Enolase 1 (ENO1) and protein disulfide-isomerase associated 3 (PDIA3) regulate Wnt/β-catenin-driven trans-differentiation of murine alveolar epithelial cells

DMM Disease Models and Mechanisms

Volumn 8, Issue 8, 2015, Pages 877-890

  Mutze, Kathrin ^a,b   Vierkotten, Sarah ^a,b   Milosevic, Jadranka ^c   Eickelberg, Oliver ^a,b   Königshoff, Melanie ^a,b  

^a LUDWIG MAXIMILIANS UNIVERSITY   (Germany)

^b German Center for Lung Research   (Germany)

^c UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

Author keywords

Alveolar epithelial cells; Beta catenin; Differentiation; Fibrosis; Lung injury and repair; Wnt pathway

Indexed keywords

ADVANCED GLYCATION END PRODUCT; ADVANCED GLYCOSYLATION END PRODUCT SPECIFIC RECEPTOR; BETA CATENIN; BLEOMYCIN; CARBONYL REDUCTASE; CARBONYL REDUCTASE 2; CYTOPLASM PROTEIN; DISHEVELLED SEGMENT POLARITY PROTEIN 3; ENOLASE; ENOLASE 1; FRIZZLED PROTEIN; GLYCOGEN SYNTHASE KINASE 3; PODOPLANIN; PROTEIN DISULFIDE ISOMERASE; PROTEIN DISULFIDE ISOMERASE ASSOCIATED 3; SMALL INTERFERING RNA; SURFACTANT PROTEIN C; TIGHT JUNCTION PROTEIN; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR FORKHEAD BOX M1; UNCLASSIFIED DRUG; WNT PROTEIN; ALCOHOL DEHYDROGENASE; BIOLOGICAL MARKER; CBR2 PROTEIN, MOUSE; ENO1 PROTEIN, MOUSE; PDIA3 PROTEIN, MOUSE;

ANIMAL CELL; ARTICLE; CELL CULTURE; CELL STRUCTURE; CELL TRANSDIFFERENTIATION; CELL VIABILITY; CONTROLLED STUDY; FEMALE; GENE SILENCING; IMMUNOBLOTTING; IN VITRO STUDY; IN VIVO STUDY; LUNG ALVEOLUS EPITHELIUM CELL; LUNG FIBROSIS; LUNG INJURY; MASS SPECTROMETRY; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; PROTEOMICS; REGULATORY MECHANISM; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SIGNAL TRANSDUCTION; STABLE EXPRESSION; WOUND HEALING; ANIMAL; C57BL MOUSE; CELL LINE; CHEMICALLY INDUCED; CYTOLOGY; METABOLISM; PATHOLOGY; TWO DIMENSIONAL GEL ELECTROPHORESIS; WNT SIGNALING PATHWAY;

MURINAE; MUS;

ALCOHOL OXIDOREDUCTASES; ALVEOLAR EPITHELIAL CELLS; ANIMALS; BETA CATENIN; BIOMARKERS; BLEOMYCIN; CELL LINE; CELL TRANSDIFFERENTIATION; ELECTROPHORESIS, GEL, TWO-DIMENSIONAL; FEMALE; GENE KNOCKDOWN TECHNIQUES; LUNG INJURY; MICE, INBRED C57BL; PHOSPHOPYRUVATE HYDRATASE; PROTEIN DISULFIDE-ISOMERASES; PROTEOMICS; RNA, SMALL INTERFERING; WNT SIGNALING PATHWAY;

EID: 84939524556     PISSN: 17548403     EISSN: 17548411     Source Type: Journal    
DOI: 10.1242/dmm.019117     Document Type: Article

References (72)

