman J, DeMaria E, Matzel K, Abraham E, Seneff M. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med 25: 1115-1124, 1997. doi:10.1097/00003246-199707000-00010.
230. Orsenigo F, Giampietro C, Ferrari A, Corada M, Galaup A, Sigismund S, Ristagno G, Maddaluno L, Koh GY, Franco D, Kurtcuoglu V, Poulikakos D, Baluk P, McDonald D, Grazia Lampugnani M, Dejana E. Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo. Nat Commun 3: 1208, 2012. doi:10.1038/ncomms2199.
231. Pacey S, Banerji U, Judson I, Workman P. Hsp90 inhibitors in the clinic. Handb Exp Pharmacol 172: 331-358, 2006. doi:10.1007/3-540-29717-0_14.
232. Pacey S, Gore M, Chao D, Banerji U, Larkin J, Sarker S, Owen K, Asad Y, Raynaud F, Walton M, Judson I, Workman P, Eisen T. A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest New Drugs 30: 341-349, 2012. doi:10.1007/s10637-010-9493-4.
233. Pacey S, Wilson RH, Walton M, Eatock MM, Hardcastle A, Zetterlund A, Arkenau HT, Moreno-Farre J, Banerji U, Roels B, Peachey H, Aherne W, de Bono JS, Raynaud F, Workman P, Judson I. A phase I study of the heat shock protein 90 inhibitor alvespimycin (17-DMAG) given intravenously to patients with advanced solid tumors. Clin Cancer Res 17: 1561-1570, 2011. doi:10.1158/1078-0432.CCR-10-1927.
234. Papaiahgari S, Kleeberger SR, Cho HY, Kalvakolanu DV, Reddy SP. NADPH oxidase and ERK signaling regulates hyperoxia-induced Nrf2-ARE transcriptional response in pulmonary epithelial cells. J Biol Chem 279: 42302-42312, 2004. doi:10.1074/jbc.M408275200.
235. Papaiahgari S, Yerrapureddy A, Hassoun PM, Garcia JG, Birukov KG, Reddy SP. EGFR-activated signaling and actin remodeling regulate cyclic stretch-induced NRF2-ARE activation. Am J Respir Cell Mol Biol 36: 304-312, 2007. doi:10.1165/rcmb.2006-0131OC.
236. Papaiahgari S, Yerrapureddy A, Reddy SR, Reddy NM, Dodd-O JM, Crow MT, Grigoryev DN, Barnes K, Tuder RM, Yamamoto M, Kensler TW, Biswal S, Mitzner W, Hassoun PM, Reddy SP. Genetic and pharmacologic evidence links oxidative stress to ventilator-induced lung injury in mice. Am J Respir Crit Care Med 176: 1222-1235, 2007. doi:10.1164/rccm.200701-060OC.
237. Parker JC, Hashizumi M, Kelly SV, Francis M, Mouner M, Meyer AL, Townsley MI, Wu S, Cioffi DL, Taylor MS. TRPV4 calcium entry and surface expression attenuated by inhibition of myosin light chain kinase in rat pulmonary microvascular endothelial cells. Physiol Rep 1: e00121, 2013. doi:10.1002/phy2.121.
238. Pedreira PR, García-Prieto E, Parra D, Astudillo A, Diaz E, Taboada F, Albaiceta GM. Effects of melatonin in an experimental model of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 295: L820-L827, 2008. doi:10.1152/ajplung.90211.2008.
239. Peng X, Hassoun PM, Sammani S, McVerry BJ, Burne MJ, Rabb H, Pearse D, Tuder RM, Garcia JG. Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. Am J Respir Crit Care Med 169: 1245-1251, 2004. doi:10.1164/rccm.200309-1258OC.
240. Piehl C, Piontek J, Cording J, Wolburg H, Blasig IE. Participation of the second extracellular loop of claudin-5 in paracellular tightening against ions, small and large molecules. Cell Mol Life Sci 67: 2131-2140, 2010. doi:10.1007/s00018-010-0332-8.
241. Piontek J, Winkler L, Wolburg H, Müller SL, Zuleger N, Piehl C, Wiesner B, Krause G, Blasig IE. Formation of tight junction: determinants of homophilic interaction between classic claudins. FASEB J 22: 146-158, 2008. doi:10.1096/fj.07-8319com.
242. Portela A, Esteller M. Epigenetic modifications and human disease. Nat Biotechnol 28: 1057-1068, 2010. doi:10.1038/nbt.1685.
243. Powers MV, Workman P. Inhibitors of the heat shock response: biology and pharmacology. FEBS Lett 581: 3758-3769, 2007. doi:10.1016/j.febslet.2007.05.040.
244. Quinn DA, Moufarrej RK, Volokhov A, Hales CA. Interactions of lung stretch, hyperoxia, and MIP-2 production in ventilator-induced lung injury. J Appl Physiol (1985) 93: 517-525, 2002. doi:10.1152/japplphysiol.00570.2001.
245. Radisavljevic Z. AKT as locus of cancer positive feedback loops and extreme robustness. J Cell Physiol 228: 522-524, 2013. doi:10.1002/jcp.24167.
246. Rafikov R, Dimitropoulou C, Aggarwal S, Kangath A, Gross C, Pardo D, Sharma S, Jezierska-Drutel A, Patel V, Snead C, Lucas R, Verin A, Fulton D, Catravas JD, Black SM. Lipopolysaccharideinduced lung injury involves the nitration-mediated activation of RhoA. J Biol Chem 289: 4710-4722, 2014. doi:10.1074/jbc.M114.547596.
247. Rafikov R, Rafikova O, Aggarwal S, Gross C, Sun X, Desai J, Fulton D, Black SM. Asymmetric dimethylarginine induces endothelial nitricoxide synthase mitochondrial redistribution through the nitration-mediated activation of Akt1. J Biol Chem 288: 6212-6226, 2013. doi:10.1074/jbc.M112.423269.
248. Rafikova O, Rafikov R, Kangath A, Qu N, Aggarwal S, Sharma S, Desai J, Fields T, Ludewig B, Yuan JX, Jonigk D, Black SM. Redox regulation of epidermal growth factor receptor signaling during the development of pulmonary hypertension. Free Radic Biol Med 95: 96-111, 2016. doi:10.1016/j.freeradbiomed.2016.02.029.
