as-605240 and Pulmonary-Fibrosis

Toll-like receptor 9 (TLR9) and Phosphatidylinositol-3-kinase gamma (PI3Kγ) are very important effectors of the immune response, however, the importance of such crosstalk for disease development is still a matter of discussion. Here we show that PI3Kγ is required for immune responses in which TLR9 is a relevant trigger. We demonstrate the requirement of PI3Kγ for TLR9-induced inflammation in a model of CpG-induced pleurisy. Such requirement was further observed in inflammatory models where DNA sensing via TLR9 contributes to disease, such as silicosis and drug-induced liver injury. Using adoptive transfer, we demonstrate that PI3Kγ is important not only in leukocytes but also in parenchymal cells for the progression of inflammation. We demonstrate this crosstalk between TLR9 and PI3Kγ in vitro using human PBMCs. The inhibition of PI3Kγ in CpG-stimulated PBMCs resulted in reduction of both cytokine production and phosphorylated Akt. Therefore, drugs that target PI3Kγ have the potential to treat diseases mediated by excessive TLR9 signalling.

Topics: Animals; Cell Survival; Class Ib Phosphatidylinositol 3-Kinase; Cytokines; Female; Gene Deletion; Inflammation; Liver; Lung; Mice, Inbred C57BL; Oligodeoxyribonucleotides; Organ Specificity; Pleura; Pulmonary Fibrosis; Quinoxalines; Signal Transduction; Silicon Dioxide; Thiazolidinediones; Toll-Like Receptor 9

Phosphoinositide 3-kinase-gamma (PI3Kgamma) has been identified to play the critical roles in inflammatory cells activation and recruitment in multiply inflammatory diseases and it promised to be a prospective target for relevant inflammatory diseases therapy. AS605240, a selective PI3Kgamma inhibitor, has been proved effective on several inflammatory diseases. In this study, we investigated the protective effect of AS605240 on bleomycin-induced pulmonary fibrosis in rats. Our results showed that orally administration of AS605240 significantly prevented lung inflammation and reduced collagen deposition. AS605240 also inhibited augmented expression of TNF-alpha and IL-1beta induced by bleomycin instillation. Moreover, the mRNA levels of TNF-alpha and IL-1beta in lung were remarkably suppressed. Histological assessment found that AS605240 reduced the expression of TGF-beta(1) and prevented T lymphocytes infiltration to lung. Phospho-Akt level in inflammatory cells by blocking PI3Kgamma was down-regulated and the inhibition of Akt phosphorylation was further confirmed by Western blot. Our findings illustrated that AS605240 was effective for preventing pulmonary fibrosis by suppressing inflammatory cells recruitment and production of inflammatory cytokines. These findings also suggest that PI3Kgamma may be a useful target in treating inflammation diseases and AS605240 may represent a promising novel agent for the future therapy of pulmonary fibrosis.

Topics: Animals; Bleomycin; Enzyme Inhibitors; Female; Phosphoinositide-3 Kinase Inhibitors; Pulmonary Fibrosis; Quinoxalines; Rats; Rats, Sprague-Dawley; Thiazolidinediones