leukotriene-b4 and Shock

Several important eicosanoids are produced during ischemic and shock states that may mediate much of the pathogenesis of these disorders. The primary substances of interest are the thromboxanes (e.g., TxA2), and the peptide leukotrienes (e.g., LTC4 and LTD4). TxA2 and the peptide leukotrienes fulfill all the criteria for a mediator in ischemia and shock. They are potent agents that exhibit a multiplicity of serious pathogenic actions. Moreover, inhibition of the formation or actions of TxA2 and the LTs is salutary in shock. TxA2 and the peptide leukotrienes therefore should be considered as important mediators of ischemia and shock, and probably as potent mediators as any known humoral substances in shock.

Topics: Animals; Fatty Acids; Humans; Ischemia; Leukotriene B4; Shock; SRS-A; Thromboxane A2

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 acti

Topics: Animals; Fatty Acids, Unsaturated; Humans; Leukotriene B4; Platelet Activating Factor; Prostaglandins; Shock; SRS-A; Thromboxane A2

Anaphylatoxins, in particular C3a and C5a, have various biological activities which suggest a role as mediators of inflammatory reactions: they cause contraction of smooth muscle, histamine release, increase in capillary permeability, adhesion of leukocytes to vascular endothelium, leukocyte chemotaxis, and aggregation of platelets and leukocytes. Most of these effects are supported by the cooperation of other mediators, in particular arachidonic acid derivatives which may be produced by anaphylatoxin-stimulated cells, e.g. leukocytes or endothelium. In vivo effects of the complement peptides depend very much on the site of their generation: intravascular release in the general circulation leads to adverse symptoms such as adult respiratory distress syndrome and shock lung, mainly due to leukocyte activation, aggregation and their accumulation in lung vessels. Intravascular release may be induced by certain drugs, and by contact of blood with the surfaces of bypass or dialysis apparatus. Induction of local inflammatory and defense reactions requires release of anaphylatoxins in tissue spaces. Tissue fluid differs quantitatively from blood plasma in its concentration of complement components. This raises some problems of how efficient concentrations of C3a and C5a can be attained at the site of a lesion to generate a chemotactic gradient capable of attracting blood leukocytes.

Topics: Anaphylatoxins; Antibody Formation; Blood Vessels; Chemotaxis, Leukocyte; Complement Activation; Complement C3; Complement C3a; Complement C5; Complement C5a; Humans; Immune Tolerance; Inflammation; Leukocytes; Leukotriene B4; Peptides; Shock; Tissue Distribution; Vasodilation

A variety of eicosanoids are produced in ischemic and circulatory shock. Many of these constrict arteries, induce platelet aggregation or adherence of other blood cells to the vasculature, and contribute to increased membrane permeability. Thromboxane A2, leukotriene C4, and leukotriene D4 fulfill all the criteria stipulated for humoral mediators of ischemia and shock. Moreover, pharmacologic modulation of these mediators by either specific inhibition of their synthesis or antagonism of their arteries at their receptor sites protects against tissue and cell damage during ischemia and shock as well as enhances survival in these life-threatening states.

Topics: Animals; Humans; Ischemia; Leukotriene B4; Prostaglandins; Shock; SRS-A; Thromboxanes; Vasoconstriction

5-Lipoxygenase (5-LO) is the key enzyme in the biosynthesis of pro-inflammatory leukotrienes (LTs) representing a potential target for pharmacological intervention with inflammation and allergic disorders. Although many LT synthesis inhibitors are effective in simple in vitro test systems, they frequently fail in vivo due to lack of efficacy. Here, we attempted to assess the pharmacological potential of the previously identified 5-LO inhibitor 2-(4-(biphenyl-4-ylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (HZ52).. We evaluated the efficacy of HZ52 in vivo using carrageenan-induced pleurisy in rats and platelet-activating factor (PAF)-induced lethal shock in mice. We also characterized 5-LO inhibition by HZ52 at the cellular and molecular level in comparison with other types of 5-LO inhibitor, that is, BWA4C, ZM230487 and hyperforin.. HZ52, 1.5 mg·kg⁻¹ i.p., prevented carrageenan-induced pleurisy accompanied by reduced LTB(4) levels and protected mice (10 mg·kg⁻¹, i.p.) against PAF-induced shock. Detailed analysis in cell-based and cell-free assays revealed that inhibition of 5-LO by HZ52 (i) does not depend on radical scavenging properties and is reversible; (ii) is not impaired by an increased peroxide tone or by elevated substrate concentrations; and (iii) is little affected by the cell stimulus or by phospholipids, glycerides, membranes or Ca²⁺.. HZ52 is a promising new type of 5-LO inhibitor with efficacy in vivo and with a favourable pharmacological profile. It possesses a unique 5-LO inhibitory mechanism different from classical 5-LO inhibitors and seemingly lacks the typical disadvantages of former classes of LT synthesis blockers.

Topics: Animals; Anti-Inflammatory Agents; Arachidonate 5-Lipoxygenase; Caprylates; Carrageenan; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mice; Neutrophils; Nuclear Envelope; Platelet Activating Factor; Pleurisy; Protein Transport; Pyrimidines; Rats; Rats, Wistar; Shock

Topics: Animals; Central Nervous System Diseases; Humans; Inflammation; Ischemia; Leukotriene B4; Shock; SRS-A

Leukotrienes have been implicated as mediators of ischemia and shock. Recent evidence has been obtained supporting the four major criteria of acceptance of leukotrienes as mediators of shock, namely (a) increased concentration in body fluids during shock states, (b) ability to exert significant pathophysiologic effects which aggravate ischemia and shock, (c) amelioration of the shock state by leukotriene synthesis inhibitors and leukotriene receptor antagonists, and (d) production of a shock-like state by exogenous administration of leukotrienes. In conclusion, both LTB4 and the peptide leukotrienes (e.g. LTC4, LTD4 and LTE4) also known as the slow reacting substance of anaphylaxis (SRS-A) can be considered as mediators of ischemia and shock. Although difficulties exist with measuring leukotrienes in circulating blood and in obtaining long lasting selective blockers of leukotriene synthesis, innovative experiments measuring leukotrienes in bile and other body fluids and in employing specific leukotriene receptor antagonists have helped in assessing the significance of the leukotrienes in shock states. Additional studies are necessary to evaluate these findings in perspective, and to compare and contrast the role of leukotrienes to that of other vascular mediators including prostaglandins and thromboxanes, as well as non-eicosanoids including serotonin, histamine, angiotensin II and vasopressin, all of which can play a mediator role in ischemia and shock states. Further clarification of these issues promises to open exciting new chapters in shock research.

Topics: Animals; Free Radicals; Humans; Ischemia; Leukotriene B4; Lipoxygenase Inhibitors; Receptors, Immunologic; Receptors, Leukotriene; Receptors, Leukotriene B4; Receptors, Prostaglandin; Shock; SRS-A