Mono-hydroxyeicosatetraenoic acids during porcine endotoxemia. Effect of a platelet-activating factor receptor antagonist.
Infusion of endotoxin into domestic pigs induces an acute respiratory failure that has many similarities with the adult respiratory distress syndrome. We hypothesized that mono-hydroxyeicosatetraenoic acids (HETE) and platelet-activating factor (PAF) might be involved in this model of respiratory failure. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized young pigs at 5 micrograms/kg the first hour, followed by 2 micrograms/kg/hour for 3 hours in the presence and absence of SRI 63-675, a specific PAF receptor antagonist. SRI 63-675 (10 mg/kg before endotoxin + 3 mg/kg/hour during endotoxemia) blocked or attenuated endotoxin-induced pulmonary hypertension, bronchoconstriction, hypoxemia, thrombocytopenia, increased permeability of the alveolar-capillary membrane, and the increases in plasma (at 3 and 4 hours) and bronchoalveolar lavage fluid concentrations of 5-, 12-, and 15-HETE. In a separate group of pigs, before treatment with SRI 63-675, ex vivo stimulation of whole blood with calcium ionophore (at -25 min) caused large increases in plasma concentrations of 5-HETE and, to a lesser extent, 12-HETE. At 4 hours, these increases were not significantly modified in blood derived from pigs treated with SRI 63-675 (10 mg/kg + 3 mg/kg/hour from 0 to 4 hours), indicating no direct inhibition of 5- or 12-lipoxygenase and suggesting that the in vivo effects were PAF receptor-mediated. We conclude that PAF contributes to the release of HETEs during endotoxemia and that this phenomenon could be important in the pathophysiology associated with endotoxin-induced lung injury in anesthetized pigs.
Olson
N C
NC
Department of Anatomy, Physiological Sciences and Radiology, College of Veterinary Medicine, North Carolina State University, Raleigh.
Joyce
P B
PB
Fleisher
L N
LN
D000818:Animals; D001792:Blood Platelets / Q000502:physiology; D000001:Calcimycin / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004731:Endotoxins / Q000633:toxicity*; D004926:Escherichia coli; D006893:Hydroxyeicosatetraenoic Acids / Q000502:physiology*; D066298:In Vitro Techniques; D009504:Neutrophils / Q000502:physiology; D010972:Platelet Activating Factor / Q000502:physiology*; D010974:Platelet Aggregation; D011804:Quinolines / Q000494:pharmacology; D012128:Respiratory Distress Syndrome / Q000503:physiopathology*; D013552:Swine
D004731:Endotoxins; D006893:Hydroxyeicosatetraenoic Acids; D010972:Platelet Activating Factor; D011804:Quinolines; C053130:SRI 63-675; D000001:Calcimycin