1. Adamson, I. Y. and Bowden, D. H. (1974). The type 2 cell as progenitor of alveolar epithelial regeneration. A cytodynamic study in mice after exposure to oxygen. Lab. Invest. 30, 35-42.
2. Akhmetshina, A. , Palumbo, K. , Dees, C. , Bergmann, C. , Venalis, P. , Zerr, P. , Horn, A. , Kireva, T. , Beyer, C. , Zwerina, J. et al. (2012). Activation of canonical wnt signalling is required for TGF-beta-mediated fibrosis. Nat. Commun. 3, 735.
3. Anathy, V. , Roberson, E. , Cunniff, B. , Nolin, J. D. , Hoffman, S. , Spiess, P. , Guala, A. S. , Lahue, K. G. , Goldman, D. , Flemer, S. et al. (2012). Oxidative processing of latent fas in the endoplasmic reticulum controls the strength of apoptosis. Mol. Cell. Biol. 32, 3464-3478.
4. Aumiller, V. , Balsara, N. , Wilhelm, J. , Günther, A. and Königshoff, M. (2013). Wnt/beta-catenin signaling induces IL-1beta expression by alveolar epithelial cells in pulmonary fibrosis. Am. J. Respir. Cell Mol. Biol. 49, 96-104.
5. Baarsma, H. A. , Königshoff, M. and Gosens, R. (2013). The WNT signaling pathway from ligand secretion to gene transcription: Molecular mechanisms and pharmacological targets. Pharmacol. Ther. 138, 66-83.
6. Barkauskas, C. E. , Cronce, M. J. , Rackley, C. R. , Bowie, E. J. , Keene, D. R. , Stripp, B. R. , Randell, S. H. , Noble, P. W. and Hogan, B. L. M. (2013). Type 2 alveolar cells are stem cells in adult lung. J. Clin. Invest. 123, 3025-3036.
7. Barnes, P. J. (2014). Cellular and molecular mechanisms of chronic obstructive pulmonary disease. Clin. Chest Med. 35, 71-86.
8. Beers, M. F. and Morrisey, E. E. (2011). The three R's of lung health and disease: Repair, remodeling, and regeneration. J. Clin. Invest. 121, 2065-2073.
9. Bhaskaran, M. , Kolliputi, N. , Wang, Y. , Gou, D. , Chintagari, N. R. and Liu, L. (2007). Trans-differentiation of alveolar epithelial type II cells to type I cells involves autocrine signaling by transforming growth factor beta 1 through the smad pathway. J. Biol. Chem. 282, 3968-3976.
10. Borok, Z. , Danto, S. I. , Zabski, S. M. and Crandall, E. D. (1994). Defined medium for primary culture de novo of adult rat alveolar epithelial cells. In Vitro Cell. Dev. Biol. Anim. 30A, 99-104.
11. Borok, Z. , Danto, S. I. , Lubman, R. L. , Cao, Y. , Williams, M. C. and Crandall, E. D. (1998). Modulation of t1alpha expression with alveolar epithelial cell phenotype in vitro. Am. J. Physiol. 275, L155-L164.
12. Butler, J. P. , Loring, S. H. , Patz, S. , Tsuda, A. , Yablonskiy, D. A. and Mentzer, S. J. (2012). Evidence for adult lung growth in humans. N. Engl. J. Med. 367, 244-247.
13. Camelo, A. , Dunmore, R. , Sleeman, M. A. and Clarke, D. L. (2014). The epithelium in idiopathic pulmonary fibrosis: Breaking the barrier. Front. Pharmacol. 4, 173.
14. Chapman, H. A. , Li, X. , Alexander, J. P. , Brumwell, A. , Lorizio, W. , Tan, K. , Sonnenberg, A. , Wei, Y. and Vu, T. H. (2011). Integrin alpha6beta4 identifies an adult distal lung epithelial population with regenerative potential in mice. J. Clin. Invest. 121, 2855-2862.
15. Chilosi, M. , Poletti, V. , Zamò, A. , Lestani, M. , Montagna, L. , Piccoli, P. , Pedron, S. , Bertaso, M. , Scarpa, A. , Murer, B. et al. (2003). Aberrant wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am. J. Pathol. 162, 1495-1502.
