Enhancing autophagy with drugs or lung-directed gene therapy reverses the pathological effects of respiratory epithelial cell proteinopathy

Journal of Biological Chemistry

Volumn 290, Issue 50, 2015, Pages 29742-29757

  Hidvegi, Tunda ^a,b   Stolz, Donna B ^a   Alcorn, John F ^a,b   Yousem, Samuel A ^c   Wang, Jieru ^a   Leme, Adriana S ^a   Houghton, A McGarry ^a   Hale, Pamela ^a,b   Ewing, Michael ^a,b   Cai, Houming ^a,b   Garchar, Evelyn Akpadock ^a,b   Pastore, Nunzia ^d   Annunziata, Patrizia ^d   Kaminski, Naftali ^a   Pilewski, Joseph ^a   Shapiro, Steven D ^a   Pak, Stephen C ^a,b   Silverman, Gary A ^a,b   Brunetti Pierri, Nicola ^d,e   Perlmutter, David H ^a,b  

^a Department of Pediatrics ^*  (United States)

^b CHILDREN S HOSPITAL OF PITTSBURGH   (United States)

^c UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^e TELETHON INSTITUTE OF GENETICS AND MEDICINE TIGEM   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CELLS; GENE THERAPY; MAMMALS;

ANIMAL MODEL; AUTOPHAGY; EPITHELIAL CELLS; LUNG FIBROSIS; MISFOLDED PROTEINS; MOUSE MODELS; PATHOLOGICAL EFFECTS; THERAPEUTIC TARGETS;

BIOLOGICAL ORGANS;

ALPHA 1 ANTITRYPSIN; ALPHA 1 ANTITRYPSIN Z; CELL PROTEIN; ELASTASE; PROTEIN ATZ; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR EB; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; AUTOPHAGY; BIOACCUMULATION; CELL INFILTRATION; COLLAGEN METABOLISM; CONTROLLED STUDY; DISORDERS OF AMINO ACID AND PROTEIN METABOLISM; GENE THERAPY; GENE TRANSFER; HISTOPATHOLOGY; HUMAN; HUMAN TISSUE; LUNG EMPHYSEMA; LUNG FIBROSIS; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FOLDING; PROTEIN HOMEOSTASIS; RESPIRATORY EPITHELIAL CELL PROTEINOPATHY; RESPIRATORY EPITHELIUM; RESPIRATORY TRACT DISEASE; SMOKING; ALPHA 1-ANTITRYPSIN DEFICIENCY; ANIMAL; DISEASE MODEL; DRUG EFFECTS; EPITHELIUM CELL; GENETICS; LUNG; PATHOLOGY;

ALPHA 1-ANTITRYPSIN DEFICIENCY; ANIMALS; AUTOPHAGY; DISEASE MODELS, ANIMAL; EPITHELIAL CELLS; GENETIC THERAPY; LUNG; MICE;

EID: 84949648966     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M115.691253     Document Type: Article

References (73)

