Format

Send to

Choose Destination
PLoS One. 2015 Jul 1;10(7):e0131923. doi: 10.1371/journal.pone.0131923. eCollection 2015.

Pulmonary Macrophages Attenuate Hypoxic Pulmonary Vasoconstriction via β3AR/iNOS Pathway in Rats Exposed to Chronic Intermittent Hypoxia.

Author information

1
Department of Forensic Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan; Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
2
Department of Pulmonary Medicine, Tokai University Tokyo Hospital, Tokyo, Japan.
3
Department of Physiology, Heart Otago, University of Otago, Dunedin, New Zealand.
4
Department of Cardiac Physiology, National Cerebral & Cardiovascular Center, Osaka, Japan.
5
Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan.
6
Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan; Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan; Department of Pathology and Microbiology, Nihon University School of Medicine, Tokyo, Japan.
7
Institute of Forensic Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.
8
Japan Synchrotron Radiation Research Institute, Hyogo, Japan.
9
Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan.
10
Department of Forensic Medicine, The University of Tokyo, Tokyo, Japan; Department of Forensic Medicine, Tokyo Medical University, Tokyo, Japan.
11
Department of Forensic Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
12
Monash Biomedical Imaging Facility and Department of Physiology, Monash University, Melbourne, Australia; Imaging and Medical therapy Beamline, Australian Synchrotron, Clayton, Australia.

Abstract

Chronic intermittent hypoxia (IH) induces activation of the sympathoadrenal system, which plays a pivotal role in attenuating hypoxic pulmonary vasoconstriction (HPV) via central β1-adrenergic receptors (AR) (brain) and peripheral β2AR (pulmonary arteries). Prolonged hypercatecholemia has been shown to upregulate β3AR. However, the relationship between IH and β3AR in the modification of HPV is unknown. It has been observed that chronic stimulation of β3AR upregulates inducible nitric oxide synthase (iNOS) in cardiomyocytes and that IH exposure causes expression of iNOS in RAW264.7 macrophages. iNOS has been shown to have the ability to dilate pulmonary vessels. Hence, we hypothesized that chronic IH activates β3AR/iNOS signaling in pulmonary macrophages, leading to the promotion of NO secretion and attenuated HPV. Sprague-Dawley rats were exposed to IH (3-min periods of 4-21% O2) for 8 h/d for 6 weeks. The urinary catecholamine concentrations of IH rats were high compared with those of controls, indicating activation of the sympathoadrenal system following chronic IH. Interestingly, chronic IH induced the migration of circulating monocytes into the lungs and the predominant increase in the number of pro-inflammatory pulmonary macrophages. In these macrophages, both β3AR and iNOS were upregulated and stimulation of the β3AR/iNOS pathway in vitro caused them to promote NO secretion. Furthermore, in vivo synchrotron radiation microangiography showed that HPV was significantly attenuated in IH rats and the attenuated HPV was fully restored by blockade of β3AR/iNOS pathway or depletion of pulmonary macrophages. These results suggest that circulating monocyte-derived pulmonary macrophages attenuate HPV via activation of β3AR/iNOS signaling in chronic IH.

PMID:
26132492
PMCID:
PMC4489089
DOI:
10.1371/journal.pone.0131923
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center