249. Rajasekaran AK, Hojo M, Huima T, Rodriguez-Boulan E. Catenins and zonula occludens-1 form a complex during early stages in the assembly of tight junctions. J Cell Biol 132: 451-463, 1996. doi:10.1083/jcb.132.3.451.
250. Rao RK, Basuroy S, Rao VU, Karnaky KJ Jr, Gupta A. Tyrosine phosphorylation and dissociation of occludin-ZO-1 and E-cadherin-betacatenin complexes from the cytoskeleton by oxidative stress. Biochem J 368: 471-481, 2002. doi:10.1042/bj20011804.
251. Reddy SP, Hassoun PM, Brower R. Redox imbalance and ventilatorinduced lung injury. Antioxid Redox Signal 9: 2003-2012, 2007. doi:10.1089/ars.2007.1770.
252. Rentsendorj O, Damarla M, Aggarwal NR, Choi JY, Johnston L, D’Alessio FR, Crow MT, Pearse DB. Knockdown of lung phosphodiesterase 2A attenuates alveolar inflammation and protein leak in a two-hit mouse model of acute lung injury. Am J Physiol Lung Cell Mol Physiol 301: L161-L170, 2011. doi:10.1152/ajplung.00073.2011.
253. Ribeiro SP, Villar J, Downey GP, Edelson JD, Slutsky AS. Effects of the stress response in septic rats and LPS-stimulated alveolar macrophages: evidence for TNF-alpha posttranslational regulation. Am J Respir Crit Care Med 154: 1843-1850, 1996. doi:10.1164/ajrccm.154.6.8970379.
254. Rich PB, Douillet CD, Hurd H, Boucher RC. Effect of ventilatory rate on airway cytokine levels and lung injury. J Surg Res 113: 139-145, 2003. doi:10.1016/S0022-4804(03)00195-1.
255. Rizzo AN, Sammani S, Esquinca AE, Jacobson JR, Garcia JG, Letsiou E, Dudek SM. Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury. Am J Physiol Lung Cell Mol Physiol 309: L1294-L1304, 2015. doi:10.1152/ajplung.00031.2015.
256. Rodrigues LM, Chung YL, Al Saffar NM, Sharp SY, Jackson LE, Banerji U, Stubbs M, Leach MO, Griffiths JR, Workman P. Effects of HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on NEU/HER2 overexpressing mammary tumours in MMTVNEU-NT mice monitored by Magnetic Resonance Spectroscopy. BMC Res Notes 5: 250, 2012. doi:10.1186/1756-0500-5-250.
257. Rouby JJ, Lherm T, Martin de Lassale E, Poète P, Bodin L, Finet JF, Callard P, Viars P. Histologic aspects of pulmonary barotrauma in critically ill patients with acute respiratory failure. Intensive Care Med 19: 383-389, 1993. doi:10.1007/BF01724877.
258. Rüffer C, Gerke V. The C-terminal cytoplasmic tail of claudins 1 and 5 but not its PDZ-binding motif is required for apical localization at epithelial and endothelial tight junctions. Eur J Cell Biol 83: 135-144, 2004. doi:10.1078/0171-9335-00366.
259. Ryb GE, Cooper C. Race/ethnicity and acute respiratory distress syndrome: a National Trauma Data Bank study. J Natl Med Assoc 102: 865-869, 2010. doi:10.1016/S0027-9684(15)30700-8.
260. Saif MW, Takimoto C, Mita M, Banerji U, Lamanna N, Castro J, O’Brien S, Stogard C, Von Hoff D. A phase 1, dose-escalation, pharmacokinetic and pharmacodynamic study of BIIB021 administered orally in patients with advanced solid tumors. Clin Cancer Res 20: 445-455, 2014. doi:10.1158/1078-0432.CCR-13-1257.
261. Saitou M, Fujimoto K, Doi Y, Itoh M, Fujimoto T, Furuse M, Takano H, Noda T, Tsukita S. Occludin-deficient embryonic stem cells can differentiate into polarized epithelial cells bearing tight junctions. J Cell Biol 141: 397-408, 1998. doi:10.1083/jcb.141.2.397.
262. Sakakibara A, Furuse M, Saitou M, Ando-Akatsuka Y, Tsukita S. Possible involvement of phosphorylation of occludin in tight junction formation. J Cell Biol 137: 1393-1401, 1997. doi:10.1083/jcb.137.6.1393.
263. Sammani S, Moreno-Vinasco L, Mirzapoiazova T, Singleton PA, Chiang ET, Evenoski CL, Wang T, Mathew B, Husain A, Moitra J, Sun X, Nunez L, Jacobson JR, Dudek SM, Natarajan V, Garcia JG. Differential effects of sphingosine 1-phosphate receptors on airway and vascular barrier function in the murine lung. Am J Respir Cell Mol Biol 43: 394-402, 2010. doi:10.1165/rcmb.2009-0223OC.
264. Sander EE, ten Klooster JP, van Delft S, van der Kammen RA, Collard JG. Rac downregulates Rho activity: reciprocal balance between both GTPases determines cellular morphology and migratory behavior. J Cell Biol 147: 1009-1022, 1999. doi:10.1083/jcb.147.5.1009.
265. Sato K, Kadiiska MB, Ghio AJ, Corbett J, Fann YC, Holland SM, Thurman RG, Mason RP. In vivo lipid-derived free radical formation by NADPH oxidase in acute lung injury induced by lipopolysaccharide: a model for ARDS. FASEB J 16: 1713-1720, 2002. doi:10.1096/fj.02-0331com.
266. Schaphorst KL, Chiang E, Jacobs KN, Zaiman A, Natarajan V, Wigley F, Garcia JG. Role of sphingosine-1 phosphate in the enhancement of endothelial barrier integrity by platelet-released products. Am J Physiol Lung Cell Mol Physiol 285: L258-L267, 2003. doi:10.1152/ajplung.00311.2002.
