Quantitative microscopy of the lung: A problem-based approach. Part 2: Stereological parameters and study designs in various diseases of the respiratory tract

American Journal of Physiology - Lung Cellular and Molecular Physiology

Volumn 305, Issue 3, 2013, Pages

  Mühlfeld, Christian ^a,b,c   Ochs, Matthias ^a,b,c  

^a HANNOVER MEDICAL SCHOOL   (Germany)

^b German Center for Lung Research   (Germany)

^c Cluster of Excellence REBIRTH (From Regenerative Biology to Reconstructive Therapy)   (Germany)

Author keywords

Acute lung injury; Asthma; Design based stereology; Diffuse parenchymal lung disease; Emphysema; Pulmonary hypertension

Indexed keywords

2 HYDROXYETHYL METHACRYLATE; MONOCROTALINE; SURFACTANT PROTEIN D; VASCULOTROPIN RECEPTOR 2;

ACUTE LUNG INJURY; AIRWAY REMODELING; APOPTOSIS; ASTHMA; BASEMENT MEMBRANE; BLOOD VESSEL WALL; EMPHYSEMA; EPITHELIUM CELL; EXTRACELLULAR MATRIX; FIBROBLAST; GAS EXCHANGE; HEART RIGHT VENTRICLE FAILURE; HEART RIGHT VENTRICLE HYPERTROPHY; HUMAN; LUNG DISEASE; LUNG EMPHYSEMA; LUNG FIBROSIS; LUNG PARENCHYMA; LUNG VOLUME; MESENCHYME CELL; MICROSCOPY; NONHUMAN; PATHOGENESIS; PATHOPHYSIOLOGY; PHENOTYPE; PRIORITY JOURNAL; PULMONARY HYPERTENSION; QUANTITATIVE MICROSCOPY; RESPIRATORY TRACT DISEASE; REVIEW; SMOKING; STEREOMETRY; THROMBOEMBOLISM; TRACHEOBRONCHIAL TREE; WORKFLOW;

ACUTE LUNG INJURY; ASTHMA; DESIGN-BASED STEREOLOGY; DIFFUSE PARENCHYMAL LUNG DISEASE; EMPHYSEMA; PULMONARY HYPERTENSION;

ACUTE LUNG INJURY; AIRWAY REMODELING; ANIMALS; ASTHMA; EMPHYSEMA; HUMANS; HYPERTENSION, PULMONARY; IMAGING, THREE-DIMENSIONAL; LUNG; LUNG DISEASES; MICE; MICROSCOPY; RATS;

EID: 84881021199     PISSN: 10400605     EISSN: 15221504     Source Type: Journal    
DOI: 10.1152/ajplung.00427.2012     Document Type: Review

References (116)