16. Corti, M. , Brody, A. R. and Harrison, J. H. (1996). Isolation and primary culture of murine alveolar type II cells. Am. J. Respir. Cell Mol. Biol. 14, 309-315.
17. Crosby, L. M. and Waters, C. M. (2010). Epithelial repair mechanisms in the lung. Am. J. Physiol. Lung Cell. Mol. Physiol. 298, L715-L731.
18. DeMaio, L. , Tseng, W. , Balverde, Z. , Alvarez, J. R. , Kim, K.-J. , Kelley, D. G. , Senior, R. M. , Crandall, E. D. and Borok, Z. (2009). Characterization of mouse alveolar epithelial cell monolayers. Am. J. Physiol. Lung Cell. Mol. Physiol. 296, L1051-L1058.
19. Desai, T. J. , Brownfield, D. G. and Krasnow, M. A. (2014). Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 507, 190-194.
20. Díaz-Ramos, A. , Roig-Borrellas, A. , García-Melero, A. and López-Alemany, R. (2012). Alpha-enolase, a multifunctional protein: Its role on pathophysiological situations. J. Biomed. Biotechnol. 2012, 156795.
21. Dihazi, H. , Dihazi, G. H. , Bibi, A. , Eltoweissy, M. , Mueller, C. A. , Asif, A. R. , Rubel, D. , Vasko, R. and Mueller, G. A. (2013). Secretion of erp57 is important for extracellular matrix accumulation and progression of renal fibrosis, and is an early sign of disease onset. J. Cell Sci. 126, 3649-3663.
22. Dobbs, L. G. , Johnson, M. D. , Vanderbilt, J. , Allen, L. and Gonzalez, R. (2010). The great big alveolar TI cell: Evolving concepts and paradigms. Cell. Physiol. Biochem. 25, 55-62.
23. Ebert, B. , Kisiela, M. and Maser, E. (2015). Human dcxr -another 'moonlighting protein' involved in sugar metabolism, carbonyl detoxification, cell adhesion and male fertility? Biol. Rev. Camb. Philos. Soc. 90, 254-278.
24. Fehrenbach, H. (2001). Alveolar epithelial type II cell: Defender of the alveolus revisited. Respir. Res. 2, 33-46.
25. Fernandez, I. E. and Eickelberg, O. (2012). New cellular and molecular mechanisms of lung injury and fibrosis in idiopathic pulmonary fibrosis. Lancet 380, 680-688.
26. Flozak, A. S. , Lam, A. P. , Russell, S. , Jain, M. , Peled, O. N. , Sheppard, K. A. , Beri, R. , Mutlu, G. M. , Budinger, G. R. S. and Gottardi, C. J. (2010). Betacatenin/ t-cell factor signaling is activated during lung injury and promotes the survival and migration of alveolar epithelial cells. J. Biol. Chem. 285, 3157-3167.
27. Fujino, N. , Kubo, H. , Ota, C. , Suzuki, T. , Suzuki, S. , Yamada, M. , Takahashi, T. , He, M. , Suzuki, T. , Kondo, T. et al. (2012). A novel method for isolating individual cellular components fromthe adult human distal lung. Am. J. Respir. Cell Mol. Biol. 46, 422-430.
28. Ghaedi, M. , Mendez, J. J. , Bove, P. F. , Sivarapatna, A. , Raredon, M. S. B. and Niklason, L. E. (2014). Alveolar epithelial differentiation of human induced pluripotent stem cells in a rotating bioreactor. Biomaterials 35, 699-710.
29. Ghosh, M. C. , Gorantla, V. , Makena, P. S. , Luellen, C. , Sinclair, S. E. , Schwingshackl, A. and Waters, C. M. (2013). Insulin-like growth factor-i stimulates differentiation of ATII cells to ATI-like cells through activation of wnt5a. Am. J. Physiol. Lung Cell. Mol. Physiol. 305, L222-L228.
30. Gonzalez, R. F. , Allen, L. and Dobbs, L. G. (2009). Rat alveolar type I cells proliferate, express OCT-4, and exhibit phenotypic plasticity in vitro. Am. J. Physiol. Lung Cell. Mol. Physiol. 297, L1045-L1055.