267. Schwartz MD, Repine JE, Abraham E. Xanthine oxidase-derived oxygen radicals increase lung cytokine expression in mice subjected to hemorrhagic shock. Am J Respir Cell Mol Biol 12: 434-440, 1995. doi:10.1165/ajrcmb.12.4.7695923.
268. Sessa C, Shapiro GI, Bhalla KN, Britten C, Jacks KS, Mita M, Papadimitrakopoulou V, Pluard T, Samuel TA, Akimov M, Quadt C, Fernandez-Ibarra C, Lu H, Bailey S, Chica S, Banerji U. Firstin-human phase I dose-escalation study of the HSP90 inhibitor AUY922 in patients with advanced solid tumors. Clin Cancer Res 19: 3671-3680, 2013. doi:10.1158/1078-0432.CCR-12-3404.
269. Shan Y, Akram A, Amatullah H, Zhou DY, Gali PL, Maron-Gutierrez T, González-López A, Zhou L, Rocco PR, Hwang D, Albaiceta GM, Haitsma JJ, dos Santos CC. ATF3 protects pulmonary resident cells from acute and ventilator-induced lung injury by preventing Nrf2 degradation. Antioxid Redox Signal 22: 651-668, 2015. doi:10.1089/ars.2014.5987.
270. Shikata Y, Rios A, Kawkitinarong K, DePaola N, Garcia JG, Birukov KG. Differential effects of shear stress and cyclic stretch on focal adhesion remodeling, site-specific FAK phosphorylation, and small GTPases in human lung endothelial cells. Exp Cell Res 304: 40-49, 2005. doi:10.1016/j.yexcr.2004.11.001.
271. Shimizu Y, Camp SM, Sun X, Zhou T, Wang T, Garcia JG. Sp1-mediated nonmuscle myosin light chain kinase expression and enhanced activity in vascular endothelial growth factor-induced vascular permeability. Pulm Circ 5: 707-715, 2015. doi:10.1086/684124.
272. Shohrati M, Karimzadeh I, Saburi A, Khalili H, Ghanei M. The role of N-acetylcysteine in the management of acute and chronic pulmonary complications of sulfur mustard: a literature review. Inhal Toxicol 26: 507-523, 2014. doi:10.3109/08958378.2014.920439.
273. Silachev DN, Plotnikov EY, Pevzner IB, Zorova LD, Babenko VA, Zorov SD, Popkov VA, Jankauskas SS, Zinchenko VP, Sukhikh GT, Zorov DB. The mitochondrion as a key regulator of ischaemic tolerance and injury. Heart Lung Circ 23: 897-904, 2014. doi:10.1016/j.hlc.2014.05.022.
274. Simon BA, Easley RB, Grigoryev DN, Ma SF, Ye SQ, Lavoie T, Tuder RM, Garcia JG. Microarray analysis of regional cellular responses to local mechanical stress in acute lung injury. Am J Physiol Lung Cell Mol Physiol 291: L851-L861, 2006. doi:10.1152/ajplung.00463.2005.
275. Singer KL, Stevenson BR, Woo PL, Firestone GL. Relationship of serine/threonine phosphorylation/dephosphorylation signaling to glucocorticoid regulation of tight junction permeability and ZO-1 distribution in nontransformed mammary epithelial cells. J Biol Chem 269: 16108-16115, 1994.
276. Singleton PA, Dudek SM, Ma SF, Garcia JG. Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family. J Biol Chem 281: 34381-34393, 2006. doi:10.1074/jbc.M603680200.
277. Slutsky AS. Basic science in ventilator-induced lung injury: implications for the bedside. Am J Respir Crit Care Med 163: 599-600, 2001. doi:10.1164/ajrccm.163.3.ed09-01c.
278. Slutsky AS. Ventilator-induced lung injury: from barotrauma to biotrauma. Respir Care 50: 646-659, 2005.
279. Staddon JM, Herrenknecht K, Smales C, Rubin LL. Evidence that tyrosine phosphorylation may increase tight junction permeability. J Cell Sci 108: 609-619, 1995.
280. Staehelin LA. Further observations on the fine structure of freezecleaved tight junctions. J Cell Sci 13: 763-786, 1973.
281. Stamatovic SM, Dimitrijevic OB, Keep RF, Andjelkovic AV. Protein kinase Calpha-RhoA cross-talk in CCL2-induced alterations in brain endothelial permeability. J Biol Chem 281: 8379-8388, 2006. doi:10.1074/jbc.M513122200.
282. Standiford TJ, Ward PA. Therapeutic targeting of acute lung injury and acute respiratory distress syndrome. Transl Res 167: 183-191, 2016.
283. Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279: 710-714, 1998. doi:10.1126/science.279.5351.710.
284. Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol 103: 755-766, 1986. doi:10.1083/jcb.103.3.755.
285. Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 277: 567-570, 1997. doi:10.1126/science.277.5325.567.
286. Stone ML, Sharma AK, Zhao Y, Charles EJ, Huerter ME, Johnston WF, Kron IL, Lynch KR, Laubach VE. Sphingosine-1-phosphate receptor 1 agonism attenuates lung ischemia-reperfusion injury. Am J Physiol Lung Cell Mol Physiol 308: L1245-L1252, 2015. doi:10.1152/ajplung.00302.2014.
287. Su CL, Du WY, Chiang LL, Lin YK, Lee HL, Chen KH, Wang J Jr, Wang D. Amelioration of superoxide dismutase on ventilator-induced lung injury by suppressing leukocyte in the lungs and systemic circulation. Chin J Physiol 56: 219-229, 2013. doi:10.4077/CJP.2013.BAB106.
288. Sud N, Sharma S, Wiseman DA, Harmon C, Kumar S, Venema RC, Fineman JR, Black SM. Nitric oxide and superoxide generation from endothelial NOS: modulation by HSP90. Am J Physiol Lung Cell Mol Physiol 293: L1444-L1453, 2007. doi:10.1152/ajplung.00175.2007.
289. Suizu F, Hiramuki Y, Okumura F, Matsuda M, Okumura AJ, Hirata N, Narita M, Kohno T, Yokota J, Bohgaki M, Obuse C, Hatakeyama S, Obata T, Noguchi M. The E3 ligase TTC3 facilitates ubiquitination and degradation of phosphorylated Akt. Dev Cell 17: 800-810, 2009. doi:10.1016/j.devcel.2009.09.007.
