Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis

Hongmei Gu, Amanda J. Fisher, Elizabeth A. Mickler, Frank Duerson, Oscar Cummings, Marc Peters-Golden, Homer Twigg, Trent M. Woodruff, David S. Wilkes, Ragini Vittal

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2336-2350
Number of pages15
JournalFASEB Journal
Volume30
Issue number6
DOIs
StatePublished - Jun 1 2016

Fingerprint

Anaphylatoxins
Idiopathic Pulmonary Fibrosis
Pulmonary Fibrosis
Complement Membrane Attack Complex
Chemical activation
Complement Activation
Complement C3a
Lung
Collagen Type I
Fibrosis
RNA Interference
Complement C5a
RNA
Decorin
Hydroxyproline
Bleomycin
Proteoglycans
Fibroblasts
Collagen Type II
Bone

Keywords

  • BMP
  • C5b-9
  • Decorin
  • IPF
  • TGF-β1

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Gu, H., Fisher, A. J., Mickler, E. A., Duerson, F., Cummings, O., Peters-Golden, M., ... Vittal, R. (2016). Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. FASEB Journal, 30(6), 2336-2350. https://doi.org/10.1096/fj.201500044

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; Peters-Golden, Marc; Twigg, Homer; Woodruff, Trent M.; Wilkes, David S.; Vittal, Ragini.

In: FASEB Journal, Vol. 30, No. 6, 01.06.2016, p. 2336-2350.

Research output: Contribution to journalArticle

Gu, H, Fisher, AJ, Mickler, EA, Duerson, F, Cummings, O, Peters-Golden, M, Twigg, H, Woodruff, TM, Wilkes, DS & Vittal, R 2016, 'Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis', FASEB Journal, vol. 30, no. 6, pp. 2336-2350. https://doi.org/10.1096/fj.201500044
Gu, Hongmei ; Fisher, Amanda J. ; Mickler, Elizabeth A. ; Duerson, Frank ; Cummings, Oscar ; Peters-Golden, Marc ; Twigg, Homer ; Woodruff, Trent M. ; Wilkes, David S. ; Vittal, Ragini. / Contribution of the anaphylatoxin receptors, C3aR and C5aR, to the pathogenesis of pulmonary fibrosis. In: FASEB Journal. 2016 ; Vol. 30, No. 6. pp. 2336-2350.
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