1. Perlmutter, D. H. (2011) α-1-Antitrypsin deficiency: importance of proteasomal and autophagic degradative pathways in disposal of liver diseaseassociated protein aggregates. Annu. Rev. Med. 62, 333-345
2. Doppler, K., Mittelbronn, M., Lindner, A., and Bornemann, A. (2009) Basement membrane remodeling and segmental fibrosis in sporadic inclusion body myositis. Neuromuscul. Disord. 19, 406-411
3. Bhuiyan, M. S., Pattison, J. S., Osinska, H., James, J., Gulick, J., McLendon, P. M., Hill, J. A., Sadoshima J., and Robbins J. (2013) Enhanced autophagy ameliorates cardiac proteinopathy. J. Clin. Invest. 123, 5284-5297
4. Zhong, Q., Zhou, B., Ann, D. K., Minoo, P., Liu, Y., Banfalvi, A., Krishnaveni, M. S., Dubourd, M., Demaio, L., Willis, B. C., Kim, K. J., duBois, R. M., Crandall, E. D., Beers, M. F., and Borok, Z. (2011) Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein. Am. J. Respir. Cell Mol. Biol. 45, 498-509
5. Lawson, W. E., Cheng, D. S., Degryse, A. L., Tanjore, H., Polosukhin, V. V., Xu, X. C., Newcomb, D. C., Jones, B. R., Roldan, J., Lane, K. B., Morrisey, E. E., Beers, M. F., Yull, F. E., and Blackwell, T. S. (2011) Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. Proc. Natl. Acad. Sci. U.S.A. 108, 10562-10567
6. Bridges, J. P., Wert, S. E., Nogee, L. M., and Weaver, T. E. (2003) Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. J. Biol. Chem. 278, 52739-52746
7. Guttentag, S. H., Akhtar, A., Tao, J. Q., Atochina, E., Rusiniak, M. E., Swank, R. T., and Bates, S. R. (2005) Defective surfactant secretion in a mouse model of Hermansky-Pudlak syndrome. Am. J. Respir. Cell Mol. Biol. 33, 14-21
8. Young, L. R., Gulleman, P. M., Bridges, J. P., Weaver, T. E., Deutsch, G. H., Blackwell, T. S., and McCormack, F. X. (2012) The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky-Pudlak syndrome. Am. J. Respir. Crit. Care Med. 186, 1014-1024
9. Hidvegi, T., Ewing, M., Hale, P., Dippold, C., Beckett, C., Kemp, C., Maurice, N., Mukherjee, A., Goldbach, C., Watkins, S., Michalopoulos, G., and Perlmutter, D. H. (2010) An autophagy-enhancing drug promotes degradation of mutant α1-antitrypsin Z and reduces hepatic fibrosis. Science 329, 229-232
10. Nogalska, A., D'Agostino, C., Terracciano, C., Engel, W. K., and Askanas, V. (2010) Impaired autophagy in sporadic inclusion-body myositis and in endoplasmic reticulum stress-provoked cultured human muscle fibers. Am. J. Pathol. 177, 1377-1387
11. Silverman, E. K., and Sandhaus, R. A. (2009) Clinical practice: α-1-antitrypsin deficiency. N. Engl. J. Med. 360, 2749-2757
12. Kamimoto, T., Shoji, S., Hidvegi, T., Mizushima, N., Umebayashi, K., Perlmutter, D. H., and Yoshimori, T. (2006) Intracellular inclusions containing mutant α1-antitrypsin Z are propagated in the absence of autophagic activity. J. Biol. Chem. 281, 4467-4476
13. Hidvegi, T., Schmidt, B. Z., Hale, P., and Perlmutter, D. H. (2005) Accumulation of mutant α1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and-12, NFκB and BAP31 but not the unfolded protein response. J. Biol. Chem. 280, 39002-33915
14. Hidvegi, T., Mirnics, K., Hale, P., Ewing, M., Beckett, C., and Perlmutter, D. H. (2007) Regulator of G signaling 16 is a marker for the distinct endoplasmic reticulum stress state associated with aggregated mutant α1-antitrypsin Z in the classical form of α1-antitrypsin deficiency. J. Biol. Chem. 282, 27769-27780
15. Li, J., Pak, S. C., O'Reilly, L. P., Benson, J. A., Wang, Y., Hidvegi, T., Hale, P., Dippold, C., Ewing, M., Silverman, G. A., and Perlmutter, D. H. (2014) Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of α-1-antitrypsin deficiency. PLoS ONE 9, e87260