290. Sumpio BE, Du W, Galagher G, Wang X, Khachigian LM, Collins T, Gimbrone MA Jr, Resnick N. Regulation of PDGF-B in endothelial cells exposed to cyclic strain. Arterioscler Thromb Vasc Biol 18: 349-355, 1998. doi:10.1161/01.ATV.18.3.349.
291. Sun X, Elangovan VR, Mapes B, Camp SM, Sammani S, Saadat L, Ceco E, Ma SF, Flores C, MacDougall MS, Quijada H, Liu B, Kempf CL, Wang T, Chiang ET, Garcia JG. The NAMPT promoter is regulated by mechanical stress, signal transducer and activator of transcription 5, and acute respiratory distress syndrome-associated genetic variants. Am J Respir Cell Mol Biol 51: 660-667, 2014. doi:10.1165/rcmb.2014-0117OC.
292. Sun X, Ma SF, Wade MS, Acosta-Herrera M, Villar J, Pino-Yanes M, Zhou T, Liu B, Belvitch P, Moitra J, Han YJ, Machado R, Noth I, Natarajan V, Dudek SM, Jacobson JR, Flores C, Garcia JG. Functional promoter variants in sphingosine 1-phosphate receptor 3 associate with susceptibility to sepsis-associated acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 305: L467-L477, 2013. doi:10.1152/ajplung.00010.2013.
293. Sun X, Ma SF, Wade MS, Flores C, Pino-Yanes M, Moitra J, Ober C, Kittles R, Husain AN, Ford JG, Garcia JG. Functional variants of the sphingosine-1-phosphate receptor 1 gene associate with asthma susceptibility. J Allergy Clin Immunol 126: 241-249e.3, 2010. doi:10.1016/j.jaci.2010.04.036.
294. Sun X, Singleton PA, Letsiou E, Zhao J, Belvitch P, Sammani S, Chiang ET, Moreno-Vinasco L, Wade MS, Zhou T, Liu B, Parastatidis I, Thomson L, Ischiropoulos H, Natarajan V, Jacobson JR, Machado RF, Dudek SM, Garcia JG. Sphingosine-1-phosphate receptor-3 is a novel biomarker in acute lung injury. Am J Respir Cell Mol Biol 47: 628-636, 2012. doi:10.1165/rcmb.2012-0048OC.
295. Suzuki T, Tada Y, Nishimura R, Kawasaki T, Sekine A, Urushibara T, Kato F, Kinoshita T, Ikari J, West J, Tatsumi K. Endothelial-tomesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype. Am J Physiol Lung Cell Mol Physiol 310: L1185-L1198, 2016. doi:10.1152/ajplung.00074.2016.
296. Suzuma I, Hata Y, Clermont A, Pokras F, Rook SL, Suzuma K, Feener EP, Aiello LP. Cyclic stretch and hypertension induce retinal expression of vascular endothelial growth factor and vascular endothelial growth factor receptor-2: potential mechanisms for exacerbation of diabetic retinopathy by hypertension. Diabetes 50: 444-454, 2001. doi:10.2337/diabetes.50.2.444.
297. Syrkina O, Jafari B, Hales CA, Quinn DA. Oxidant stress mediates inflammation and apoptosis in ventilator-induced lung injury. Respirology 13: 333-340, 2008. doi:10.1111/j.1440-1843.2008.01279.x.
298. Taddei A, Giampietro C, Conti A, Orsenigo F, Breviario F, Pirazzoli V, Potente M, Daly C, Dimmeler S, Dejana E. Endothelial adherens junctions control tight junctions by VE-cadherin-mediated upregulation of claudin-5. Nat Cell Biol 10: 923-934, 2008. doi:10.1038/ncb1752.
299. Takata M, Abe J, Tanaka H, Kitano Y, Doi S, Kohsaka T, Miyasaka K. Intraalveolar expression of tumor necrosis factor-alpha gene during conventional and high-frequency ventilation. Am J Respir Crit Care Med 156: 272-279, 1997. doi:10.1164/ajrccm.156.1.9607072.
300. Takeda H, Tsukita S. Effects of tyrosine phosphorylation on tight junctions in temperature-sensitive v-src-transfected MDCK cells. Cell Struct Funct 20: 387-393, 1995. doi:10.1247/csf.20.387.
301. Takenaga Y, Takagi N, Murotomi K, Tanonaka K, Takeo S. Inhibition of Src activity decreases tyrosine phosphorylation of occludin in brain capillaries and attenuates increase in permeability of the bloodbrain barrier after transient focal cerebral ischemia. J Cereb Blood Flow Metab 29: 1099-1108, 2009. doi:10.1038/jcbfm.2009.30.
302. Takenaka K, Nishimura Y, Nishiuma T, Sakashita A, Yamashita T, Kobayashi K, Satouchi M, Ishida T, Kawashima S, Yokoyama M. Ventilator-induced lung injury is reduced in transgenic mice that overexpress endothelial nitric oxide synthase. Am J Physiol Lung Cell Mol Physiol 290: L1078-L1086, 2006. doi:10.1152/ajplung.00239.2005.
303. Tang BT, Pickard SS, Chan FP, Tsao PS, Taylor CA, Feinstein JA. Wall shear stress is decreased in the pulmonary arteries of patients with pulmonary arterial hypertension: an image-based, computational fluid dynamics study. Pulm Circ 2: 470-476, 2012. doi:10.4103/2045-8932.105035.
304. Tao S, Rojo de la Vega M, Quijada H, Wondrak GT, Wang T, Garcia JG, Zhang DD. Bixin protects mice against ventilation-induced lung injury in an NRF2-dependent manner. Sci Rep 6: 18760, 2016. doi:10.1038/srep18760.
305. Thangjam GS, Birmpas C, Barabutis N, Gregory BW, Clemens MA, Newton JR, Fulton D, Catravas JD. Hsp90 inhibition suppresses NF-κB transcriptional activation via Sirt-2 in human lung microvascular endothelial cells. Am J Physiol Lung Cell Mol Physiol 310: L964-L974, 2016. doi:10.1152/ajplung.00054.2016.
