Progress in biochemical pharmacology最新文献

Gram-negative endotoxemia in chronically instrumented sheep causes diffuse lung inflammation. Pathophysiologic responses of the lung include marked changes in lung mechanics, pulmonary vasoconstriction, increased lung vascular permeability, and capillary endothelial injury. Over the course of the response to endotoxemia, cyclooxygenase and lipoxygenase products of arachidonic acid are released into lung lymph and the time course of the two classes of compounds is different. Thromboxane concentrations in lung lymph increase early, coincident with the most marked changes in lung mechanics and the most severe pulmonary hypertension. Concentrations of a prostacyclin metabolite also increase during this early phase of the endotoxin response but peak levels in lung lymph appear slightly later than that for thromboxane. Concentrations of these cyclooxygenase products subside as the later phase of increased vascular permeability develops. Lung lymph concentrations of two lipoxygenase products, 5- and 12-HETE, increase late in the endotoxin reaction, approximately coincident with physiologic evidence of increased lung vascular permeability. Neutrophil chemotactic activity appears in lung lymph early after endotoxin infusion and persists for several hours. Drugs which inhibit cyclooxygenase attenuate the early changes in lung mechanics and the early pulmonary hypertension after endotoxemia, but do not prevent the late phase increase in vascular permeability, suggesting that the net effect of endogenous generation of cyclooxygenase products explains the early constrictor phase of the reaction, but not the later capillary injury. However, neutrophil depletion prevents the early changes in lung mechanics without preventing the coincident pulmonary hypertension or the increase in lung lymph thromboxane concentrations which may indicate that the cell source of constrictor cyclooxygenase products mediating changes in lung mechanics is different than that for products causing pulmonary vasoconstriction. The specific role of prostacyclin in the lungs' response to endotoxemia is not clear. The temporal course of prostacyclin release suggests that it may play a role in moderating the pulmonary hypertension and changes in lung mechanics. The fact that neutrophil depletion, corticosteroids, and the antioxidant n-acetylcysteine diminish both the endotoxin-induced increase in lung vascular permeability and lung prostacyclin release may indicate that the release of prostacyclin is a response to endothelial injury.(ABSTRACT TRUNCATED AT 400 WORDS)

The leukotrienes are important mediators of numerous responses in lung tissue. Both direct injury and immune injury result in the production of these arachidonate products. Several cellular components participate in the immune surveillance system including monocytes, mast cells and PMNs. Each cell type produces different quantities and types of leukotrienes in response to ionophore (A23187) activation. A common feature shared by each of these cells is control of arachidonic acid metabolism at the level of the 5-lipoxygenase. One provocative interpretation of our results is that the 5-lipoxygenase is activated by C5a and that concomitant modulation of 5-lipoxygenase activity provides a means whereby arachidonic acid metabolism is directed in these cells to either the cyclooxygenase or lipoxygenase pathway. Another common feature that these cells share is that they utilize arachidonic acid mobilized from other cells such as stimulated platelets, certain monocytes, or even damaged tissue. For example, free nonesterified arachidonic acid has been measured at 100 microM in inflamed tissue. Therefore, fluctuations in exogenous arachidonate levels may provide a significant modulation of the inflammatory response by controlling the levels of lipoxygenase products formed by leukocytes. In this scenario the humoral factor C5a is the initiator of the host's response to provide a variety of functional arachidonate products. Another feature that the cellular components of the immune system share is that they may utilize other exogenous lipid substrates. In this case, a lipid product of one cell type may serve as a signal or substrate for a second cell's lipoxygenase pathway. This hypothesis may explain the apparent synergy observed in this and other studies when mixed cell populations were activated. Several hydroperoxy lipids are proposed to be regulatory for the lipoxygenase pathway. Another valid interpretation could be that 5-hyperoxy-eicosatetraenoic acid and LTA4 produced in one cell may diffuse to another cell and be utilized by the lipoxygenase pathway of that cell type. From the results of this study we conclude that the secondary mediator profile obtained when cells are activated by arachidonic acid and C5a depends on the cell composition. We can extend this interpretation of our results to explain two seemingly opposite results obtained when C5a is administered to experimental animals either intrabronchially or intravenously. Future evaluations of the biological effects of C5a should therefore take into consideration the composition of the cells at the target tissue site.(ABSTRACT TRUNCATED AT 400 WORDS)