Cell volume-dependent regulation of L-selectin shedding in neutrophils. A role for p38 mitogen-activated protein kinase.

摘要: Neutrophil-mediated organ damage is a common feature of many disease states. We previously demonstrated that resuscitation with hypertonic salt solutions prevented the endotoxin-induced leukosequestration and consequent lung injury, this effect was partially attributed to an altered surface expression adhesion molecules, CD11b L-selectin. In study we investigated mechanisms whereby osmotic stress evokes L-selectin shedding. The metalloprotease inhibitor RO 31-9790 down-regulation L-selectin, indicating process catalyzed by same "sheddase" responsible for cleavage induced diverse inflammatory stimuli. trigger shedding cell shrinkage not increased osmolarity, ionic strength, or intracellular pH. Volume reduction caused robust tyrosine phosphorylation its inhibition genistein erbstatin abrogated Shrinkage stimulated kinases Hck, Syk, Pyk2, but prevention their activation Src-family PP1 failed affect response. Hypertonicity elicited Src family-independent p38, kinase SB203580 strongly reduced p38 also essential N-formyl-methionyl-leucyl-phenylalanine- lipopolysaccharide-induced phorbol ester-induced Thus, volume regulates in p38-mediated, metalloprotease-dependent manner. Moreover, has central role mediators.