Proposed role for leukotrienes in the pathophysiology of multiple systems organ failure.

The leukotrienes are a group of biologically active products of arachidonic acid metabolism that have been demonstrated to possess the capability to alter vascular reactivity as well as vascular permeability when applied topically to tissues or infused into the vascular bed of various organs. These biologic effects of the exogenous leukotrienes have led to the speculation that these arachidonic acid metabolites could be important mediators in the pathophysiologic events that culminate in the development of acute lung injury and MSOF. Increased production of inflammatory mediators is undoubtedly a contributing factor to the pathophysiologic events that culminate in MSOF. LTB4 has been shown to be a potent stimulator of neutrophil chemotaxis and adhesion. It is possible that LTB4 may be responsible for initiation or amplification of the inflammatory response in this syndrome. The sulfidopeptide leukotrienes have profound effects on cardiac function, which may be mediated through effects on both coronary blood flow and cardiac contractility. These arachidonic acid metabolites are also capable of altering blood flow to several vascular beds and, when synthesized endogenously and released, may be important in the regulation of the peripheral circulation. Endogenous leukotrienes may have physiologic or pathophysiologic effects on cardiac output and its distribution to peripheral vascular beds or on systemic blood pressure. In view of the observations that alterations in cardiac output, blood pressure, and individual organ blood flow have been demonstrated in the clinical setting of ARDs and MSOF, it is attractive to suggest that the leukotrienes may contribute to the hemodynamic alterations observed in these clinical conditions. In addition to their effects on vascular smooth muscle and the myocardium, the leukotrienes have been shown to increase the permeability of blood vessels. In the case of the sulfidopeptide leukotrienes, the enhanced vascular permeability appears to be a direct effect of these lipoxygenase metabolites. Although LTB4 may directly increase vascular permeability, several lines of evidence suggest that the recruitment and activity of neutrophils is required for edema formation to develop following application of this leukotriene. Enhanced capillary permeability, at least in the pulmonary circulation, is a hallmark of ARDS and is also frequently present in MSOF. The leukotrienes, either through direct effects on vessels or through recruitment of inflammatory cells, are likely contributors to the nonhydrostatic edema associated with these syndromes.