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  • Title: [Intervention effect of PI3Kgamma inhibitor AS605240 on autoimmune myocarditis in mice].
    Author: Jin K, Song LF, He CM, Wang ZL, Hu XH, Wu XH.
    Journal: Sichuan Da Xue Xue Bao Yi Xue Ban; 2009 Sep; 40(5):817-20, 825. PubMed ID: 19950590.
    Abstract:
    OBJECTIVE: To investigate the therapeutic effect of PI3Kgamma inhibitor AS605240 on autoimmune myocarditis in mice. METHODS: BALB/c mice were randomly divided into three groups, AS605240 group and vehicle group were injected subcutaneously with emulsions containing CFA and 100 ng peptide which derived from murine cardiac alpha-myosin heavy chain on day 0 and 7 while control group were injected with emulsions containing CFA and PBS. AS605240 group received the oral administration of AS605240 50 mg/(kg x d). The vehicle group received the oral administration of an equal volume of 0.5% carboxymethylcellulose. 21 days after the first immunization, mice were sacrificed, heart and body weight were measured. Myocarditis severity was evaluated according to a semi-quantitative scoring system in heart sections. Immunohistochemistry was performed to determine the effect of AS605240 on myocardium macrophage infiltration; TNF-alpha levels in myocardium were determined by ELISA. In vitro and in vivo chemotaxis assays were performed to determine the effect of AS605240 on MCP-1-induced macrophage chemotaxis. RESULTS: Histological examination of the heart showed that AS605240 significantly relieved the murine myocarditis and reduced heart/body weight ratios in experimental autoimmune myocarditis (EAM) (P< 0.01). Immunohistochemical detection showed that AS605240 significantly suppressed macrophage infiltration into the heart with EAM. ELISA demonstrated that AS605240 down-regulated TNF-alpha levels in myocardium (P<0.01). In vitro and in vivo chemotaxis assays indicated that AS605240 significantly suppressed MCP-1-induced macrophage chemotaxis (P<0.01). CONCLUSION: AS605240 may be an effective drug for autoimmune myocarditis, of which the mechanism is relating to suppress macrophage chemotaxis and macrophage infiltration into myocardium, and to decrease TNF-alpha levels in myocardium.
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