31. Halliday, H. L. (2008). Surfactants: Past, present and future. J. Perinatol. 28 Suppl. 1, S47-S56.
32. Henderson, W. R. Jr, Chi, E. Y. , Ye, X. , Nguyen, C. , Tien, Y.-T. , Zhou, B. , Borok, Z. , Knight, D. A. and Kahn, M. (2010). Inhibition of Wnt/beta-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis. Proc. Natl. Acad. Sci. USA 107, 14309-14314.
33. Hogan, B. L. M. , Barkauskas, C. E. , Chapman, H. A. , Epstein, J. A. , Jain, R. , Hsia, C. C. W. , Niklason, L. , Calle, E. , Le, A. , Randell, S. H. et al. (2014). Repair and regeneration of the respiratory system: Complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15, 123-138.
34. Honma, M. , Minami-Hori, M. , Takahashi, H. and Iizuka, H. (2012). Podoplanin expression in wound and hyperproliferative psoriatic epidermis: Regulation by TGF-beta and stat-3 activating cytokines, IFN-gamma, IL-6, and IL-22. J. Dermatol. Sci. 65, 134-140.
35. Jain, R. , Barkauskas, C. E. , Takeda, N. , Bowie, E. J. , Aghajanian, H. , Wang, Q. , Padmanabhan, A. , Manderfield, L. J. , Gupta, M. , Li, D. et al. (2015). Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung. Nat. Commun. 6, 6727.
36. Johnson, M. D. , Widdicombe, J. H. , Allen, L. , Barbry, P. and Dobbs, L. G. (2002). Alveolar epithelial type I cells contain transport proteins and transport sodium, supporting an active role for type I cells in regulation of lung liquid homeostasis. Proc. Natl. Acad. Sci. USA 99, 1966-1971.
37. Kneidinger, N. , Yildirim, A. Ö. , Callegari, J. , Takenaka, S. , Stein, M. M. , Dumitrascu, R. , Bohla, A. , Bracke, K. R. , Morty, R. E. , Brusselle, G. G. et al. (2011). Activation of the WNT/beta-catenin pathway attenuates experimental emphysema. Am. J. Respir. Crit. Care Med. 183, 723-733.
38. Königshoff, M. and Eickelberg, O. (2010). Wnt signaling in lung disease: A failure or a regeneration signal? Am. J. Respir. Cell Mol. Biol. 42, 21-31.
39. Königshoff, M. , Balsara, N. , Pfaff, E.-M. , Kramer, M. , Chrobak, I. , Seeger, W. and Eickelberg, O. (2008). Functional wnt signaling is increased in idiopathic pulmonary fibrosis. PLoS ONE 3, e2142.
40. Königshoff, M. , Kramer, M. , Balsara, N. , Wilhelm, J. , Amarie, O. V. , Jahn, A. , Rose, F. , Fink, L. , Seeger, W. , Schaefer, L. et al. (2009). Wnt1-inducible signaling protein-1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis. J. Clin. Invest. 119, 772-787.
41. Krishnan, H. , Ochoa-Alvarez, J. A. , Shen, Y. , Nevel, E. , Lakshminarayanan, M. , Williams, M. C. , Ramirez, M. I. , Miller, W. T. and Goldberg, G. S. (2013). Serines in the intracellular tail of podoplanin (pdpn) regulate cell motility. J. Biol. Chem. 288, 12215-12221.
42. Lam, A. P. , Herazo-Maya, J. D. , Sennello, J. A. , Flozak, A. S. , Russell, S. , Mutlu, G. M. , Budinger, G. R. S. , DasGupta, R. , Varga, J. , Kaminski, N. et al. (2014). Wnt coreceptor Lrp5 is a driver of idiopathic pulmonary fibrosis. Am. J. Respir. Crit. Care Med. 190, 185-195.
43. Lepourcelet, M. , Chen, Y.-N. P. , France, D. S. , Wang, H. , Crews, P. , Petersen, F. , Bruseo, C. , Wood, A. W. and Shivdasani, R. A. (2004). Small-molecule antagonists of the oncogenic Tcf/beta-catenin protein complex. Cancer Cell 5, 91-102.