16. Pastore, N., Blomenkamp, K., Annunziata, F., Piccolo, P., Mithbaokar, P., Maria Sepe, R., Vetrini, F., Palmer, D., Ng, P., Polishchuk, E., Iacobacci, S., Polishchuk, R., Teckman, J., Ballabio, A., and Brunetti-Pierri, N. (2013) Gene transfer of master autophagy regulator TFEB results in clearance of toxic protein and corrects hepatic disease in α-1-antitrypsin deficiency. EMBO Mol. Med. 5, 397-412
17. Carlson, J. A., Rogers, B. B., Sifers, R. N., Hawkins, H. K., Finegold, M. J., and Woo, S. L. (1988) Multiple tissues express α 1-antitrypsin in transgenic mice and man. J. Clin. Invest. 82, 26-36
18. Koopman, P., Povey S., and Lovell-Badge, R. H. (1989) Widespread expression of human α1-antitrypsin in transgenic mice revealed by in situ hybridization. Genes Devel. 3, 16-25
19. Wang, D., Haviland, D. L., Burns, A. R., Zsigmond, E., and Wetsel, R. A. (2007) A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells. Proc. Natl. Acad. Sci. U.S.A. 104, 4449-4454
20. Cichy, J., Potempa, J., and Travis, J. (1997) Biosynthesis of α1-proteinase inhibitor by human lung derived epithelial cells. J. Biol. Chem. 272, 8250-8255
21. Hu, C., and Perlmutter, D. H. (2002) Cell-specific involvement of HNF-1β in α1-antitrypsin gene expression in human respiratory epithelial cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 282, L757-L765
22. Perlmutter, D. H., Cole, F. S., Kilbridge, P., Rossing, T. H., and Colten, H. R. (1985) Expression of the α1-proteinase inhibitor gene in human monocytes and macrophages. Proc. Natl. Acad. Sci. U.S.A. 82, 795-799
23. Blackwell, T. S., Tager, A. M., Borok, Z., Moore, B. B., Schwartz, D. A., Anstrom, K. J., Bar-Joseph, Z., Bitterman, P., Blackburn, M. R., Bradford, W., Brown, K. K., Chapman, H. A., Collard, H. R., Cosgrove, G. P., Deterding, R., Doyle, R., Flaherty, K. R., Garcia, C. K., Hagood, J. S., Henke, C. A., Herzog, E., Hogaboam, C. M., Horowitz, J. C., King, T. E., Jr., Loyd, J. E., Lawson, W. E., Marsh, C. B., Noble, P. W., Noth, I., Sheppard, D., Olsson, J., Ortiz, L. A., O'Riordan, T. G., Oury, T. D., Raghu, G., Roman, J., Sime, P. J., Sisson, T. H., Tschumperlin, D., Violette, S. M., Weaver, T. E., Wells, R. G., White, E. S., Kaminski, N., Martinez, F. J., Wynn, T. A., and Thannickal, V. J., and Eu, J. P. (2014) Future directions in idiopathic pulmonary fibrosis research: an NHLBI workshop report. Am. J. Respir Crit. Care Med. 189, 214-222
24. Komatsu, M., Waguri, S., Ueno, T., Iwata, J., Murata, S., Tanida, I., Ezaki, J., Mizushima, N., Ohsumi, Y., Uchiyama, Y., Kominami, E., Tanaka, K., and Chiba, T. (2005) Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169, 425-434
25. Maeda, S., Chang, L., Li, Z. W., Luo, J. L., Leffert, H., and Karin, M. (2003) IKKβ is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFα. Immunity 19, 725-737
26. Nakagawa, T., Zhu, H., Morishima, N., Li, E., Xu, J., Yankner, B. A., and Yuan, J. (2000) Caspase-12 mediates endoplasmic reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 403, 98-103
27. Yue, Z., Jin, S., Yang, C., Levine, A. J., and Heintz, N. (2003) Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. U.S.A. 100, 15077-15082
28. Messier, E. M., Mason, R. J., and Kosmider, B. (2012) Efficient and rapid isolation and purification of mouse alveolar type II epithelial cells. Exp Lung Res. 38, 363-373
29. Mizushima, N., and Yoshimori, T. (2007) How to interpret LC3 immunoblotting. Autophagy 3, 542-545
30. Pociask, D. A., Scheller, E. V., Mandalapu, S., McHugh, K. J., Enelow, R. I., Fattman, C. L., Kolls, J. K., and Alcorn, J. F. (2013) IL-22 is essential for lung epithelial repair following influenza infection. Am. J. Pathol. 182, 1286-1296
