Role of intrapulmonary release of eicosanoids and superoxide anion as mediators of pulmonary dysfunction and endothelial injury in sheep with intermittent complement activation.
In 30 anesthetized sheep, we show that repeated bolus injections of autologous zymosan-activated plasma produce pulmonary hypertension, hypoxemia, intrapulmonary thromboxane release, pulmonary leukostasis, and sustained increases in lung lymph flow and protein clearance. Studies with platelet-rich plasma demonstrated that addition of zymosan-activated plasma does not induce platelet aggregation or thromboxane release. We studied the role of cyclooxygenase products as mediators of these pathophysiological responses by pretreating sheep with either meclofenamate (4 mg/kg) or ibuprofen (12.5 mg/kg). Both drugs inhibited thromboxane release and hypoxemia. Ibuprofen, but not meclofenamate, reproducibly attenuated the hypertensive responses and the increases in lymph flow and protein clearance. Neither drug prevented pulmonary leukostasis. These results demonstrate that cyclooxygenase products mediate the development of complement-induced hypoxemia but are not sole mediators of pulmonary hypertension or increases in vascular permeability. Furthermore, ibuprofen has anti-inflammatory actions, not shared by meclofenamate, which enhance the effectiveness of this drug. Since activated leukocytes release reactive oxygen metabolites, we treated sheep with superoxide dismutase (2800 U/kg per hour) to determine the role of superoxide anions in these responses. This treatment significantly attenuated the increases in lung lymph flow and protein clearance. The results suggest that multiple mediators, which may originate from activated leukocytes sequestered in the pulmonary circulation, contribute to the pathophysiological changes seen with intermittent complement activation. Cyclooxygenase products of arachidonic acid contribute to the hypertension and are solely responsible for the hypoxemia. Reactive oxygen metabolites are important mediators of the complement-induced increases in lung vascular permeability.
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D003167:Complement Activation; D004727:Endothelium / Q000378:metabolism / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology; D007052:Ibuprofen / Q000494:pharmacology; D008171:Lung Diseases / Q000378:metabolism / Q000503:physiopathology*; D008469:Meclofenamic Acid / Q000494:pharmacology; D008954:Models, Biological; D011652:Pulmonary Circulation / Q000187:drug effects; D012756:Sheep; D013481:Superoxides / Q000378:metabolism*; D013931:Thromboxanes / Q000378:metabolism
D013931:Thromboxanes; D013481:Superoxides; D008469:Meclofenamic Acid; D007052:Ibuprofen