1. Albertine KH. Histopathology of pulmonary edema and the acute respiratory distress syndrome. In: Pulmonary Edema, edited by Matthay MA, Ingbar DH. New York: Marcel Dekker, pp. 37-83, 1998.
2. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 152: S78-S83, 1995.
3. Avdalovic MV, Putney LF, Schelegle ES, Miller L, Usachenko JL, Tyler NK, Plopper CG, Gershwin LJ, Hyde DM. Vascular remodeling is airway generation-specific in a primate model of chronic asthma. Am J Respir Crit Care Med 174: 1069-1076, 2006.
4. Bachofen M, Weibel ER. Alterations of the gas exchange apparatus in adult respiratory insufficiency associated with septicaemia. Am Rev Respir Dis 116: 589-615, 1977.
5. Baddeley AJ, Gundersen HJ, Cruz-Orive LM. Estimation of surface area from vertical sections. J Microsc 142: 259-276, 1986.
6. Bates JHT, Rincon M, Irvin CG. Animal models of asthma. Am J Physiol Lung Cell Mol Physiol 297: L401-L410, 2009.
7. Bourdin A, Neveu D, Vachier I, Paganin F, Godard P, Chanez P. Specificity of basement membrane thickening in severe asthma. J Allergy Clin Immunol 119: 1367-1374, 2007.
8. Brightling CE, Gupta S, Gonem S, Siddiqui S. Lung damage and airway remodelling in severe asthma. Clin Exp Allergy 42: 638-649, 2011.
9. Burkhardt A. Alveolitis and collapse in the pathogenesis of pulmonary fibrosis. Am Rev Respir Dis 140: 513-524, 1989.
10. Burkhardt A, Cottier H. Cellular events in alveolitis and the evolution of pulmonary fibrosis. Virchows Arch B Cell Pathol Incl Mol Pathol 58: 1-13, 1989.
11. Cavarra E, Bartalesi B, Lucatelli M, Fineschi S, Lunghi B, Gambelli F, Ortiz LA, Martorana PA, Lungarella G. Effects of cigarette smoke in mice with different levels of alpha(1)-proteinase inhibitor and sensitivity to oxidants. Am J Respir Crit Care Med 164: 886-890, 2001.
12. Cruz-Orive LM. Particle number can be estimated using a dissector of unknown thickness: the selector. J Microsc 145: 121-142, 1992.
13. Degryse AL, Tanjore H, Xu XC, Polosukhin VV, Jones BR, McMahon FB, Gleaves LA, Blackwell TS, Lawson WE. Repetitive intratracheal bleomycin models several features of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 299: L442-L452, 2010.
14. Detoraki A, Granata F, Staibano S, Rossi FW, Marone G, Genovese A. Angiogenesis and lymphangiogenesis in bronchial asthma. Allergy 65: 946-958, 2010.
15. Dorph-Petersen KA, Nyengaard JR, Gundersen HJ. Tissue shrinkage and unbiased stereological estimation of particle number and size. J Microsc 204: 232-246, 2001.
16. Dreyer N, Mühlfeld C, Fehrenbach A, Pech T, von Berg S, Nagib R, Richter J, Wittwer T, Wahlers T, Ochs M. Exogenous surfactant application in a rat lung ischemia reperfusion injury model: effects on edema formation and alveolar type II cells. Respir Res 9: 5, 2008.
17. Durani SR, Viswanathan RK, Busse WW. What effect does asthma treatment have on airway remodeling? Current perspectives. J Allergy Clin Immunol 128: 439-448, 2011.
18. Evans MJ, Van Winkle LS, Fanucchi MV, Plopper CG. The attenuated fibroblast sheath of the respiratory tract epithelial-mesenchymal trophic unit. Am J Respir Cell Mol Biol 21: 655-657, 1999.
19. Fehrenbach A, Ochs M, Warnecke T, Wahlers T, Wittwer T, Schmiedl A, Elki S, Meyer D, Richter J, Fehrenbach H. Beneficial effect of lung transplantation is related to ultrastructural integrity of tubular myelin after experimental ischemia and reperfusion. Am J Respir Crit Care Med 161: 2058-2065, 2000.
20. Fehrenbach A, Fehrenbach H, Wittwer T, Ochs M, Wahlers T, Richter J. Evaluation of pulmonary edema: stereological versus gravimetrical analysis. Eur Surg Res 33: 270-278, 2001.