306. Thorneloe KS, Cheung M, Bao W, Alsaid H, Lenhard S, Jian MY, Costell M, Maniscalco-Hauk K, Krawiec JA, Olzinski A, Gordon E, Lozinskaya I, Elefante L, Qin P, Matasic DS, James C, Tunstead J, Donovan B, Kallal L, Waszkiewicz A, Vaidya K, Davenport EA, Larkin J, Burgert M, Casillas LN, Marquis RW, Ye G, Eidam HS, Goodman KB, Toomey JR, Roethke TJ, Jucker BM, Schnackenberg CG, Townsley MI, Lepore JJ, Willette RN. An orally active TRPV4 channel blocker prevents and resolves pulmonary edema induced by heart failure. Sci Transl Med 4: 159ra148, 2012. doi:10.1126/scitranslmed.3004276.
307. To EE, Broughton BR, Hendricks KS, Vlahos R, Selemidis S. Influenza A virus and TLR7 activation potentiate NOX2 oxidase-dependent ROS production in macrophages. Free Radic Res 48: 940-947, 2014. doi:10.3109/10715762.2014.927579.
308. Tremblay LN, Slutsky AS. Ventilator-induced lung injury: from the bench to the bedside. Intensive Care Med 32: 24-33, 2006. doi:10.1007/s00134-005-2817-8.
309. Tremblay LO, Nagy Kovács E, Daniels E, Wong NK, Sutton-Smith M, Morris HR, Dell A, Marcinkiewicz E, Seidah NG, McKerlie C, Herscovics A. Respiratory distress and neonatal lethality in mice lacking Golgi alpha1,2-mannosidase IB involved in N-glycan maturation. J Biol Chem 282: 2558-2566, 2007. doi:10.1074/jbc.M608661200.
310. Tschumperlin DJ. EGFR autocrine signaling in a compliant interstitial space: mechanotransduction from the outside in. Cell Cycle 3: 994-995, 2004. doi:10.4161/cc.3.8.1061.
311. Tschumperlin DJ, Dai G, Maly IV, Kikuchi T, Laiho LH, McVittie AK, Haley KJ, Lilly CM, So PT, Lauffenburger DA, Kamm RD, Drazen JM. Mechanotransduction through growth-factor shedding into the extracellular space. Nature 429: 83-86, 2004. doi:10.1038/nature02543.
312. Tschumperlin DJ, Margulies SS. Alveolar epithelial surface areavolume relationship in isolated rat lungs. J Appl Physiol (1985) 86: 2026-2033, 1999.
313. Tschumperlin DJ, Oswari J, Margulies AS. Deformation-induced injury of alveolar epithelial cells. Effect of frequency, duration, and amplitude. Am J Respir Crit Care Med 162: 357-362, 2000. doi:10.1164/ajrccm.162.2.9807003.
314. Tschumperlin DJ, Shively JD, Swartz MA, Silverman ES, Haley KJ, Raab G, Drazen JM. Bronchial epithelial compression regulates MAP kinase signaling and HB-EGF-like growth factor expression. Am J Physiol Lung Cell Mol Physiol 282: L904-L911, 2002. doi:10.1152/ajplung.00270.2001.
315. Tsukimoto K, Mathieu-Costello O, Prediletto R, Elliott AR, West JB. Ultrastructural appearances of pulmonary capillaries at high transmural pressures. J Appl Physiol (1985) 71: 573-582, 1991.
316. Turksen K, Troy TC. Barriers built on claudins. J Cell Sci 117: 2435-2447, 2004. doi:10.1242/jcs.01235.
317. Uddin M, Lau LC, Seumois G, Vijayanand P, Staples KJ, Bagmane D, Cornelius V, Dorinsky P, Davies DE, Djukanović R. EGF-induced bronchial epithelial cells drive neutrophil chemotactic and anti-apoptotic activity in asthma. PLoS One 8: e72502, 2013. doi:10.1371/journal.pone.0072502.
318. Uddin M, Seumois G, Lau LC, Rytila P, Davies DE, Djukanovic R. Enhancement of neutrophil function by the bronchial epithelium stimulated by epidermal growth factor. Eur Respir J 31: 714-724, 2008. doi:10.1183/09031936.00144307.
319. Ulfhammer E, Ridderstråle W, Andersson M, Karlsson L, Hrafnkelsdóttir T, Jern S. Prolonged cyclic strain impairs the fibrinolytic system in cultured vascular endothelial cells. J Hypertens 23: 1551-1557, 2005. doi:10.1097/01.hjh.0000175931.71150.02.
320. Umeda K, Ikenouchi J, Katahira-Tayama S, Furuse K, Sasaki H, Nakayama M, Matsui T, Tsukita S, Furuse M, Tsukita S. ZO-1 and ZO-2 independently determine where claudins are polymerized in tightjunction strand formation. Cell 126: 741-754, 2006. doi:10.1016/j.cell.2006.06.043.
321. Usatyuk PV, Singleton PA, Pendyala S, Kalari SK, He D, Gorshkova IA, Camp SM, Moitra J, Dudek SM, Garcia JG, Natarajan V. Novel role for non-muscle myosin light chain kinase (MLCK) in hyperoxiainduced recruitment of cytoskeletal proteins, NADPH oxidase activation, and reactive oxygen species generation in lung endothelium. J Biol Chem 287: 9360-9375, 2012. doi:10.1074/jbc.M111.294546.
322. van Meer G, Simons K. The function of tight junctions in maintaining differences in lipid composition between the apical and the basolateral cell surface domains of MDCK cells. EMBO J 5: 1455-1464, 1986.
323. Vaporidi K, Francis RC, Bloch KD, Zapol WM. Nitric oxide synthase 3 contributes to ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 299: L150-L159, 2010. doi:10.1152/ajplung.00341.2009.
324. Vaporidi K, Vergadi E, Kaniaris E, Hatziapostolou M, Lagoudaki E, Georgopoulos D, Zapol WM, Bloch KD, Iliopoulos D. Pulmonary microRNA profiling in a mouse model of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 303: L199-L207, 2012. doi:10.1152/ajplung.00370.2011.