31. Brunetti-Pierri, N., Palmer, D. J., Beaudet, A. L., Carey, K. D., Finegold, M., and Ng, P. (2004) Acute toxicity after high-dose systemic injection of helper-dependent adenoviral vectors into nonhuman primates. Hum. Gene Ther. 15, 35-46
32. Palmer, D., and Ng, P. (2003) Improved system for helper-dependent adenoviral vector production. Mol. Ther. 8, 846-852
33. Suzuki, M., Cela, R., Clarke, C., Bertin, T. K., Mouriño, S., and Lee, B. (2010) Large-scale production of high-quality helper-dependent adenoviral vectors using adherent cells in cell factories. Hum. Gene Ther. 21, 120-126
34. Koehler, D. R., Martin, B., Corey, M., Palmer, D., Ng, P., Tanswell, A. K., and Hu, J. (2006) Readministration of helper-dependent adenovirus to mouse lung. Gene Ther. 13, 773-780
35. Shapiro, S. D., Goldstein, N. M., Houghton, A. M., Kobayashi, D. K., Kelley, D., and Belaaouaj, A. (2003) Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice. Am. J. Pathol. 163, 2329-2335
36. Devor, D. C., Bridges, R. J., and Pilewski, J. M. (2000) Pharmacological modulation of ion transport across wild-type and ΔF508 CFTR-expressing human bronchial epithelia. Am. J. Physiol. Cell Physiol. 279, C461-C479
37. Wang, J., Edeen, K., Manzer, R., Chang, Y., Wang, S., Chen, X., Funk, C. J., Cosgrove, G. P., Fang, X., and Mason, R. J. (2007) Differentiated human alveolar epithelial cells and reversibility of their phenotype in vitro. Am. J. Respir. Cell Mol Biol. 36, 661-668
38. Mizushima, N., Yamamoto, A., Matsui, M., Yoshimori, T., and Ohsumi, Y. (2004) In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol. Biol. Cell 15, 1101-1111
39. Qu, X., Yu, J., Bhagat, G., Furuya, N., Hibshoosh, H., Troxel, A., Rosen, J., Eskelinen, E. L., Mizushima, N., Ohsumi, Y., Cattoretti, G., and Levine, B. (2003) Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809-1820
40. Zhou, Z., Song, R., Fattman, C. L., Greenhill, S., Alber, S., Oury, T. D., Choi, A. M., and Morse, D. (2005) Carbon monoxide suppresses bleomycininduced lung fibrosis. Am. J. Pathol. 166, 27-37
41. O'Donnell, D. E., and Fitzpatrick, M. F. (2003) Physiology of interstitial lung disease. In Interstitial Lung Disease (Schwarz, M. I., and King, T. E., eds) 4th Ed., pp. 54-74, BC Decker, Hamilton, Ontario, Canada
42. Fulmer, J. D., Roberts, W. C., von Gal, E. R., and Grystal, R. G. (1977) Small airways in idiopathic pulmonary fibrosis: comparison of morphologic and physiologic observations. J. Clin. Invest. 60, 595-610
43. Lovgren, A. K., Jania, L. A., Hartney, J. M., Parsons, K. K., Audoly, L. P., Fitzgerald, G. A., Tilley, S. L., and Koller, B. H. (2006) COX-2-derived prostacyclin protects against bleomycin-induced pulmonary fibrosis. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L144-LL156
44. Dackor, R. T., Cheng, J., Voltz, J. W., Card, J. W., Ferguson, C. D., Garrett, R. C., Bradbury, J. A., DeGraff, L. M., Lih, F. B., Tomer, K. B., Flake, G. P., Travlos, G. S., Ramsey, R. W., Jr., Edin, M. L., Morgan, D. L., and Zeldin, D. C. (2011) Prostaglandin E2 protects murine lungs from bleomycininduced pulmonary fibrosis and lung dysfunction. Am. J. Physiol. Lung Cell. Mol. Physiol. 301, L645-L655
45. Ding, Q., Cai, G. Q., Hu, M., Yang, Y., Zheng, A., Tang, Q., Gladson, C. L., Hayasaka, H., Wu, H., You, Z., Southern, B. D., Grove, L. M., Rahaman, S. O., Fang, H., and Olman, M. A. (2013) FAK-related non-kinase is a multifunctional negative regulator of pulmonary fibrosis. Am. J. Pathol. 182, 1572-1584
