Prostaglandins, leukotrienes, and platelet-activating factor in shock.
Three major lines of evidence support a role of eicosanoids and PAF in shock. Formation of each of the cyclooxygenase metabolites of arachidonate is enhanced at some point during the shock; these metabolites include PGE2, PGF2 alpha, PGI2, and TXA2. Enhanced formation of 5-HETE and the cysteinyl-LTs provides evidence for activation of the 5-lipoxygenase pathway of arachidonate metabolism, and preliminary biochemical evidence suggests that formation of PAF in anaphylactic and endotoxic shock is also enhanced. Second, TXA2, cysteinyl-leukotrienes, and, to an even greater extent, PAF are able to produce shock and death in intact animals. Third, pharmacological studies show that selective antagonists or synthesis inhibitors modify the course of the shock. While any of these lines of evidence may not by itself provide proof for a cause-effect relationship, the data taken together strongly suggest that vasoactive lipids might be involved in fundamental processes in the pathophysiology of shock. However, the role of vasoactive lipids might vary in different shock paradigms, change at various time points during the evolution of the shock, and depend on the species studied. Moreover, while the majority of the reports tend to focus on a specific substance, the metabolism of all of the eicosanoids mentioned, as well as PAF and probably other arachidonate metabolites (e.g. 15-lipoxygenase products such as lipoxins), changes during shock states. This fact probably causes most of the discrepancies in studies using specific antagonists or synthesis inhibitors to modify the state of shock. Thus, while blockade of one mediator might provide some protection, it might not be sufficient to halt or reverse the main course of the pathophysiological process. For example, the increase in vascular permeability, a fundamental phenomenon in trauma, anaphylaxis, or endotoxemia, might be mediated by PAF, LTs, PGs, peptides (e.g. kinins, substance P, CGRP) and amines (e.g. histamine in some species). Attempting to reverse such a complex phenomenon by blocking one specific factor might not be productive unless the specific substance played a key role in generation of the other factors. It seems, however, that while interactions between PGs, LTs, and PAF do occur (31, 32, 70), none of the shock states are crucially dependent on one class of the vasoactive lipids. Therefore, the therapeutic strategy should be based on multiple sites of action, either by drug combinations or multiple actions of a specific drug.(ABSTRACT TRUNCATED AT 400 WORDS)
D000818:Animals; D005231:Fatty Acids, Unsaturated / Q000097:blood*; D006801:Humans; D007975:Leukotriene B4 / Q000097:blood; D010972:Platelet Activating Factor / Q000097:blood*; D011453:Prostaglandins / Q000097:blood; D013189:SRS-A / Q000097:blood; D012769:Shock / Q000097:blood*; D013928:Thromboxane A2 / Q000097:blood
D005231:Fatty Acids, Unsaturated; D010972:Platelet Activating Factor; D011453:Prostaglandins; D013189:SRS-A; D007975:Leukotriene B4; D013928:Thromboxane A2