325. Verin AD, Gilbert-McClain LI, Patterson CE, Garcia JG. Biochemical regulation of the nonmuscle myosin light chain kinase isoform in bovine endothelium. Am J Respir Cell Mol Biol 19: 767-776, 1998. doi:10.1165/ajrcmb.19.5.3126.
326. Villalta PC, Rocic P, Townsley MI. Role of MMP2 and MMP9 in TRPV4-induced lung injury. Am J Physiol Lung Cell Mol Physiol 307: L652-L659, 2014. doi:10.1152/ajplung.00113.2014.
327. Villar J, Cabrera NE, Valladares F, Casula M, Flores C, Blanch L, Quilez ME, Santana-Rodríguez N, Kacmarek RM, Slutsky AS. Activation of the Wnt/β-catenin signaling pathway by mechanical ventilation is associated with ventilator-induced pulmonary fibrosis in healthy lungs. PLoS One 6: e23914, 2011. doi:10.1371/journal.pone.0023914.
328. Villar J, Sulemanji D, Kacmarek RM. The acute respiratory distress syndrome: incidence and mortality, has it changed? Curr Opin Crit Care 20: 3-9, 2014. doi:10.1097/MCC.0000000000000057.
329. Von Offenberg Sweeney N, Cummins PM, Cotter EJ, Fitzpatrick PA, Birney YA, Redmond EM, Cahill PA. Cyclic strain-mediated regulation of vascular endothelial cell migration and tube formation. Biochem Biophys Res Commun 329: 573-582, 2005. doi:10.1016/j.bbrc.2005.02.013.
330. Wachtel M, Frei K, Ehler E, Fontana A, Winterhalter K, Gloor SM. Occludin proteolysis and increased permeability in endothelial cells through tyrosine phosphatase inhibition. J Cell Sci 112: 4347-4356, 1999.
331. Wakabayashi K, Wilson MR, Tatham KC, O’Dea KP, Takata M. Volutrauma, but not atelectrauma, induces systemic cytokine production by lung-marginated monocytes. Crit Care Med 42: e49-e57, 2014. doi:10.1097/CCM.0b013e31829a822a.
332. Wang HW, Liu M, Zhong TD, Fang XM. Saikosaponin-d attenuates ventilator-induced lung injury in rats. Int J Clin Exp Med 8: 15137-15145, 2015.
333. Wang T, Moreno-Vinasco L, Ma SF, Zhou T, Shimizu Y, Sammani S, Epshtein Y, Watterson DM, Dudek SM, Garcia JG. Nonmuscle myosin light chain kinase regulates murine asthmatic inflammation. Am J Respir Cell Mol Biol 50: 1129-1135, 2014. doi:10.1165/rcmb.2013-0434OC.
334. Wang W, Liu Z, Su J, Chen WS, Wang XW, Bai SX, Zhang JZ, Yu SQ. Macrophage microRNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats. Am J Physiol Lung Cell Mol Physiol 311: L494-L506, 2016. doi:10.1152/ajplung.00001.2016.
335. Wang Y, McAlpine SR. C-terminal heat shock protein 90 modulators produce desirable oncogenic properties. Org Biomol Chem 13: 4627-4631, 2015. doi:10.1039/C5OB00044K.
336. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 342: 1334-1349, 2000. doi:10.1056/NEJM200005043421806.
337. Watanabe T, Wang S, Kaibuchi K. IQGAPs as key regulators of actin-cytoskeleton dynamics. Cell Struct Funct 40: 69-77, 2015. doi:10.1247/csf.15003.
338. Watson CJ, Rowland M, Warhurst G. Functional modeling of tight junctions in intestinal cell monolayers using polyethylene glycol oligomers. Am J Physiol Cell Physiol 281: C388-C397, 2001.
339. Webb HH, Tierney DF. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures. Protection by positive end-expiratory pressure. Am Rev Respir Dis 110: 556-565, 1974.
340. Weinbroum A, Nielsen VG, Tan S, Gelman S, Matalon S, Skinner KA, Bradley E Jr, Parks DA. Liver ischemia-reperfusion increases pulmonary permeability in rat: role of circulating xanthine oxidase. Am J Physiol 268: G988-G996, 1995.
341. Weissbach L, Settleman J, Kalady MF, Snijders AJ, Murthy AE, Yan YX, Bernards A. Identification of a human rasGAP-related protein containing calmodulin-binding motifs. J Biol Chem 269: 20517-20521, 1994.
342. West JB. Invited review: pulmonary capillary stress failure. J Appl Physiol (1985) 89: 2483-2489, 2000.
343. West JB, Tsukimoto K, Mathieu-Costello O, Prediletto R. Stress failure in pulmonary capillaries. J Appl Physiol (1985) 70: 1731-1742, 1991.
344. White CD, Erdemir HH, Sacks DB. IQGAP1 and its binding proteins control diverse biological functions. Cell Signal 24: 826-834, 2012. doi:10.1016/j.cellsig.2011.12.005.
345. Whitesell L, Bagatell R, Falsey R. The stress response: implications for the clinical development of hsp90 inhibitors. Curr Cancer Drug Targets 3: 349-358, 2003. doi:10.2174/1568009033481787.
346. Whitmore LC, Goss KL, Newell EA, Hilkin BM, Hook JS, Moreland JG. NOX2 protects against progressive lung injury and multiple organ dysfunction syndrome. Am J Physiol Lung Cell Mol Physiol 307: L71-L82, 2014. doi:10.1152/ajplung.00054.2014.
347. Wildenberg GA, Dohn MR, Carnahan RH, Davis MA, Lobdell NA, Settleman J, Reynolds AB. p120-catenin and p190RhoGAP regulate cell-cell adhesion by coordinating antagonism between Rac and Rho. Cell 127: 1027-1039, 2006. doi:10.1016/j.cell.2006.09.046.
348. Willott E, Balda MS, Fanning AS, Jameson B, Van Itallie C, Anderson JM. The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions. Proc Natl Acad Sci USA 90: 7834-7838, 1993. doi:10.1073/pnas.90.16.7834.
