| Docosahexaenoic Acid Derivative Prevents Inflammation and Hyperreactivity in Lung: Implication of PKC-Potentiated Inhibitory Protein for Heterotrimeric Myosin Light Chain Phosphatase of 17 kD in Asthma. | |
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MedLine Citation:
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PMID: 21057106 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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The effects of a newly synthesized docosahexaenoic acid (DHA) derivative, CRBM-0244, on lung inflammation and airway hyperresponsiveness were determined in an in vitro model of TNF-α-stimulated human bronchi and in an in vivo model of allergic asthma. Mechanical tension measurements revealed that CRBM-0244 prevented bronchial hyperresponsiveness in TNF-α-pretreated human bronchi. Moreover, treatment with CRBM-0244 resulted in a decrease in NF-κB activation and cyclooxygenase-2 (COX-2) overexpression triggered by TNF-α. The inhibition of peroxisome proliferator-activated receptor-γ with GW9662 abolished the CRBM-0244-mediated anti-inflammatory effects. CRBM-0244 reduced the Ca(2+) sensitivity of bronchial smooth muscle through a decrease in the phosphorylation and expression of the PKC-potentiated inhibitory protein for heterotrimeric myosin light chain phosphatase of 17 kDa (CPI-17). Results also revealed an overexpression of CPI-17 protein in lung biopsies derived from patients with asthma. Furthermore, the presence of specialized enzymes such as 5-lipoxygenase and 15-lipoxygenase in the lung may convert CRBM-0244 into active mediators, leading to the resolution of inflammation. The in vivo anti-inflammatory properties of CRBM-0244 were also investigated in a guinea pig model of allergic asthma. After oral administration of CRBM-0244, airway leukocyte recruitment, airway mucus, ovalbumin-specific IgE, and proinflammatory markers such as TNF-α and COX-2 were markedly reduced. Hence, CRBM-0244 treatment prevents airway hyperresponsiveness, Ca(2+) hypersensitivity, and the overexpression of CPI-17 in lung tissue. Together, these findings provide key evidence regarding the mode of action of CRBM-0244 in the lung, and point to new therapeutic strategies for modulating inflammation in patients with asthma. |
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Authors:
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Caroline Morin; Samuel Fortin; André M Cantin; Eric Rousseau |
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Publication Detail:
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Type: Journal Article Date: 2010-11-05 |
Journal Detail:
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Title: American journal of respiratory cell and molecular biology Volume: 45 ISSN: 1535-4989 ISO Abbreviation: Am. J. Respir. Cell Mol. Biol. Publication Date: 2011 Aug |
Date Detail:
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Created Date: 2011-08-04 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8917225 Medline TA: Am J Respir Cell Mol Biol Country: United States |
Other Details:
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Languages: eng Pagination: 366-75 Citation Subset: IM |
Affiliation:
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Department of Physiology and Biophysics, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 3001 12th Avenue North, Sherbrooke, PQ, J1H 5N4 Canada. Eric.Rousseau@USherbrooke.ca. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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