Abstract
While our previous studies suggest that limiting bleomycin-induced complement activation suppresses TGF-β signaling, the specific hierarchical interactions between TGF-β and complement in lung fibrosis are unclear. Herein, we investigated the mechanisms underlying TGF-β-induced complement activation in the pathogenesis of lung fibrosis. C57-BL6 mice were given intratracheal instillations of adenoviral vectors overexpressing TGF-β (Ad-TGFβ) or the firefly gene-luciferase (Ad-Luc; control). Two weeks later, mice with fibrotic lungs were instilled RNAi specific to receptors for C3a or C5a-C3ar or C5ar, and sacrificed at day 28. Histopathological analyses revealed that genetic silencing of C3ar or C5ar arrested the progression of TGF-β-induced lung fibrosis, collagen deposition and content (hydroxyproline, col1a1/2); and significantly suppressed local complement activation. With genetic silencing of either C3ar or C5ar, in Ad-TGFβ-injured lungs: we detected the recovery of Smad7 (TGF-β inhibitor) and diminished local release of DAF (membrane-bound complement inhibitor); in vitro: TGF-β-mediated loss of DAF was prevented. Conversely, blockade of the TGF-β receptor prevented C3a-mediated loss of DAF in both normal primary human alveolar and small airway epithelial cells. Of the 52 miRNAs analyzed as part of the Affymetrix array, normal primary human SAECs exposed to C3a, C5a or TGF-β caused discrete and overlapping miRNA regulation related to epithelial proliferation or apoptosis (miR-891A, miR-4442, miR-548, miR-4633), cellular contractility (miR-1197) and lung fibrosis (miR-21, miR-200C, miR-31HG, miR-503). Our studies present potential mechanisms by which TGF-β activates complement and promotes lung fibrosis.
Highlights
Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease characterized by progressive scarring of the lung
RNA-interference specific to C3ar or C5ar arrests the progression of TGF-β-induced lung fibrosis
Blockade of C3aR and C5aR expression mitigated the progression of bleomycin-induced lung fibrosis by suppressing local TGF-β-related signaling and systemic TGF-β activity [4]
Summary
Idiopathic Pulmonary Fibrosis (IPF) is a devastating disease characterized by progressive scarring of the lung. The architectural remodeling has long been debated as a process involving multiple alveolar epithelial injuries which triggers a number of chronic inflammatory signals which in turn drives dysregulated tissue repair. TGF-β has emerged as the undisputed master regulator of fibrosis which triggers a number of other pro-fibrotic signals which serve as a feed-forward loop and augment lung remodeling. A number of other inflammatory signals trigger the autocrine synthesis of TGF-β in the lung. Our recent report suggests that IL-17A may drive fibrosis via the complement cascade [3]. Signaling interactions between these pro-fibrotic pathways may shed significant insights on the specific drivers of epithelial injury and dysregulated tissue repair
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