| Early macrophage recruitment and alternative activation are critical for the later development of hypoxia-induced pulmonary hypertension. | |
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MedLine Citation:
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PMID: 21518986 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Lung inflammation precedes the development of hypoxia-induced pulmonary hypertension (HPH); however, its role in the pathogenesis of HPH is poorly understood. We sought to characterize the hypoxic inflammatory response and to elucidate its role in the development of HPH. We also aimed to investigate the mechanisms by which heme oxygenase-1, an anti-inflammatory enzyme, is protective in HPH. METHODS AND RESULTS: We generated bitransgenic mice that overexpress human heme oxygenase-1 under doxycycline control in an inducible, lung-specific manner. Hypoxic exposure of mice in the absence of doxycycline resulted in early transient accumulation of monocytes/macrophages in the bronchoalveolar lavage. Alveolar macrophages acquired an alternatively activated phenotype (M2) in response to hypoxia, characterized by the expression of found in inflammatory zone-1, arginase-1, and chitinase-3-like-3. A brief 2-day pulse of doxycycline delayed, but did not prevent, the peak of hypoxic inflammation, and could not protect against HPH. In contrast, a 7-day doxycycline treatment sustained high heme oxygenase-1 levels during the entire period of hypoxic inflammation, inhibited macrophage accumulation and activation, induced macrophage interleukin-10 expression, and prevented the development of HPH. Supernatants from hypoxic M2 macrophages promoted the proliferation of pulmonary artery smooth muscle cells, whereas treatment with carbon monoxide, a heme oxygenase-1 enzymatic product, abrogated this effect. CONCLUSIONS: Early recruitment and alternative activation of macrophages in hypoxic lungs are critical for the later development of HPH. Heme oxygenase-1 may confer protection from HPH by effectively modifying the macrophage activation state in hypoxia. |
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Authors:
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Eleni Vergadi; Mun Seog Chang; Changjin Lee; Olin D Liang; Xianlan Liu; Angeles Fernandez-Gonzalez; S Alex Mitsialis; Stella Kourembanas |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-04-25 |
Journal Detail:
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Title: Circulation Volume: 123 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-05-10 Completed Date: 2011-07-19 Revised Date: 2012-05-14 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 1986-95 Citation Subset: AIM; IM |
Affiliation:
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Division of Newborn Medicine, Children's Hospital Boston, Harvard Medical School, MA 02115, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Anoxia / immunology*, pathology Carbon Dioxide / metabolism Cell Division / immunology Heme Oxygenase-1 / genetics, immunology*, metabolism Humans Hypertension, Pulmonary / immunology*, pathology Interleukin-10 / metabolism Macrophage Activation / immunology* Macrophages, Alveolar / immunology*, pathology Mice Mice, Transgenic Monocytes / immunology, pathology Muscle, Smooth, Vascular / immunology, pathology Pneumonia / immunology, pathology Pulmonary Artery / immunology, pathology Transcriptional Activation / immunology |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL 055454/HL/NHLBI NIH HHS; R01 HL055454-15/HL/NHLBI NIH HHS; R01 HL085446/HL/NHLBI NIH HHS; R01 HL085446-05/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/IL10 protein, mouse; 124-38-9/Carbon Dioxide; 130068-27-8/Interleukin-10; EC 1.14.99.3/Heme Oxygenase-1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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