In vitro and in vivo effects of leukotriene B4 antagonism in a primate model of asthma.

Abstract

To test the hypothesis that leukotriene (LT) B 4 antagonists may be clinically useful in the treatment of asthma, CP-105,696 was evaluated in vitro, using chemotaxis and flow cytometry assays, and in vivo, using a primate asthma model. CP

Requirement of Phosphatidylinositol 3-Kinase Activation and Calcium Influx for Leukotriene B4-induced Enzyme Release

“…Although G protein-coupled receptor-mediated activation of PI3-K was also found in fMLP-stimulated human neutrophils and thrombin-stimulated human platelets (16 -19), the physiological role of PI3-K in these cells and its relation to calcium increase are somewhat uncertain. Here we demonstrate that LTB 4 -induced enzyme release requires a PI3-K␥ activation and calcium influx by the interaction of BLT1 and G i . was from Funakoshi (Tokyo, Japan).…”

“…Leukotreine B 4 (LTB 4 ), 1 a metabolite of arachidonic acid, is one of the most potent chemoattractants for neutrophils. LTB 4 activates leukocytes, leading to chemotaxis, release of lysosomal enzyme, and production of superoxide anions, thus playing important roles in host defense (1,2).…”

“…LTB 4 activates leukocytes, leading to chemotaxis, release of lysosomal enzyme, and production of superoxide anions, thus playing important roles in host defense (1,2). Overproduction of LTB 4 is involved in various inflammatory diseases including psoriasis (3), bronchial asthma (4), rheumatoid arthritis (5), inflammatory bowel diseases (6), and ischemic renal failure (7).…”

“…Overproduction of LTB 4 is involved in various inflammatory diseases including psoriasis (3), bronchial asthma (4), rheumatoid arthritis (5), inflammatory bowel diseases (6), and ischemic renal failure (7). LTB 4 binds to a specific G protein-coupled receptor named BLT1, which was cloned in our laboratory (8). Signaling to activate leukocytes through BLT1 is poorly understood, in part because most of the previous studies have been done using peripheral leukocytes, especially granulocytes.…”

“…We have previously analyzed signaling pathway from BLT1 using Chinese hamster ovary cells stably expressing human BLT1 (8). In these cells, LTB 4 increases intracellular IP3 levels by G q -like protein(s), inhibits adenylyl cyclase activity, and activates chemotaxis through G i -like protein(s). In hematopoietic cells, however, the intracellular events leading to release of lysosomal enzymes and generation of oxygen species are poorly understood.…”