46. Settembre, C., Di Malta, C., Polito, V. A., Garcia Arencibia, M., Vetrini, F., Erdin, S., Erdin, S. U., Huynh, T., Medina, D., Colella, P., Sardiello, M., Rubinsztein, D. C., and Ballabio, A. (2011) TFEB links autophagy to lysosomal biogenesis. Science 332, 1429-1433
47. Tomashefski, J. F., Jr., Crystal, R. G., Wiedemann, H. P., Mascha, E., Stoller, J. K., Alpha 1-Antitrypsin Deficiency Registry Study Group (2004) The bronchopulmonary pathology of anti-1-antitrypsin (AAT) deficiency: findings of the death review committee of the national registry for individuals with severe deficiency of α-1-antitrypsin. Hum. Pathol. 35, 1452-1461
48. King, T. E. (2011) Smoking and subclinical interstitial lung disease. N. Engl. J. Med. 364, 968-970
49. Vlahovic, G., Russell, M. L., Mercer, R. R., and Crapo, J. D. (1999) Cellular and connective tissue changes in alveolar septal walls in emphysema. Am. J. Resp Crit. Care Med. 160, 2086-2092
50. Washko, G. R., Hunninghake, G. M., Fernandez, I. E., Nishino, M., Okajima, Y., Yamashiro, T., Ross, J. C., Estépar, R. S., Lynch, D. A., Brehm, J. M., Andriole, K. P., Diaz, A. A., Khorasani, R., D'Aco, K., Sciurba, F. C., Silverman, E. K., Hatabu, H., and Rosas, I. O., COPDGene Investigators (2011) Lung volumes and emphysema in smokers with interstitial lung abnormalities. N. Engl. J. Med. 364, 897-906
51. Wang, Y., Kuan, P. J., Xing, C., Cronkhite, J. T., Torres, F., Rosenblatt, R. L., DiMaio, J. M., Kinch, L. N., Grishin, N. V., and Garcia, C. K. (2009) Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am. J. Hum. Genet. 84, 52-59
52. Lawson, W. E., Polosukhin, V. V., Stathopoulos, G. T., Zoia, O., Han, W., Lane, K. B., Li, B., Donnelly, E. F., Holburn, G. E., Lewis, K. G., Collins, R. D., Hull, W. M., Glasser, S. W., Whitsett, J. A., and Blackwell, T. S. (2005) Increased and prolonged pulmonary fibrosis in surfactant protein C-deficient mice following intratracheal bleomycin. Am. J. Pathol. 167, 1267-1277
53. Long, O. S., Benson, J. A., Kwak, J. H., Luke, C. J., Gosai, S. J., O'Reilly, L. P., Wang, Y., Li, J., Vetica, A. C., Miedel, M. T., Stolz D. B., Watkins, S. C., Züchner, S., Perlmutter, D. H., Silverman, G. A., and Pak, S. C. (2014) A C. elegans model of human α1-antitrypsin deficiency links components of the RNAi pathway to misfolded protein turnover. Hum. Mol. Genet. 23, 5109-5122
54. DeMaio, L., Buckley, S. T., Krishnaveni, M. S., Flodby, P., Dubourd, M., Banfalvi, A., Xing, Y., Ehrhardt, C., Minoo, P., Zhou, B., Crandall, E. D., and Borok, Z. (2012) Ligand-independent transforming growth factor-β type I receptor signaling mediates type I collagen-induced epithelial mesenchymal transition. J. Pathol. 226, 633-644
55. Tanjore, H., Cheng, D.-S., Degryse, A. L., Zoz, D. F., Abdolrasulnia, R., Lawson, W. E., Blackwell, T. S. (2011) Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress. J. Biol. Chem. 286, 30972-30980
56. Rockey, D. C., Bell, P. D., and Hill, J. A. (2015) Fibrosis: a common pathway to organ injury and failure. N. Engl. J. Med. 372, 1138-1149
57. Puls, F., Goldschmidt, I., Bantel, H., Agne, C., Bröcker, V., Dämmrich, M., Lehmann, U., Berrang, J., Pfister, E. D., Kreipe, H. H., and Baumann, U. (2013) Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease. J Hepatol. 59, 626-630
58. Demeo, D. L., Sandhaus, R. A., Barker, A. F., Brantly, M. L., Eden, E., McElvaney, N. G., Rennard, S., Burchard, E., Stocks, J. M., Stoller, J. K., Strange, C., Turino, G. M., Campbell, E. J., and Silverman, E. K. (2007) Determinants of airflow obstruction in severe α-1-antitrypsin deficiency. Thorax 62, 806-813