21. Fehrenbach H. Animal models of pulmonary emphysema: a stereologist's perspective. Eur Respir Rev 15: 136-147, 2006.
22. Fehrenbach H, Ochs M. Studying lung ultrastructure. In: Methods in Pulmonary Research, edited by Uhlig S, Taylor AE. Basel: Birkhäuser, 1998, pp. 429-454
23. Fehrenbach H, Schepelmann D, Albes JM, Bando T, Fischer F, Fehrenbach A, Stolte N, Wahlers T, Richter J. Pulmonary ischemia/reperfusion injury: a quantitative study of structure and function in isolated heart-lungs of the rat. Anat Rec 255: 84-89, 1999.
24. Ferrando RE, Nyengaard JR, Hays SR, Fahy JV, Woodruff PG. Applying stereology to measure thickness of the basement membrane zone in bronchial biopsy specimens. J Allergy Clin Immunol 112: 1243-1245, 2003.
25. Gomez-Arroyo J, Saleem SJ, Mizuno S, Syed AA, Bogaard HJ, Abbate A, Taraseviciene-Stewart L, Sung Y, Kraskauskas D, Farkas D, Conrad DH, Nicolls MR, Voelkel NF. A brief overview of mouse models of pulmonary arterial hypertension: problems and prospects. Am J Physiol Lung Cell Mol Physiol 302: L977-L991, 2012.
26. Gross TJ, Hunninghake GW. Idiopathic pulmonary fibrosis. N Engl J Med 345: 517-525, 2001.
27. Gundersen HJ. Stereology of arbitrary particles. A review of unbiased number and size estimators and the presentation of some new ones, in memory of William R Thompson. J Microsc 143: 3-45, 1986.
28. Gundersen HJ. The nucleator. J Microsc 151: 3-21, 1988.
29. Gundersen HJ. The smooth fractionator. J Microsc 207: 191-210, 2002.
30. Günther A, Schmidt R, Nix F, Yabut-Perez M, Guth C, Rosseau S, Siebert C, Grimminger F, Morr H, Velcovsky HG, Seeger W. Surfactant abnormalities in idiopathic pulmonary fibrosis, hypersensitivity pneumonitis and sarcoidosis. Eur Respir J 14: 565-573, 1999.
31. Günther A, Korfei M, Mahavadi P, von der Beck D, Ruppert C, Markart P. Unravelling the progressive pathophysiology of idiopathic pulmonary fibrosis. Eur Respir Rev 21: 152-160, 2012.
32. Hanumegowda C, Farkas L, Kolb M. Angiogenesis in pulmonary fibrosis. Too much or not enough? Chest 142: 200-207, 2012.
33. Holgate ST, Davies DE, Lackie PM, Wilson SJ, Puddicombe SM, Lordan JL. Epithelial-mesenchymal interactions in the pathogenesis of asthma. J Allergy Clin Immunol 105: 193-204, 2000.
34. Holgate ST. Pathogenesis of asthma. Clin Exp Allergy 38: 872-897, 2008.
35. Horiuchi T, Ikegami M, Cherniack RM, Mason RJ. Increased surface tension of the lung and surfactant in bleomycin-induced pulmonary fibrosis in rats. Am J Respir Crit Care Med 154: 1002-1005, 1996.
36. Howell K, Preston RJ, McLoughlin P. Chronic hypoxia causes angiogenesis in addition to remodelling in the adult rat pulmonary circulation. J Physiol 547: 133-145, 2003.
37. Hsia CCW, Hyde DM, Ochs M, Weibel ER, ATS/ERS. Joint Task Force on Quantitative Assessment of Lung Structure. An official research policy statement of the American Thoracic Society/European Respiratory Society: standards for quantitative assessment of lung structure. Am J Respir Crit Care Med 181: 394-418, 2010.
38. Hyde DM, Tyler NK, Putney LF, Singh P, Gundersen HJ. Total number and mean size of alveoli in mammalian lung estimated using fractionator sampling and unbiased estimates of the Euler characteristic of alveolar openings. Anat Rec A Discov Mol Cell Evol Biol 277: 216-226, 2004.
39. Hyde DM, Miller LA, Schelegle ES, Fanucchi MV, Van Winkle LS, Tyler NK, Avdalovic MV, Evans MJ, Kajekar R, Buckpitt AR, Pinkerton KE, Joad JP, Gershwin LJ, Wu R, Plopper CG. Asthma: a comparison of animal models using stereological methods. Eur Respir Rev 15: 122-135, 2006.
