Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis
Gu, Hongmei; Fisher, Amanda J.; Mickler, Elizabeth A.; Duerson, Frank; Cummings, Oscar W.; Peters‐golden, Marc; Twigg, Homer L.; Woodruff, Trent M.; Wilkes, David S.; Vittal, Ragini
2016-06
Citation
Gu, Hongmei; Fisher, Amanda J.; Mickler, Elizabeth A.; Duerson, Frank; Cummings, Oscar W.; Peters‐golden, Marc ; Twigg, Homer L.; Woodruff, Trent M.; Wilkes, David S.; Vittal, Ragini (2016). "Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis." The FASEB Journal 30(6): 2336-2350.
Abstract
Complement activation, an integral arm of innate immunity, may be the critical link to the pathogenesis of idiopathic pulmonary fibrosis (IPF). Whereas we have previously reported elevated anaphylatoxinsâ complement component 3a (C3a) and complement component 5a (C5a)â in IPF, which interact with TGFâ β and augment epithelial injury in vitro, their role in IPF pathogenesis remains unclear. The objective of the current study is to determine the mechanistic role of the binding of C3a/C5a to their respective receptors (C3aR and C5aR) in the progression of lung fibrosis. In normal primary human fetal lung fibroblasts, C3a and C5a induces mesenchymal activation, matrix synthesis, and the expression of their respective receptors. We investigated the role of C3aR and C5aR in lung fibrosis by using bleomycinâ injured mice with fibrotic lungs, elevated local C3a and C5a, and overexpression of their receptors via pharmacologic and RNA interference interventions. Histopathologic examination revealed an arrest in disease progression and attenuated lung collagen deposition (Masson’s trichrome, hydroxyproline, collagen type I α 1 chain, and collagen type I α 2 chain). Pharmacologic or RNA interferenceâ specific interventions suppressed complement activation (C3a and C5a) and soluble terminal complement complex formation (C5bâ 9) locally and active TGFâ β1 systemically. C3aR/C5aR antagonists suppressed local mRNA expressions of tgfb2, tgfbr1/2, ltbp1/2, serpine1, tsp1, bmp1/4, pdgfbb, igf1, but restored the proteoglycan, dcn. Clinically, compared with pathologically normal human subjects, patients with IPF presented local induction of C5aR, local and systemic induction of soluble C5bâ 9, and amplified expression of C3aR/C5aR in lesions. The blockade of C3aR and C5aR arrested the progression of fibrosis by attenuating local complement activation and TGFâ β/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with IPF.â Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Petersâ Golden, M., Twigg, H. L., III, Woodruff, T. M., Wilkes, D. S., Vittal, R. Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. FASEB J. 30, 2336â 2350 (2016). www.fasebj.orgPublisher
Wiley Periodicals, Inc. Federation of American Societies for Experimental Biology
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0892-6638 1530-6860
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