349. Wilson MR, Choudhury S, Goddard ME, O’Dea KP, Nicholson AG, Takata M. High tidal volume upregulates intrapulmonary cytokines in an in vivo mouse model of ventilator-induced lung injury. J Appl Physiol (1985) 95: 1385-1393, 2003. doi:10.1152/japplphysiol.00213.2003.
350. Wilson MR, O’Dea KP, Zhang D, Shearman AD, van Rooijen N, Takata M. Role of lung-marginated monocytes in an in vivo mouse model of ventilator-induced lung injury. Am J Respir Crit Care Med 179: 914-922, 2009. doi:10.1164/rccm.200806-877OC.
351. Wilson MR, Patel BV, Takata M. Ventilation with “clinically relevant” high tidal volumes does not promote stretch-induced injury in the lungs of healthy mice. Crit Care Med 40: 2850-2857, 2012. doi:10.1097/CCM.0b013e31825b91ef.
352. Wilson MR, Takata M. Inflammatory mechanisms of ventilator-induced lung injury: a time to stop and think? Anaesthesia 68: 175-178, 2013. doi:10.1111/anae.12085.
353. Wirtz HR, Dobbs LG. The effects of mechanical forces on lung functions. Respir Physiol 119: 1-17, 2000. doi:10.1016/S0034-5687(99)00092-4.
354. Wolfson RK, Mapes B, Garcia JG. Excessive mechanical stress increases HMGB1 expression in human lung microvascular endothelial cells via STAT3. Microvasc Res 92: 50-55, 2014. doi:10.1016/j.mvr.2013.12.005.
355. Woods SJ, Waite AA, O’Dea KP, Halford P, Takata M, Wilson MR. Kinetic profiling of in vivo lung cellular inflammatory responses to mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 308: L912-L921, 2015. doi:10.1152/ajplung.00048.2015.
356. Wu F, Szczepaniak WS, Shiva S, Liu H, Wang Y, Wang L, Wang Y, Kelley EE, Chen AF, Gladwin MT, McVerry BJ. Nox2-dependent glutathionylation of endothelial NOS leads to uncoupled superoxide production and endothelial barrier dysfunction in acute lung injury. Am J Physiol Lung Cell Mol Physiol 307: L987-L997, 2014. doi:10.1152/ajplung.00063.2014.
357. Wung BS, Cheng JJ, Chao YJ, Lin J, Shyy YJ, Wang DL. Cyclical strain increases monocyte chemotactic protein-1 secretion in human endothelial cells. Am J Physiol Heart Circ Physiol 270: H1462-H1468, 1996.
358. Xiang T, Ohashi A, Huang Y, Pandita TK, Ludwig T, Powell SN, Yang Q. Negative Regulation of AKT Activation by BRCA1. Cancer Res 68: 10040-10044, 2008. doi:10.1158/0008-5472.CAN-08-3009.
359. Xiao F, Weng J, Fan K, Wang W. Detailed regulatory mechanism of the interaction between ZO-1 PDZ2 and connexin43 revealed by MD simulations. PLoS One 6: e21527, 2011. doi:10.1371/journal.pone.0021527.
360. Yamada S, Nelson WJ. Localized zones of Rho and Rac activities drive initiation and expansion of epithelial cell-cell adhesion. J Cell Biol 178: 517-527, 2007. doi:10.1083/jcb.200701058.
361. Yamamoto M, Ramirez SH, Sato S, Kiyota T, Cerny RL, Kaibuchi K, Persidsky Y, Ikezu T. Phosphorylation of claudin-5 and occludin by rho kinase in brain endothelial cells. Am J Pathol 172: 521-533, 2008. doi:10.2353/ajpath.2008.070076.
362. Yamamoto T, Harada N, Kano K, Taya S, Canaani E, Matsuura Y, Mizoguchi A, Ide C, Kaibuchi K. The Ras target AF-6 interacts with ZO-1 and serves as a peripheral component of tight junctions in epithelial cells. J Cell Biol 139: 785-795, 1997. doi:10.1083/jcb.139.3.785.
363. Yamamoto Y, Sousse LE, Enkhbaatar P, Kraft ER, Deyo DJ, Wright CL, Taylor A, Traber MG, Cox RA, Hawkins HK, Rehberg SW, Traber LD, Herndon DN, Traber DL.-Tocopherol nebulization decreases oxidative stress, arginase activity, and collagen deposition after burn and smoke inhalation in the ovine model. Shock 38: 671-676, 2012. doi:10.1097/SHK.0b013e3182758759.
364. Yang B, Huang W, Han J, Liang Z. Study of the role of epidermal growth factor on lung fluid transport in rabbits with acute lung injury caused by endotoxin. Exp Ther Med 4: 611-614, 2012. doi:10.3892/etm.2012.670.
365. Yang C, Moriuchi H, Takase J, Ishitsuka Y, Irikura M, Irie T. Oxidative stress in early stage of acute lung injury induced with oleic acid in guinea pigs. Biol Pharm Bull 26: 424-428, 2003. doi:10.1248/bpb.26.424.
366. Yap AS, Kovacs EM. Direct cadherin-activated cell signaling: a view from the plasma membrane. J Cell Biol 160: 11-16, 2003. doi:10.1083/jcb.200208156.
367. Ye S, Lowther S, Stambas J. Inhibition of reactive oxygen species production ameliorates inflammation induced by influenza A viruses via upregulation of SOCS1 and SOCS3. J Virol 89: 2672-2683, 2015. doi:10.1128/JVI.03529-14.
368. Ye SQ, Simon BA, Maloney JP, Zambelli-Weiner A, Gao L, Grant A, Easley RB, McVerry BJ, Tuder RM, Standiford T, Brower RG, Barnes KC, Garcia JG. Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury. Am J Respir Crit Care Med 171: 361-370, 2005. doi:10.1164/rccm.200404-563OC.
369. Yehya N, Xin Y, Oquendo Y, Cereda M, Rizi RR, Margulies SS. Cecal ligation and puncture accelerates development of ventilator-induced lung injury. Am J Physiol Lung Cell Mol Physiol 308: L443-L451, 2015. doi:10.1152/ajplung.00312.2014.