44. Lhert, F. , Yan, W. , Biswas, S. C. and Hall, S. B. (2007). Effects of hydrophobic surfactant proteins on collapse of pulmonary surfactant monolayers. Biophys. J. 93, 4237-4243.
45. Liu, Y. , Sadikot, R. T. , Adami, G. R. , Kalinichenko, V. V. , Pendyala, S. , Natarajan, V. , Zhao, Y.-Y. and Malik, A. B. (2011). Foxm1 mediates the progenitor function of type II epithelial cells in repairing alveolar injury induced by pseudomonas aeruginosa. J. Exp. Med. 208, 1473-1484.
46. Lopez-Alemany, R. , Suelves, M. and Munoz-Canoves, P. (2003). Plasmin generation dependent on alpha-enolase-type plasminogen receptor is required for myogenesis. Thromb. Haemost. 90, 724-733.
47. Marconett, C. N. , Zhou, B. , Rieger, M. E. , Selamat, S. A. , Dubourd, M. , Fang, X. , Lynch, S. K. , Stueve, T. R. , Siegmund, K. D. , Berman, B. P. et al. (2013). Integrated transcriptomic and epigenomic analysis of primary human lung epithelial cell differentiation. PLoS Genet. 9, e1003513.
48. Matsuura, K. , Bunai, Y. , Ohya, I. , Hara, A. , Nakanishi, M. and Sawada, H. (1994). Ultrastructural localization of carbonyl reductase in mouse lung. Histochem. J. 26, 311-316.
49. Oliver, J. D. , Roderick, H. L. , Llewellyn, D. H. and High, S. (1999). Erp57 functions as a subunit of specific complexes formed with the er lectins calreticulin and calnexin. Mol. Biol. Cell 10, 2573-2582.
50. Robertson, J. D. , Enoksson, M. , Suomela, M. , Zhivotovsky, B. and Orrenius, S. (2002). Caspase-2 acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis. J. Biol. Chem. 277, 29803-29809.
51. Rock, J. R. , Barkauskas, C. E. , Cronce, M. J. , Xue, Y. , Harris, J. R. , Liang, J. , Noble, P. W. and Hogan, B. L. M. (2011). Multiple stromal populations contribute to pulmonary fibrosis without evidence for epithelial to mesenchymal transition. Proc. Natl. Acad. Sci. USA 108, E1475-E1483.
52. Ryu, S. Y. , Hong, G. U. , Kim, D. Y. and Ro, J. Y. (2012). Enolase 1 and calreticulin regulate the differentiation and function of mouse mast cells. Cell. Signal. 24, 60-70.
53. Selman, M. and Pardo, A. (2006). Role of epithelial cells in idiopathic pulmonary fibrosis: From innocent targets to serial killers. Proc. Am. Thorac. Soc. 3, 364-372.
54. Selman, M. , Pardo, A. and Kaminski, N. (2008). Idiopathic pulmonary fibrosis: Aberrant recapitulation of developmental programs? PLoS Med. 5, e62.
55. Song, Y. , Luo, Q. , Long, H. , Hu, Z. , Que, T. , Zhang, X. , Li, Z. , Wang, G. , Yi, L. , Liu, Z. et al. (2014). Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma. Mol. Cancer 13, 65.
56. Stone, K. C. , Mercer, R. R. , Freeman, B. A. , Chang, L.-Y. and Crapo, J. D. (1992). Distribution of lung cell numbers and volumes between alveolar and nonalveolar tissue. Am. Rev. Respir. Dis. 146, 454-456.
57. Strunk, R. C. , Eidlen, D. M. and Mason, R. J. (1988). Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways. J. Clin. Invest. 81, 1419-1426.
58. Tanjore, H. , Degryse, A. L. , Crossno, P. F. , Xu, X. C. , McConaha, M. E. , Jones, B. R. , Polosukhin, V. V. , Bryant, A. J. , Cheng, D.-S. , Newcomb, D. C. et al. (2013). Beta-catenin in the alveolar epithelium protects from lung fibrosis after intratracheal bleomycin. Am. J. Respir. Crit. Care Med. 187, 630-639.