40. Hyde DM, Hamid Q, Irvin CG. Anatomy, pathology, and physiology of the tracheobronchial tree: Emphasis on the distal airways. J Allergy Clin Immunol 124: S72-S77, 2009.
41. Jeffery P, Holgate S, Wenzel S. on behalf of the endobronchial biopsy workshop authors. Methods for the assessment of endobronchial biopsies in clinical research Application to studies of pathogenesis and the effects of treatment. Am J Respir Crit Care Med 168: S1-S17, 2003.
42. Jensen EB, Gundersen HJ, Osterby R. Determination of membrane thickness distribution from orthogonal intercepts. J Microsc 115: 19-33, 1979.
43. Jung A, Allen L, Nyengaard JR, Gundersen HJ, Richter J, Hawgood S, Ochs M. Design-based stereological analysis of the lung parenchymal architecture and alveolar type II cells in surfactant protein A and D double deficient mice. Anat Rec A Discov Mol Cell Evol Biol 286: 885-890, 2005.
44. Katzenstein AL, Bloor CM, Liebow AA. Diffuse alveolar damage-the role of oxygen, shock and related factors. Am J Pathol 85: 210-222, 1976
45. Katzenstein AL. Pathogenesis of "fibrosis" in the interstitial pneumonia: an electron microscopic study. Hum Pathol 16: 1015-1024, 1985.
46. Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual interstitial pneumonia and distinction from other fibrosing interstitial lung diseases. Hum Pathol 39: 1275-1294, 2008.
47. Kerzel S, Rogosch T, Wagner J, Preisser K, Yildirim AÖ, Fehrenbach H, Garn H, Maier RF, Schroeder HW Jr, Zemlin M. A single DH gene segment is sufficient for the establishment of an asthma phenotype in a murine model of allergic airway inflammation. Int Arch Allergy Immunol 156: 247-258, 2011.
48. Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, Frank JA, Brumwell AN, Wheeler SE, Kreidberg JA, Chapman HA. Epithelial cell α3β1integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest 119: 213-224, 2009.
49. King TE Jr, Schwarz MI, Brown K, Tooze JA. Idiopathic pulmonary fibrosis: relationship between histopathologic features and mortality. Am J Respir Crit Care Med 164: 1025-1032, 2001.
50. Knudsen L, Ochs M. Microscopy-based quantitative analysis of lung structure: Application in diagnosis. Expert Opin Med Diag 5: 319-331, 2011.
51. Knudsen L, Weibel ER, Gundersen HJ, Weinstein FV, Ochs M. Assessment of air space size characteristics by intercept (chord) measurement: an accurate and efficient stereological approach. J Appl Physiol 108: 412-421, 2010.
52. Knudsen L, Waizy H, Fehrenbach H, Richter J, Wahlers T, Wittwer T, Ochs M. Ultrastructural changes of the intracellular surfactant pool in a rat model of lung transplantation-related events. Respir Res 12: 79, 2011.
53. Korfei M, Ruppert C, Mahavadi P, Henneke Markart P I, Koch M, Lang G, Fink L, Bohle RM, Seeger W, Weaver TE, Guenther A. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 178: 838-846, 2008.
54. Lambrecht BN, Hamad H. The airway epithelium in asthma. Nat Med 18: 684-692, 2012.
55. Lanzetti M, da Costa CA, Nesi RT, Barroso MV, Martins V, Victoni T, Lagente V, Pires KMP, Rodriguez e Silva PM, Resende AC, Porto LC, Benjamin CF, Valenca SS. Oxidative stress and nitrosative stress are involved in different stages of proteolytic pulmonary emphysema. Free Radic Biol Med 53: 1993-2001, 2012.
56. Lee CG, Link H, Baluk P, Homer RJ, Chapoval S, Bhandari V, Kang MJ, Cohn L, Lim YK, McDonald DM, Elias JA. Vascular endothelial growth factor (VEGF) induces remodelling and enhances T(H)2-mediated sensitization and inflammation in the lung. Nat Med 10: 1095-1103, 2004.
57. Liesker JJW, Ten Hacken NH, Zeinstra-Smith M, Rutgers SR, Postma DS, Timens W. Reticular basement membrane in asthma and COPD: Similar thickness, yet different composition. Int J COPD 4: 127-135, 2009.
