title: Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in mice.
abstract: BACKGROUND
  Evidence suggests a role of both innate and adaptive immunity in the development of pulmonary arterial hypertension. The complement system is a key sentry of the innate immune system and bridges innate and adaptive immunity. To date there are no studies addressing a role for the complement system in pulmonary arterial hypertension.
  
  
  RESULTS
  Immunofluorescent staining revealed significant C3d deposition in lung sections from IPAH patients and C57Bl6/J wild-type mice exposed to three weeks of chronic hypoxia to induce pulmonary hypertension. Right ventricular systolic pressure and right ventricular hypertrophy were increased in hypoxic vs. normoxic wild-type mice, which were attenuated in C3-/- hypoxic mice. Likewise, pulmonary vascular remodeling was attenuated in the C3-/- mice compared to wild-type mice as determined by the number of muscularized peripheral arterioles and morphometric analysis of vessel wall thickness. The loss of C3 attenuated the increase in interleukin-6 and intracellular adhesion molecule-1 expression in response to chronic hypoxia, but not endothelin-1 levels. In wild-type mice, but not C3-/- mice, chronic hypoxia led to platelet activation as assessed by bleeding time, and flow cytometry of platelets to determine cell surface P-selectin expression. In addition, tissue factor expression and fibrin deposition were increased in the lungs of WT mice in response to chronic hypoxia. These pro-thrombotic effects of hypoxia were abrogated in C3-/- mice.
  
  
  CONCLUSIONS
  Herein, we provide compelling genetic evidence that the complement system plays a pathophysiologic role in the development of PAH in mice, promoting pulmonary vascular remodeling and a pro-thrombotic phenotype. In addition we demonstrate C3d deposition in IPAH patients suggesting that complement activation plays a role in the development of PAH in humans.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Bauer
authors.forename: Han
authors.initials: H
authors.lastname: Zheng
authors.forename: Suzy
authors.initials: S
authors.lastname: Comhair
authors.forename: Serpil
authors.initials: S
authors.lastname: Erzurum
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Billiar
authors.forename: Philip M
authors.initials: PM
authors.lastname: Bauer
mesh_terms: D000818:Animals; D001160:Arterioles / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002908:Chronic Disease; D003176:Complement C3 / Q000172:deficiency* / Q000378:metabolism; D015926:Complement C3a / Q000378:metabolism; D015936:Complement C5a / Q000378:metabolism; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D005337:Fibrin / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D015539:Platelet Activation; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D013925:Thromboplastin / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics
chemical_list: D015415:Biomarkers; D003176:Complement C3; D015926:Complement C3a; D015936:Complement C5a; D005337:Fibrin; D013925:Thromboplastin