59. Treutlein, B. , Brownfield, D. G. , Wu, A. R. , Neff, N. F. , Mantalas, G. L. , Espinoza, F. H. , Desai, T. J. , Krasnow, M. A. and Quake, S. R. (2014). Reconstructing lineage hierarchies of the distal lung epithelium using single-cell rna-seq. Nature 509, 371-375.
60. Tsuji, T. , Aoshiba, K. and Nagai, A. (2006). Alveolar cell senescence in patients with pulmonary emphysema. Am. J. Respir. Crit. Care Med. 174, 886-893.
61. Turano, C. , Gaucci, E. , Grillo, C. and Chichiarelli, S. (2011). Erp57/grp58: A protein with multiple functions. Cell. Mol. Biol. Lett. 16, 539-563.
62. Uhl, F. E. , Vierkotten, S. , Wagner, D. E. , Burgstaller, G. , Costa, R. , Koch, I. , Lindner, M. , Meiners, S. , Eickelberg, O. and Königshoff, M. (2015). Preclinical validation and imaging of Wnt-induced repair in human 3D lung tissue cultures. Eur. Respir. J. (in press).
63. Ulsamer, A. , Wei, Y. , Kim, K. K. , Tan, K. , Wheeler, S. , Xi, Y. , Thies, R. S. and Chapman, H. A. (2012). Axin pathway activity regulates in vivo py654-betacatenin accumulation and pulmonary fibrosis. J. Biol. Chem. 287, 5164-5172.
64. Vaughan, A. E. , Brumwell, A. N. , Xi, Y. , Gotts, J. E. , Brownfield, D. G. , Treutlein, B. , Tan, K. , Tan, V. , Liu, F. C. , Looney, M. R. et al. (2015). Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury. Nature 517, 621-625.
65. Wang, R. , Ahmed, J. , Wang, G. , Hassan, I. , Strulovici-Barel, Y. , Hackett, N. R. and Crystal, R. G. (2011). Down-regulation of the canonical wnt beta-catenin pathway in the airway epithelium of healthy smokers and smokers with COPD. PLoS ONE 6, e14793.
66. Wang, Y. , Huang, C. , Reddy Chintagari, N. , Bhaskaran, M. , Weng, T. , Guo, Y. , Xiao, X. and Liu, L. (2013). Mir-375 regulates rat alveolar epithelial cell transdifferentiation by inhibiting Wnt/beta-catenin pathway. Nucleic Acids Res. 41, 3833-3844.
67. Weibel, E. R. (2015). On the tricks alveolar epithelial cells play to make a good lung. Am. J. Respir. Crit. Care Med. 191, 504-513.
68. Wenz, H. M. , Hinck, L. , Cannon, P. , Navre, M. and Ringold, G. M. (1992). Reduced expression of ap27 protein, the product of a growth factor-repressible gene, is associated with diminished adipocyte differentiation. Proc. Natl. Acad. Sci. USA 89, 1065-1069.
69. Wesselkamper, S. C. , Case, L. M. , Henning, L. N. , Borchers, M. T. , Tichelaar, J. W. , Mason, J. M. , Dragin, N. , Medvedovic, M. , Sartor, M. A. , Tomlinson, C. R. et al. (2005). Gene expression changes during the development of acute lung injury: Role of transforming growth factor beta. Am. J. Respir. Crit. Care Med. 172, 1399-1411.
70. Yee, M. , Vitiello, P. F. , Roper, J. M. , Staversky, R. J. , Wright, T. W. , McGrath-Morrow, S. A. , Maniscalco, W. M. , Finkelstein, J. N. and O'Reilly, M. A. (2006). Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development. Am. J. Physiol. Lung Cell. Mol. Physiol. 291, L1101-L1111.
71. Zhang, B. , Wang, Z. , Deng, B. , Wu, X. , Liu, J. and Feng, X. (2013). Identification of enolase 1 and thrombospondin-1 as serum biomarkers in hbv hepatic fibrosis by proteomics. Proteome Sci. 11, 30.
72. Zhao, L. , Yee, M. and O'Reilly, M. A. (2013). Transdifferentiation of alveolar epithelial type II to type I cells is controlled by opposing TGF-beta and bmp signaling. Am. J. Physiol. Lung Cell. Mol. Physiol. 305, L409-L418.