Mono-hydroxyeicosatetraenoic acids during porcine endotoxemia. Effect of a platelet-activating factor receptor antagonist.

Abstract

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.

• Authors: N C Olson, P B Joyce, L N Fleisher
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 63 Issue 2 Pg. 221-32 (Aug 1990) ISSN: 0023-6837 [Print] United States
• PMID: 2116563 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Endotoxins
• Hydroxyeicosatetraenoic Acids
• Platelet Activating Factor
• Quinolines
• SRI 63-675
• Calcimycin

Topics

• Animals
• Blood Platelets (physiology)
• Calcimycin (pharmacology)
• Chromatography, High Pressure Liquid
• Disease Models, Animal
• Endotoxins (toxicity)
• Escherichia coli
• Hydroxyeicosatetraenoic Acids (physiology)
• In Vitro Techniques
• Neutrophils (physiology)
• Platelet Activating Factor (physiology)
• Platelet Aggregation
• Quinolines (pharmacology)
• Respiratory Distress Syndrome (physiopathology)
• Swine