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Potential Mechanisms Underlying TGF-Beta-Mediated Complement Activation in Lung Fibrosis

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A2227 - Potential Mechanisms Underlying TGF-Beta-Mediated Complement Activation in Lung Fibrosis
Author Block: R. Vittal1, A. Fisher2, H. Gu2, A. Varre1, E. Mickler2, E. Cipolla1; 1Internal Medicine-PULM, University of Michigan, Ann Arbor, MI, United States, 2Medicine-PULM, Indiana University School of Medicine, Indianapolis, IN, United States.
While our previous studies suggest that limiting bleomycin-induced complement activation suppresses TGF-beta signaling, the specific hierarchical interactions between TGF-beta and complement in lung fibrosis are unclear. Herein, we investigated the mechanisms underlying TGF-beta-induced complement activation in the pathogenesis of lung fibrosis. C57-BL6 mice were given intratracheal instillations of adenoviral vectors overexpressing TGF-beta (Ad-TGFbeta) or the firefly gene - luciferase (Ad-Luc; control). Two weeks later, mice with fibrotic lungs were instilled siRNA specific to C3ar or C5ar, and sacrificed at day 28. Histopathological analyses revealed that genetic silencing of C3ar or C5ar arrested the progression of TGF-beta-induced lung fibrosis, collagen deposition and content (hydroxyproline, col1a1/2); and significantly suppressed local complement activation. With genetic silencing of either C3ar or C5ar: while in Ad-TGFbeta-injured lungs we detected the recovery of Smad7 (negative modulator of TGF-beta) and diminished local levels of cleaved DAF; TGF-beta-mediated loss of cellular DAF was prevented in vitro. Conversely, blockade of the TGF-beta receptor prevented C3a-mediated loss of DAF in both normal primary human alveolar and small airway epithelial cells. Normal primary human small airway epithelial cells exposed to C3a, C5a or TGF-beta caused discrete and overlapping miRNA regulation related to epithelial proliferation/apoptosis (mir-891A, -4442, -548, -4633), cellular contractility (mir-1197), lung fibrosis (mir-21, -200C, -let-7a) among several others detected by Affymetrix array analyses. Our studies present potential mechanisms by which TGF-beta activates complement and promotes lung fibrosis.
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