Epithelial responses to lung injury: Role of the extracellular matrix
ABSTRACT The key role of extracellular matrices in alveolar epithelial cell (AEC) biology is highlighted by the phenotypes of primary AECs cultured on a soft laminin gel contrasted with that on a stiff, fibronectin matrix. On laminin, AECs maintain an epithelial phenotype, and progenitor cells within this population proliferate. In contrast, on fibronectin, AECs rapidly lose surfactant expression and spread extensively, changes that depend on activation of latent TGF-β1 by engagement of fibronectin-binding integrins. The progenitor subpopulation responding to TGF-β1 undergoes epithelial mesenchymal transition (EMT). Although it remains uncertain to what degree EMT contributes directly to collagen 1 production, signaling pathways critical to EMT are important for repair and fibrosis, implying that EMT is part of the general program of lung repair. EMT reprogramming requires not only Smad signaling but also pY654-β-catenin. Generation of pY654-β-catenin requires assembly of complexes of the integrin α3β1, E-cadherin, and TGF-β1 receptors, and such assembly is a function of cell-cell and cell-matrix contacts. Sequestration of α3β1 or E-cadherin in such contacts prevents complex assembly, TGF-β1 induced pY654-β-catenin generation and EMT. Disruption of these contacts is a signal for the cells to initiate repair. Critical remaining questions center around better definition of direct versus indirect effects of EMT on collagen deposition and the nature of AEC progenitors differentiating during fibrogenesis. Elucidation of specific inhibitors of EMT should further test the question of whether the process is important to fibrosis in vivo and a viable therapeutic target.
Article: Myofibroblasts[Show abstract] [Hide abstract]
ABSTRACT: PURPOSE OF REVIEW: Interest in the myofibroblast as a key player in propagation of chronic progressive fibrosis continues to elicit many publications, with focus on its cellular origins and the mechanisms underpinning their differentiation and/or transition. The objective of the review is to highlight this recent progress. RECENT FINDINGS: The epithelial origin of the myofibroblast in fibrosis has been challenged by recent studies, with the pericyte suggested as a possible precursor instead. Additional signaling pathways, including Notch, Wnt, and hedgehog, are implicated in myofibroblast differentiation. The importance of NADPH oxidase 4 was highlighted recently to suggest a potential link between cellular/oxidative stress and the genesis of the myofibroblast. Recent observations on the importance of lysophosphatidic acid in fibrosis suggest that this may be due, in part, to its ability to regulate myofibroblast differentiation. Finally, there is increasing evidence for the role of epigenetic mechanisms in regulating myofibroblast differentiation, including DNA methylation and miRNA regulation of gene expression. SUMMARY: These recent discoveries open up a whole new array of potential targets for novel antifibrotic therapies. This is of special importance given the current bleak outlook for chronic progressive fibrotic diseases, such as scleroderma, due to lack of effective therapies.Current opinion in rheumatology 10/2012; 25(1). DOI:10.1097/BOR.0b013e32835b1352 · 5.07 Impact Factor
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ABSTRACT: RATIONALE: Injury to alveolar epithelial cells (AECs) and to their repair process are integral to the pathogenesis of acute lung injury (ALI) and idiopathic pulmonary fibrosis (IPF). The mechanisms regulating the integrity of AECs and its intrinsic regulators remain unclear. Pten is a tumor suppressor, and its function in epithelial cells during organ fibrosis is unknown. OBJECTIVES: To determine the role of epithelial Pten in ALI and lung fibrosis. METHODS: Bronchioalveolar epithelium-specifically Pten-deleted [SP-C-rtTA/(tetO)7-Cre/PtenΔ/Δ (SOPtenΔ/Δ) mice were studied by structural, biochemical, and physiological analyses and compared with wild-type mice. Further mechanistic studies were performed in vivo, in vitro, and on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: SOPtenΔ/Δ mice demonstrated exacerbated alveolar flooding and subsequent augmented lung scarring with enhanced disassembly of tight junctions (TJs) of AECs and degradation of basement membranes. The induction of dominant negative PTEN gene in lung epithelial cells led to augmented transforming growth factor-1-induced disruptions of TJs. Epithelial-derived myofibroblasts were increased in the epithelium-specific Pten-deficient mice. The lungs of bleomycin-treated SOPtenΔ/Δ mice showed increased pAkt, pS6K, Snail, and matrix metalloproteinase expressions and decreased claudin-4, E-cadherin, and laminin-β1 expressions. Akt inactivation definitively saved SOPtenΔ/Δ mice through amelioration of ALI and retention of AEC integrity. We detected a reduction of PTEN expression and AKT hyperactivation in the AECs of human IPF lungs. CONCLUSIONS: Our results highlight epithelial Pten as a crucial gatekeeper controlling ALI and lung fibrosis by modulating AEC integrity, and the Pten/PI3K/Akt pathway as a potential therapeutic target in these intractable diseases.American Journal of Respiratory and Critical Care Medicine 12/2012; 187(3). DOI:10.1164/rccm.201205-0851OC · 11.99 Impact Factor
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ABSTRACT: MicroRNAs are implicated in many biological and pathological processes and are emerging as key actors in lung health and disease. Specific patterns of dysre- gulated microRNAs have been found in idiopathic pulmonary fibrosis (IPF), an untreatable interstitial lung disease of unknown etiology. IPF is characterized by dramatic and extensive phenotypic changes in the lung that include alveolar cell hyperplasia, fibroblast proliferation and formation of myofibroblast foci, deposition of extracellular matrix, and changes in lung transcrip- tional programming. Here, we discuss the latest insights about the role of microRNAs in lung fibrosis with a focus on the contribution of animal models of disease to the derivation of these insightsDrug Discovery Today Disease Models 01/2013; DOI:10.1016/j.ddmod.2012.11.003