Opposing regulatory roles of complement factor 5 in the development of bleomycin-induced pulmonary fibrosis.
The mechanisms of idiopathic pulmonary fibrosis pathogenesis, a chronic and progressive interstitial lung disease, remain elusive. The complement system, a crucial arm of the innate immune response, plays a pivotal role in several pathological disorders; however, the contribution of individual complement components to lung fibrosis has not yet been examined. Complement factor 5 (C5) and its cleavage product C5a are critical mediators in inflammatory diseases. Thus, to evaluate the role of C5 in lung fibrosis, we compared congenic C5-sufficient and C5-deficient mice in a well-characterized murine model of bleomycin-induced pulmonary fibrosis. C5-deficient mice had an exaggerated inflammatory phenotype compared with C5-sufficient mice during acute bleomycin-induced lung injury. These findings suggest a protective and anti-inflammatory role for C5, which was linked to the regulation of matrix metalloproteinases involved in cell migration. In contrast, C5 had a detrimental effect during chronic stages of bleomycin-induced injury, indicating a profibrotic role for C5. This deleterious activity for C5 was associated with expression of the fibrogenic cytokine TGF-beta1 and matrix metalloproteinase-3, an important mediator in fibroblast contraction. Altogether, our data reveal novel and opposing roles for C5 in both inflammation and tissue repair. Furthermore, these findings provide insight into the development of new therapeutic strategies for idiopathic pulmonary fibrosis patients.
Addis-Lieser
Erin
E
Division of Immunobiology, Cincinnati Children's Hospital Research Foundation, Department of Pediatrics, University of Cincinnati, Cincinnati, OH 45229, USA.
Köhl
Jörg
J
Chiaramonte
Mónica G
MG
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D001761:Bleomycin; D002908:Chronic Disease; D003094:Collagen / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D003182:Complement C5 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015936:Complement C5a / Q000502:physiology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D003182:Complement C5; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D015936:Complement C5a; D003094:Collagen; D020782:Matrix Metalloproteinases; D019278:Matrix Metalloproteinase 3