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).
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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| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
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| Contributors: |
| Contribution | Contributors Name | Email | Pitt Username | ORCID  |
|---|
| Editor | Ushio-Fukai, Masuko | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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| 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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