370. Yilmaz MZ, Guzel A, Torun AC, Okuyucu A, Salis O, Karli R, Gacar A, Guvenc T, Paksu S, Urey V, Murat N, Alacam H. The therapeutic effects of anti-oxidant and anti-inflammatory drug quercetin on aspiration-induced lung injury in rats. J Mol Histol 45: 195-203, 2014. doi:10.1007/s10735-013-9542-3.
371. Yin J, Hoffmann J, Kaestle SM, Neye N, Wang L, Baeurle J, Liedtke W, Wu S, Kuppe H, Pries AR, Kuebler WM. Negative-feedback loop attenuates hydrostatic lung edema via a cGMP-dependent regulation of transient receptor potential vanilloid 4. Circ Res 102: 966-974, 2008. doi:10.1161/CIRCRESAHA.107.168724.
372. Yin J, Kuebler WM. Mechanotransduction by TRP channels: general concepts and specific role in the vasculature. Cell Biochem Biophys 56: 1-18, 2010. doi:10.1007/s12013-009-9067-2.
373. Yin J, Michalick L, Tang C, Tabuchi A, Goldenberg N, Dan Q, Awwad K, Wang L, Erfinanda L, Nouailles G, Witzenrath M, Vogelzang A, Lv L, Lee WL, Zhang H, Rotstein O, Kapus A, Szaszi K, Fleming I, Liedtke WB, Kuppe H, Kuebler WM. Role of transient receptor potential vanilloid 4 in neutrophil activation and acute lung injury. Am J Respir Cell Mol Biol 54: 370-383, 2016. doi:10.1165/rcmb.2014-0225OC.
374. Yu Y, Keller SH, Remillard CV, Safrina O, Nicholson A, Zhang SL, Jiang W, Vangala N, Landsberg JW, Wang JY, Thistlethwaite PA, Channick RN, Robbins IM, Loyd JE, Ghofrani HA, Grimminger F, Schermuly RT, Cahalan MD, Rubin LJ, Yuan JX. A functional single-nucleotide polymorphism in the TRPC6 gene promoter associated with idiopathic pulmonary arterial hypertension. Circulation 119: 2313-2322, 2009. doi:10.1161/CIRCULATIONAHA.108.782458.
375. Yuan L, Le Bras A, Sacharidou A, Itagaki K, Zhan Y, Kondo M, Carman CV, Davis GE, Aird WC, Oettgen P. ETS-related gene (ERG) controls endothelial cell permeability via transcriptional regulation of the claudin 5 (CLDN5) gene. J Biol Chem 287: 6582-6591, 2012. doi:10.1074/jbc.M111.300236.
376. Yumoto M, Nishida O, Nakamura F, Katsuya H. Propofol attenuates oxidant-induced acute lung injury in an isolated perfused rabbit-lung model. J Anesth 19: 287-294, 2005. doi:10.1007/s00540-005-0338-9.
377. Zebda N, Tian Y, Tian X, Gawlak G, Higginbotham K, Reynolds AB, Birukova AA, Birukov KG. Interaction of p190RhoGAP with C-terminal domain of p120-catenin modulates endothelial cytoskeleton and permeability. J Biol Chem 288: 18290-18299, 2013. doi:10.1074/jbc.M112.432757.
378. Zenri H, Rodriquez-Capote K, McCaig L, Yao LJ, Brackenbury A, Possmayer F, Veldhuizen R, Lewis J. Hyperoxia exposure impairs surfactant function and metabolism. Crit Care Med 32: 1155-1160, 2004. doi:10.1097/01.CCM.0000126264.00551.C8.
379. Zhan X, Desiderio DM. Nitroproteins from a human pituitary adenoma tissue discovered with a nitrotyrosine affinity column and tandem mass spectrometry. Anal Biochem 354: 279-289, 2006. doi:10.1016/j.ab.2006.05.024.
380. Zhang XQ, Lv CJ, Liu XY, Hao D, Qin J, Tian HH, Li Y, Wang XZ. Genome-wide analysis of DNA methylation in rat lungs with lipopolysaccharide-induced acute lung injury. Mol Med Rep 7: 1417-1424, 2013. doi:10.3892/mmr.2013.1405.
381. Zhao H, Hiroi T, Hansen BS, Rade JJ. Cyclic stretch induces cyclooxygenase-2 gene expression in vascular endothelial cells via activation of nuclear factor kappa-beta. Biochem Biophys Res Commun 389: 599-601, 2009. doi:10.1016/j.bbrc.2009.09.028.
382. Zhao T, Liu M, Gu C, Wang X, Wang Y. Activation of c-Src tyrosine kinase mediated the degradation of occludin in ventilator-induced lung injury. Respir Res 15: 158, 2014. doi:10.1186/s12931-014-0158-2.
383. Zhao T, Zhao H, Li G, Zheng S, Liu M, Gu C, Wang Y. Role of the PKCα-c-Src tyrosine kinase pathway in the mediation of p120-catenin degradation in ventilator-induced lung injury. Respirology 21: 1404-1410, 2016. doi:10.1111/resp.12858.
384. Zhao W, Zhou S, Yao W, Gan X, Su G, Yuan D, Hei Z. Propofol prevents lung injury after intestinal ischemia-reperfusion by inhibiting the interaction between mast cell activation and oxidative stress. Life Sci 108: 80-87, 2014. doi:10.1016/j.lfs.2014.05.009.
385. Zheng W, Christensen LP, Tomanek RJ. Stretch induces upregulation of key tyrosine kinase receptors in microvascular endothelial cells. Am J Physiol Heart Circ Physiol 287: H2739-H2745, 2004. doi:10.1152/ajpheart.00410.2004.
386. Zhou T, Garcia JG, Zhang W. Integrating microRNAs into a system biology approach to acute lung injury. Transl Res 157: 180-190, 2011. doi:10.1016/j.trsl.2011.01.010.
387. Zinter MS, Spicer A, Orwoll BO, Alkhouli M, Dvorak CC, Calfee CS, Matthay MA, Sapru A. Plasma angiopoietin-2 outperforms other markers of endothelial injury in prognosticating pediatric ARDS mortality. Am J Physiol Lung Cell Mol Physiol 310: L224-L231, 2016. doi:10.1152/ajplung.00336.2015.