59. Wencker, M., Fuhrmann, B., Banik, N., and Konietzko, N., Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (2001) Longitudinal follow-up of patients with α1-protease inhibitor deficiency before or during therapy with IV α1-protease inhibitor. Chest 119, 737-744
60. Dirksen, A., Piitulainen, E., Parr, D. G., Deng, C., Wencker, M., Shaker, S. B., and Stockley, R. A. (2009) Exploring the role of CT densitometry: a randomized study of augmentation therapy in α1-antitrypsin deficiency. Eur. Respir J. 33, 1345-1353
61. Gotzsche, P. C., and Johansen, H. K. (2010) Intravenous α-1-antitrypsin augmentation therapy for treating patients with α-1-antitrypsin deficiency and lung disease. Cochrane Database Syst. Rev. 10.1002/ 14651858.CDOO7851.pub2
62. Tanash, H. A., Riise, G. C., Hansson, L., Nilsson, P. M., and Piitulainen, E.(2011) Survival benefit of lung transplantation in individuals with severe α1-antitrypsin deficiency (PiZZ) and emphysema. J. Heart Lung Transplant 30, 1342-1347
63. Strange, C., Stoller, J. K., Sandhaus, R. A., Dickson, R., and Turino, G. (2006) Results of a survey of patients with α-1-antitrypsin deficiency. Respiration 73, 185-190
64. Christie, J. D., Edwards, L. B., Kucheryavaya, A. Y., Benden, C., Dipchand, A. I., Dobbels, F., Kirk, R., Rahmel, A. O., Stehlik, J., and Hertz, M. I., International Society of Heart and Lung Transplantation (2012) The registry of the international society for heart and lung transplantation: 29th adult lung and heart-lung transplant report-2012. J. Heart Lung Transplant 31, 1073-1086
65. Carey, E. J., Iyer, V. N., Nelson, D. R., Nguyen, J. H., and Krowka, M. J. (2013) Outcomes for recipients of liver transplantation forα-1-antitrypsin deficiency-related cirrhosis. Liver Transpl. 19, 1370-1376
66. Piitulainen, E., Carlson, J., Ohlsson, K., and Sveger, T. (2005) α-1-Antitrypsin deficiency in 26-year-old subjects: lung, liver and protease-protease inhibitor studies. Chest 128, 2076-2081
67. Tafaleng, E. N., Chakraborty, S., Han, B., Hale, P., Wu, W., Soto-Gutierrez, A., Feghali-Bostwick, C. A., Wilson, A. A., Kotton, D. N., Nagaya, M., Strom, S. C., Roy-Chowdhury J., Stolz, D. B., Perlmutter, D. H., and Fox, I. J. (2015) Induced pluripotent stem cells model personalized variations in liver disease due to α1-antitrypsin deficiency. Hepatology 62, 147-157
68. Dickens, J. A., and Lomas, D. A. (2011)Whyhas it been so difficult to prove the efficacy of α-1-antitrypsin replacement therapy? Insights from the study of disease pathogenesis. Drug Des. Devel. Ther. 5, 391-405
69. Elliott, P. R., Bilton, D., and Lomas, D. A. (1998) Lung polymers in Z α1-antitrypsin deficiency-related emphysema. Am. J. Respir. Cell Mol. Biol. 18, 670-674
70. Mahadeva, R., Atkinson, C., Li, Z., Stewart, S., Janciauskiene, S., Kelley, D. G., Parmar, J., Pitman, R., Shapiro, S. D., and Lomas, D. A. (2005) Polymers of Z α1-antitrypsin co-localize with neutrophils in emphysematous alveoli and are chemotactic in vivo. Am. J. Pathol. 166, 377-386
71. Hubbard, R. C., Fells, G., Gadek, J., Pacholok, S., Humes, J., and Crystal, R. G.(1991) Neutrophil accumulation in the lung in α1-antitrypsin deficiency: spontaneous release of leukotriene B4 by alveolar macrophages. J. Clin. Invest. 88, 891-897
72. Woolhouse, I. S., Bayley, D. L., and Stockley, R. A. (2002) Sputum chemotactic activity in chronic obstructive pulmonary disease: effect of α 1)-antitrypsin deficiency and role of leukotriene B(4) and interleukin 8. Thorax 57, 709-714
73. Mulgrew, A. T., Taggart, C. C., Lawless, M. W., Greene, C. M., Brantly, M. L., O'Neill, S. J., and McElvaney, N. G. (2004) Z α1-antitrypsin polymerizes in the lung and acts as a neutrophil chemoattractant. Chest 125, 1952-1957