The association between leukocytosis and increased morbidity and mortality of ischemic vascular disease has been observed for more than half a century, and recent studies in >350 000 patients confirm the robustness of the association and the dramatically higher relative and absolute acute and chronic mortality rates in patients with high versus low leukocyte counts. Although there is reason to believe that the association is not causal (that is, that leukocytosis is simply a marker of inflammation), there is also reason to believe that the leukocytosis directly enhances acute thrombosis and chronic atherosclerosis. Leukocytosis also is associated with poor prognosis and vaso-occlusive events in patients with sickle cell disease, and experimental data suggest a direct role for leukocytes in microvascular obstruction. The only way to test whether leukocytes contribute directly to poor outcome in ischemic cardiovascular disease is to assess the effect of modifying leukocyte function or number. Because selective blockade of leukocyte integrin αMβ2 and P-selectin have thus far been disappointing as therapeutic strategies in human cardiovascular and cerebrovascular disease, I discuss the potential risks and benefits of short-term treatment with hydroxyurea to decrease the leukocyte count in select populations of patients at the highest risk of short-term death.

Leukocytosis and ischemic vascular disease morbidity and mortality: is it time to intervene?

Endothelial pathomechanisms in acute lung injury

Mitogen-activated protein kinases (MAPKs) have been the focus of a number of studies, as these compounds are involved in a number of important inflammatory cell signaling mechanisms. Recent studies have further elucidated the role of MAPKs in the inflammatory response, as a result of trauma and/or ischemia–reperfusion (I/R) injury. There are three major classes of MAPKs that may be involved in the inflammatory response: extracellular signal-regulated kinases (ERKs), stress-activated protein kinases (SAPKs)/c-Jun NH2-terminal kinases (JNKs), and p38 MAPKs (p38). This is clinically relevant, because these pathways may be a possible target for anti-inflammatory drug intervention. This review studies the role of MAPKs in trauma and/or I/R.

The role of MAP kinases in trauma and ischemia-reperfusion.

BACKGROUND Resuscitation from hemorrhagic shock triggers an inflammatory response characterized by upregulation of cytokine and adhesion molecule expression, increased leukocyte activity, and accumulation of polymorphonuclear neutrophils in a variety of tissues. This study investigated the capability of an exogenous nitric oxide (NO) donor, sodium nitroprusside (NP); a NO substrate, L-arginine; and an inducible NO synthase inhibitor, L-N6-(1-iminoethyl)lysine (L-NIL) to reduce lung injury in an animal model of mixed controlled and uncontrolled hemorrhagic shock. METHODS For this study, 72 Sprague-Dawley rats weighing 250 to 300 g were subjected to a model of uncontrolled hemorrhagic shock for 150 minutes. Six groups of animals were included in this study (12 per group): sham-saline, sham-NP, shock-saline, shock-NP, shock-L-arginine, and shock-L-N6-(1-iminoethyl)lysine. After the period of hemorrhagic shock, resuscitation of the groups was accomplished using normal saline (groups 1 and 3), NP (0.5 mg/kg) (groups 2 and 4), L-arginine (300 mg/kg) (group 5), or L-NIL (50 mg/kg) (group 6). The following indices were evaluated: fluid requirements for resuscitation, mean arterial pressure (MAP), arterial po2, pco2, and pH, lung wet-to-dry weight ratio, lung histology and cytokine (interleukin [IL]-1 alpha, IL-beta 1, tumor necrosis factor-beta [TNF beta], IL-3, IL-4, IL-5, IL-6, IL-10, TNF alpha, IL-2, interferon-gamma [IFN gamma]), and mRNA expression in the lung by a ribonuclease protection assay (RPA). RESULTS Sodium nitroprusside significantly increased MAP and reduced fluid requirements during resuscitation after hemorrhage. There also was a significant improvement in lung function, as expressed by improvements in po2, pco2, and pH, and reduction of the wet-to-dry weight ratio. In addition, a significant reduction in acute lung injury was observed in the histologic studies. Furthermore, the expression of cytokines was reduced by NP treatment. The use of L-arginine and L-NIL offered similar protective results for the injured lung. CONCLUSIONS These data suggest that limiting inducible NO synthase-generated NO availability with the exogenous NO donor, sodium nitroprusside, may reduce lung injury after severe hemorrhage, possibly, among other effects, by downregulating the expression of inflammatory cytokines. L-arginine and L-NIL also had a beneficial effect on lung function and structure.

Exogenous nitric oxide donor and related compounds protect against lung inflammatory response after hemorrhagic shock and resuscitation.

Objective:The incidence of multiple organ failure in pediatric trauma victims is lower than in the adult population. However, the molecular mechanisms are not yet defined. We investigated whether the pathophysiologic characteristics of hemorrhage-induced lung injury may be age dependent and may be r

/pdf/lung-injury-after-hemorrhage-is-age-dependent-role-of-m4b7r6m3oo.pdf

Lung injury after hemorrhage is age dependent: Role of peroxisome proliferator-activated receptor γ*

Adhesion molecules and hemorrhagic shock.

Reperfusion of an acutely ischemic tissue is recog-nized to elicit an intense inﬂammatory response thatcauses tissue injury The mechanisms of reperfusioninjury are multifactorial, including all the biochemicaland molecular events following ischemia While resto-ration of blood ﬂow is essential in ameliorating theprogression of cellular injury associated with de-creased oxygen and nutrient delivery, it is also followedby a series of complex reactions that paradoxicallyinjures tissue [1–3] Ischemic liver injury is a signiﬁ-cant problem in clinical medicine that can occur as aconsequence of circulatory shock or hepatic surgery(trauma, tumor resection, or liver transplantation) andmay lead to local and organ systemic dysfunction Thepurpose of this review is to analyze all importantchanges associated with the response of cell adhesionmolecules (CAMs) after hepatic ischemia/reperfusion(I/R) injury

RESEARCH REVIEW Adhesion Molecules in Liver Ischemia and Reperfusion

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Adhesion molecules and hemorrhagic shock.

RESEARCH REVIEW Adhesion Molecules in Liver Ischemia and Reperfusion