title: Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis.
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 anaphylatoxins-complement component 3a (C3a) and complement component 5a (C5a)-in IPF, which interact with TGF-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 bleomycin-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 interference-specific interventions suppressed complement activation (C3a and C5a) and soluble terminal complement complex formation (C5b-9) locally and active TGF-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 C5b-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 TGF-β/bone morphologic protein signaling as well as restoring decorin, which suggests a promising therapeutic strategy for patients with IPF.-Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., III, Cummings, O. W., Peters-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.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA;
authors.forename: Hongmei
authors.initials: H
authors.lastname: Gu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA;
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Fisher
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA;
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Mickler
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA;
authors.forename: Frank
authors.initials: F
authors.lastname: Duerson
authors.affiliation: Department of Pathology, Indiana University School of Medicine, Indianapolis, Indiana, USA;
authors.forename: Oscar W
authors.initials: OW
authors.lastname: Cummings
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA;
authors.forename: Homer L
authors.initials: HL
authors.lastname: Twigg
authors.affiliation: School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Trent M
authors.initials: TM
authors.lastname: Woodruff
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA;
authors.forename: David S
authors.initials: DS
authors.lastname: Wilkes
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA rvittal@med.umich.edu.
authors.forename: Ragini
authors.initials: R
authors.lastname: Vittal
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D002460:Cell Line; D000090602:Collagen Type I, alpha 1 Chain; D015938:Complement Membrane Attack Complex / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D005347:Fibroblasts / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D055370:Lung Injury / Q000139:chemically induced; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D034622:RNA Interference; D044087:Receptor, Anaphylatoxin C5a / Q000235:genetics / Q000378:metabolism*; D011951:Receptors, Complement / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000903:Antibiotics, Antineoplastic; C000716127:COL1A1 protein, human; D000090602:Collagen Type I, alpha 1 Chain; D015938:Complement Membrane Attack Complex; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D016212:Transforming Growth Factor beta; C085567:complement C3a receptor; D001761:Bleomycin
keywords: BMP; C5b-9; IPF; TGF-β1; decorin