Abstract
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. Figure
Highlights
Ill patients requiring intensive care are at risk of iatrogenic ocular damage
Intensive Care Unit (ICU) management of critically ill patients often includes the requirement for tracheostomy and feeding access, most often a pecutaneous endoscopic gastrostomy (PEG)
Percutaneous tracheostomy is performed routinely in many medical intensive care unit (ICU) settings, in high risk surgical and trauma patients who often have unstable cervical spine injury and tissue edema, direct visualization of the cervical structures and trachea is imperative during tracheostomy
Summary
Ill patients requiring intensive care are at risk of iatrogenic ocular damage. We designed an experimental situation where external cardiac pressure conditions were controlled and adjusted to physiological extremes to mimic clinically relevant situations, while cardiac performance was assessed using left ventricular pressure–volume relationships (LVPVR) which are relatively preload and afterload independent This prospective, controlled study was undertaken to evaluate the response to therapy aimed at achieving supranormal cardiac and oxygen transport values (cardiac index >4.5 l/min/m2, oxygen delivery >600 l/min/m2, and oxygen consumption >170 l/min/m2) in patients older than 60 or with previous severe cardiorespiratory illnesses, who have undergone elective extensive ablative surgery planned for carcinoma or abdominal aortic aneurism. Whilst some human studies conducted in the critically ill and in high risk surgical patients have suggested that dopexamine may cause an increase in tonometrically measured gastric intra-mucosal pH (pHi) and an improvement in clinical outcome, this has not been confirmed in other randomised trials. In the present study the association of platelet function to inflammatory markers indicating disease severity was investigated
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