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Hypertonicity induces shedding of L-selectin: a role for p38 activation

Hemorrhagic shock predisposes to adult respiratory distress syndrome, which frequently results in prolonged ICU stay and carries a 50% mortality. We have previously shown that resuscitation with hypertonic saline (NaCl 7.5%) attenuates the post-hemorrhage lung injury by preventing neutrophil (PMN) sequestration. This beneficial effect was due to multiple effects on PMN function and included shedding of the PMN adhesion molecule L-selectin. The aim of the present study was to investigate the signalling pathway underlying this immunological effect. Isolated human PMN were treated with either iso (290 mOsm) or hypertonic (500 mOsm) medium, for up to 2 h. Hypertonicity induced extensive tyrosine phosphorylation in multiple bands. The broad-spectrum inhibitor genistein, abrogated this effect and concomitantly prevented the hypertonic (HT) shedding of L-selectin (graph). In order to characterize the tyrosine kinases involved in this process, we investigated which kinases were phosphorylated, upon shrinkage, and then whether pharmacological inhibition prevented shedding. We found that the non-receptor tyrosine kinases Syk, Pyk-2 and the Src-family kinase Hck were strongly phosphorylated upon shrinkage. However, PP1, a Src-family inhibitor, prevented their phosphorylation but not the HT shedding of L-selectin, suggesting that this effect is independent of Src activation. Next, we found that the p38 was activated upon hypertonic shrinkage in a genistein sensitive but PP1 insensitive way.

Moreover, the inhibition of p38 activation by SB203580 significantly reduced the HT shedding suggesting that p38 is involved in this process (graph). The LPS- and FMLP-induced shedding of L-selectin was also abrogated by SB203580. THUS: Hypertonicity induces a unique pattern of tyrosine phosphorylation in human neutrophils, involving a variety of kinases, most Src-dependent. However, the hypertonic shedding of L-selectin seems to be selectively coupled to p38 activation. In fact, p38 appears to be a central mediator of L-selectin shedding induced by various stimuli. Hypertonicity-induced, p38-mediated L-selectin shedding appears to have an imporant role in the beneficial immune modulatory effect of hypertonicity, preventing neutrophil lung sequestration and cell-mediated tissue damage.

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Rizoli, S., Rotstein, O. & Kapus, A. Hypertonicity induces shedding of L-selectin: a role for p38 activation. Crit Care 3 (Suppl 1), P087 (2000).

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