58. March TH, Barr EB, Finch GL, Hahn FF, Hobbs CH, Ménache MG, Nikula KJ. Cigarette smoke exposure produces more evidence of emphysema in B6C3F1 than in F344 rats. Toxicol Sci 51: 289-299, 1999.
59. Massaro GD, Massaro D. Retinoic acid treatment abrogates elastaseinduced pulmonary emphysema in rats. Nat Med 3: 675-677, 1997.
60. Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 295: L379-L399, 2008.
61. McParland BE, Macklem PT, Pare PD. Airway wall remodeling: friend or foe? J Appl Physiol 95: 426-434, 2003.
62. Moore BB, Hogaboam CM. Murine models of pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 294: L152-L160, 2008.
63. Mühlfeld C. Quantitative morphology of the vascularisation of organs: a stereological approach illustrated using the cardiac circulation. Ann Anat. In press.
64. Mühlfeld C, Müller K, Pallesen LP, Sandhaus T, Madershahian N, Richter J, Wahlers T, Wittwer T, Ochs M. Impact of preservation solution on the extent of blood-air barrier damage and edema formation in experimental lung transplantation. Anat Rec 290: 491-500, 2007.
65. Mühlfeld C, Liakopoulos OJ, Schaefer IM, Schöndube FA, Richter J, Dörge H. Methylprednisolone fails to preserve pulmonary surfactant and blood-air barrier integrity in a porcine cardiopulmonary bypass model. J Surg Res 146: 57-65, 2008.
66. Mühlfeld C, Schaefer IM, Becker L, Bussinger C, Vollroth M, Bosch A, Nagib R, Madershahian N, Richter J, Wahlers T, Wittwer T, Ochs M. Pre-ischaemic exogenous surfactant reduces pulmonary injury in rat ischaemia/reperfusion. Eur Respir J 33: 625-633, 2009.
67. Mühlfeld C, Becker L, Bussinger C, Vollroth M, Nagib R, Schaefer IM, Knudsen L, Richter J, Madershahian N, Wahlers T, Wittwer T, Ochs M. Exogenous surfactant in ischemia/reperfusion: effects on endogenous surfactant pools. J Heart Lung Transplant 29: 327-334, 2010.
68. Mühlfeld C, Weibel ER, Hahn U, Kummer W, Nyengaard JR, Ochs M. Is length an appropriate estimator to characterize pulmonary alveolar capillaries? A critical evaluation in the human lung. Anat Rec 293: 1270-1275, 2010.
69. Mühlfeld C, Knudsen L, Ochs M. Stereology and morphometry of lung tissue. Methods Mol Biol 931: 367-390, 2013.
70. Nyengaard JR, Gundersen HJG. The isector: a simple and direct method for generating isotropic, uniform random sections from small specimens. J Microsc 165: 427-431, 1992.
71. Nyengaard JR Number and dimensions of rat glomerular capillaries in normal development and after nephrectomy. Kidney Int 43: 1049-1057, 1993.
72. Ochs M. Stereological analysis of acute lung injury. Eur Respir Rev 15: 115-121, 2006.
73. Ochs M, Mühlfeld C. Quantitative microscopy of the lung-a problembased approach. Part 1: Basic principles of lung stereology. Am J Physiol Lung Cell Mol Physiol 305: L15-L22, 2013.
74. Ochs M, Nenadic I, Fehrenbach A, Albes JM, Wahlers T, Richter J, Fehrenbach H. Ultrastructural alterations in intraalveolar surfactant subtypes after experimental ischemia and reperfusion. Am J Respir Crit Care Med 160: 718-724, 1999.
75. Ochs M, Fehrenbach H, Nenadic I, Bando T, Fehrenbach A, Schepelmann D, Albes JM, Wahlers T, Richter J. Preservation of intraalveolar surfactant in a rat lung ischaemia/reperfusion injury model. Eur Respir J 15: 526-531, 2000.
76. Ochs M, Nyengaard JR, Jung A, Knudsen L, Voigt M, Wahlers T, Richter J, Gundersen HJ. The number of alveoli in the human lung. Am J Respir Crit Care Med 169: 120-124, 2004.
