as-605240 and Sepsis

A key component during sepsis is the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, of which the PI3K-γ isoform is a major regulator in many inflammatory responses. However, the role of PI3K-γ in the development of sepsis-induced myocardial dysfunction (SIMD) is unknown. In this study, we established a model of SIMD induced by lipopolysaccharide (LPS), subsequently used the selective inhibitor LY294002 and AS605240 to block the effect of PI3K and PI3K-γ, respectively. Cardiac function was evaluated by echocardiography, hearts were obtained for histological and protein expression examinations. ELISA was used to measure the serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), cardiac troponin I (cTnI) and heart-type fatty acid binding protein (H-FABP). LPS-treated mice showed an increase to cardiac inflammation, myocardial damage and production of TNF-α, IL-6, NF-κB, cTnI and H-FABP. Administration of AS605240 to LPS-treated mice reduced some patho-physiological characteristics of SIMD and reduced TNF-α, IL-6, cTnI and H-FABP production. However, administration of LY294002 did not improve those same conditions. The results showed that PI3K-γ is likely a crucial element in SIMD by regulating the PI3K/Akt pathway, and become a new marker of myocardial injury. Inhibition of PI3K-γ might be a potential therapeutic target in SIMD.

Topics: Animals; Cardiomyopathies; Chromones; Class II Phosphatidylinositol 3-Kinases; Cytokines; Disease Models, Animal; Down-Regulation; Interleukin-6; Lipopolysaccharides; Mice; Morpholines; Myocardium; Quinoxalines; Sepsis; Signal Transduction; Thiazolidinediones; Tumor Necrosis Factor-alpha

The integrity of endothelial monolayer is a sine qua non for vascular homeostasis and maintenance of tissue-fluid balance. However, little is known about the signaling pathways regulating regeneration of the endothelial barrier after inflammatory vascular injury.. Using genetic and pharmacological approaches, we demonstrated that endothelial regeneration selectively requires activation of p110γPI3K signaling, which thereby mediates the expression of the endothelial reparative transcription factor Forkhead box M1 (FoxM1). We observed that FoxM1 induction in the pulmonary vasculature was inhibited in mice treated with a p110γ-selective inhibitor and in Pik3cg(-/-) mice after lipopolysaccharide challenge. Pik3cg(-/-) mice exhibited persistent lung inflammation induced by sepsis and sustained increase in vascular permeability. Restoration of expression of either p110γ or FoxM1 in pulmonary endothelial cells of Pik3cg(-/-) mice restored endothelial regeneration and normalized the defective vascular repair program. We also observed diminished expression of p110γ in pulmonary vascular endothelial cells of patients with acute respiratory distress syndrome, suggesting that impaired p110γ-FoxM1 vascular repair signaling pathway is a critical factor in persistent leaky lung microvessels and edema formation in the disease.. We identify p110γ as the critical mediator of endothelial regeneration and vascular repair after sepsis-induced inflammatory injury. Thus, activation of p110γ-FoxM1 endothelial regeneration may represent a novel strategy for the treatment of inflammatory vascular diseases.

Topics: Androstadienes; Animals; Capillary Leak Syndrome; Capillary Permeability; Cells, Cultured; Class Ib Phosphatidylinositol 3-Kinase; Endothelium, Vascular; Enzyme Activation; Enzyme Induction; Forkhead Box Protein M1; Forkhead Transcription Factors; Furans; Humans; Lung; Mice; Mice, Knockout; Microvessels; Neutrophils; Phosphoinositide-3 Kinase Inhibitors; Protein Isoforms; Pulmonary Edema; Pyridines; Pyrimidines; Quinoxalines; Recombinant Fusion Proteins; Regeneration; Respiratory Distress Syndrome; Sepsis; Signal Transduction; Thiazolidinediones; Transfection; Wortmannin