| PI3K-γ Inhibition Ameliorates Acute Lung Injury Through Regulation of IκBα/NF-κB Pathway and Innate Immune Responses. | |
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MedLine Citation:
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PMID: 22198681 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND: Acute lung injury (ALI) is a devastating disorder of the lung by various causes and its cardinal features are tissue inflammation, pulmonary edema, low lung compliance, and widespread capillary leakage. Among phosphoinositide 3-kinases (PI3Ks), PI3K-γ isoform has been shown to play an important role in a number of immune/inflammatory responses. METHODS: We investigated the role of PI3K-γ and its molecular basis in lipopolysaccharide (LPS)-induced ALI using a selective inhibitor for PI3K-γ, AS 605240, and LPS-treated C57BL/6 mice. RESULTS: Treatment of mice with LPS showed an increase of lung inflammation and vascular leakage. Production of reactive oxygen species (ROS), interleukin (IL)-1β, tumor necrosis factor-α, and IL-4, adhesion molecule, and vascular endothelial growth factor (VEGF) was also increased. Administration of AS 605240 to LPS-treated mice markedly reduced the pathophysiological features of ALI and the increased production of ROS, cytokines, adhesion molecule, and VEGF in the lung. Our results also showed that treatment of mice with LPS activates nuclear factor-κB (NF-κB) and degradation of inhibitory κBα (IκBα) through PI3K-γ. Additionally, infiltration of dendritic cells (DCs) and expression of toll-like receptor 4 (TLR4) were significantly increased in the lung of LPS-treated mice, and inhibition of PI3K-γ reduced the infiltration of DCs and TLR4 expression in the lung. CONCLUSIONS: These results indicate that PI3K-γ is critically involved in LPS-induced ALI by regulating IκBα/NF-κB pathway and innate immune responses. Based on our data, we suggest that PI3K-γ isoform is a promising target for the treatment of ALI. |
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Authors:
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Dong Im Kim; So Ri Kim; Hee Jung Kim; Su Jeong Lee; Heung Bum Lee; Seoung Ju Park; Mie-Jae Im; Yong Chul Lee |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-12-24 |
Journal Detail:
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Title: Journal of clinical immunology Volume: - ISSN: 1573-2592 ISO Abbreviation: - Publication Date: 2011 Dec |
Date Detail:
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Created Date: 2011-12-26 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8102137 Medline TA: J Clin Immunol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, San 2-20, Geumam-dong, Deokjin-gu, Jeonju, 561-180, South Korea. |
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