77. Ochs M, Knudsen L, Allen L, Stumbaugh A, Levitt S, Nyengaard JR, Hawgood S. GM-CSF mediates alveolar epithelial type II cell changes, but not emphysema-like pathology, in SP-D-deficient mice. Am J Physiol Lung Cell Mol Physiol 287: L1333-L1341, 2004.
78. Parameswaran H, Majumdar A, Ito S, Alencar AM, Suki B. Quantitative characterization of airspace enlargement in emphysema. J Appl Physiol 100: 186-193, 2006.
79. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY, Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest 114: 438-446, 2004.
80. Rabinovitch M. Pathobiology of pulmonary hypertension. Annu Rev Pathol 2: 369-399, 2007.
81. Reader JR, Tepper JS, Schelegle ES, Aldrich MC, Putney LF, Pfeiffer JW, Hyde DM. Pathogenesis of mucous cell metaplasia in a murine asthma model. Am J Pathol 162: 2069-2078, 2003.
82. Regamey N, Ochs M, Hilliard TN, Mühlfeld C, Cornish N, Fleming L, Saglani S, Alton EW, Bush A, Jeffery PK, Davies JC. Increased airway smooth muscle mass in children with asthma, cystic fibrosis, and non-cystic fibrosis bronchiectasis. Am J Respir Crit Care Med 177: 837-843, 2008.
83. Richter A, Yeager ME, Zaiman A, Cool CD, Voelkel NF, Tuder RM. Impaired transforming growth factor-_ signalling in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 170: 1340-1348, 2004.
84. Riede UN, Joachim H, Hassenstein J, Costabel U, Sandritter W, Augustin P, Mittermayer C. The pulmonary air blood barrier of human shock lungs (a clinical, ultrastructural and morphometric study). Pathol Res Pract 162: 41-72, 1978.
85. Roche WR, Beasley R, Williams JH, Holgate ST. Subepithelial fibrosis in the bronchi of asthmatics. Lancet 1: 520-524, 1989.
86. Ryan J, Bloch K, Archer SL. Rodent models of pulmonary hypertension: harmonisation with the world health organization's categorization of human PH. Int J Clin Pract Suppl 172: 15-34, 2011.
87. Scherle W. A simple method for volumetry of organs in quantitative stereology. Mikroskopie 26, 57-60, 1970.
88. Schermuly RT, Ghofrani HA, Wilkins MR, Grimminger F. Mechanisms of diseases: Pulmonary arterial hypertension. Nat Rev Cardiol 8: 443-455, 2011.
89. Schmiedl A, Lempa T, Hoymann HG, Rittinghausen S, Popa D, Tschernig T, Fehrenbach H, Pabst R, Hoeper MM, Hohlfeld JM. Elastase-induced lung emphysema in rats is not reduced by hematopoietic growth factors when applied preventionally. Virchows Arch 452: 675-688, 2008.
90. Scotton CJ, Chambers RC. Bleomycin revisited: towards a more representative model of IPF? Am J Physiol Lung Cell Mol Physiol 299: L439-L441, 2010.
91. Shahana S, Björnsson E, Ludviksdottir D, Janson C, Nettelbladt O, Venge P, Roomans GM, BHR. Group Ultrastructure of bronchial biopsies from patients with allergic and non-allergic asthma. Respir Med 99: 429-443, 2005.
92. Shebani E, Shahana S, Janson C, Roomans GM. Attachment of columnar airway epithelial cells in asthma. Tissue Cell 37: 145-152, 2005.
93. Siddiqui S, Mistry V, Doe C, Roach K, Morgan A, Wardlaw A, Pavord I, Bradding P, Brightling C. Airway hyperresponsiveness is dissociated from airway wall structural remodelling. J Allergy Clin Immunol 122: 335-341, 2008.
94. Sisson TH, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A, Dave A, Engelhardt JF, Liu X, White ES, Thannickal VJ, Moore BB, Christensen PJ, Simon RH. Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med 181: 254-263, 2010.
95. Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, Jessup M, Grizzle WE, Aldred MA, Cool CD, Tuder RM. Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 186: 261-272, 2012.
96. Steele MP, Schwartz DA. Molecular mechanisms in progressive idiopathic pulmonary fibrosis. Annu Rev Med 64: 12.1-12.12, 2013.
