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Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in mice

Bauer, EM and Zheng, H and Comhair, S and Erzurum, S and Billiar, TR and Bauer, PM (2011) Complement C3 deficiency attenuates chronic hypoxia-induced pulmonary hypertension in mice. PLoS ONE, 6 (12).

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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. Methodology/Principal Findings: 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. © 2011 Bauer et al.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Bauer, EMemb62@pitt.eduEMB62
Zheng, H
Comhair, S
Erzurum, S
Billiar, TRbilliar@pitt.eduBILLIAR
Bauer, PM
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorUshio-Fukai, MasukoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 14 December 2011
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 6
Number: 12
DOI or Unique Handle: 10.1371/journal.pone.0028578
Schools and Programs: School of Medicine > Pharmacology and Chemical Biology
Refereed: Yes
MeSH Headings: Animals; Anoxia--complications; Anoxia--physiopathology; Arterioles--metabolism; Arterioles--pathology; Biological Markers--metabolism; Cell Proliferation; Chronic Disease; Complement C3--deficiency; Complement C3--metabolism; Complement C3a--metabolism; Complement C5a--metabolism; Endothelium, Vascular--pathology; Endothelium, Vascular--physiopathology; Fibrin--metabolism; Gene Deletion; Humans; Hypertension, Pulmonary--etiology; Hypertension, Pulmonary--physiopathology; Hypertension, Pulmonary--prevention & control; Mice; Mice, Inbred C57BL; Myocytes, Smooth Muscle--metabolism; Myocytes, Smooth Muscle--pathology; Platelet Activation; Pulmonary Artery--pathology; Pulmonary Artery--physiopathology; Thromboplastin--metabolism; Up-Regulation--genetics
Other ID: NLM PMC3237464
PubMed Central ID: PMC3237464
PubMed ID: 22194859
Date Deposited: 07 Sep 2012 19:38
Last Modified: 04 Feb 2019 15:57
URI: http://d-scholarship.pitt.edu/id/eprint/14004

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