97. Stenmark KR, Meyrick B, Galie N, Mooi WJ, McMurtry IF. Animal models of pulmonary arterial hypertension: the hope for etiological discovery and pharmacological cure. Am J Physiol Lung Cell Mol Physiol 297: L1013-L1032, 2009.
98. Sullivan P, Stephens D, Ansari T, Costello J, Jeffery P. Variation in the measurements of basement membrane thickness and inflammatory cell number in bronchial biopsies. Eur Respir J 12: 811-815, 1998.
99. Tang Y, Nyengaard JR, Andersen JB, Baandrup U, Gundersen HJ. The application of stereological methods for estimating structural parameters in the human heart. Anat Rec 292: 1630-1647, 2009.
100. Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon G, Waltenberger J, Voelkel NF, Tuder RM. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe hypertension. FASEB J 15: 427-438, 2001.
101. Task Force for Diagnosis, and Treatment of Pulmonary Hypertension of European Society of Cardiology (ESC), European Respiratory Society (ERS), International Society of Heart and Lung Transplantation (ISHLT), Galiè N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G. Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 34: 1219-1263, 2009.
102. Tomashefski JF Jr Pulmonary pathology of acute respiratory distress syndrome. Clin Chest Med 21: 435-466, 2000.
103. Tomashefski JF Jr Pulmonary pathology of the acute respiratory distress syndrome. Diffuse alveolar damage. In: Acute Respiratory Distress Syndrome, edited by Matthay MA. New York: Marcel Dekker, 2003, pp. 75-114.
104. Tuder RM. Pathology of pulmonary arterial hypertension. Semin Respir Crit Care Med 30: 376-385, 2009.
105. Tuder RM, Abman SH, Braun T, Capron F, Stevens T, Thistlethwaite PA, Haworth SG. Development and pathology of pulmonary hypertension. J Am Coll Cardiol 54: S3-S9, 2009.
106. Valenca SS, da Hora K, Castro P, Morales VG, Carvalho L, Cristovao L, Porto MS. Emphysema and metalloelastase expression in mouse lung induced by cigarette smoke. Toxicol Pathol 32: 351-356, 2004.
107. Vasilescu DM, Gao Z, Saha PK, Yin L, Wang G, Haefeli-Bleuer B, Ochs M, Weibel ER, Hoffman EA. Assessment of morphometry of pulmonary acini in mouse lungs by non-destructive imaging using multiscale microcomputed tomography. Proc Natl Acad Sci USA 109: 17105-17110, 2012.
108. Vedel-Jensen EB, Gundersen HJG. The rotator. J Microsc 170: 35-44, 1993.
109. Weibel ER. Morphological quantitation of emphysema: a debate. J Appl Physiol 100: 1419-1420, 2006.
110. Weibel ER, Hsia CC, Ochs M. How much is there really? Why stereology is essential in lung morphometry. J Appl Physiol 102: 459-467, 2007.
111. Wiebe BM, Burton CM, Milman N, Iversen M, Andersen CB. Morphometric examination of native lungs in human lung allograft recipients. APMIS 114: 795-804, 2006.
112. Wilkins MR. Pulmonary hypertension: the science behind the disease spectrum. Eur Respir Rev 21: 19-26, 2012.
113. Woodruff PG, Innes AL. Quantitative morphology using bronchial biopsies. Eur Respir Rev 15: 157-161, 2006.
114. Wygrecka M, Kwapiszewska G, Jablonska E, von Gerlach S, Henneke I, Zakrzewicz D, Guenther A, Preissner KT, Markart P. Role of protease-activated receptor-2 in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 183: 1703-1714, 2011.
115. Yan X, Polo Carbayo JJ, Weibel ER, Hsia CC. Variation of lung volume after fixation when measured by immersion of Cavalieri method. Am J Lung Cell Mol Physiol 284, L242-L245, 2003.
116. Yildirim AÖ, Muyal V, John G, Müller B, Seifart C, Kasper M, Fehrenbach H. Palifermin induces alveolar maintenance programs in emphysematous mice. Am J Respir Crit Care Med 181: 705-717, 2010.