Role of platelet-activating factor and eicosanoids during endotoxin-induced lung injury in pigs.
We hypothesized that platelet-activating factor (PAF) and eicosanoids might be important mediators of endotoxin-induced respiratory failure in pigs. Escherichia coli endotoxin (055-B5) was infused intravenously into anesthetized 10- to 14-wk-old pigs at 5 micrograms/kg the 1st h, followed by 2 micrograms.kg-1.h-1 for 3 h in the presence and absence of SRI 63-675, a specific PAF receptor antagonist. During phase I (i.e., 0-2 h), endotoxin caused pulmonary hypertension and hypoxemia, decreased cardiac index, increased pulmonary vascular resistance, and increased plasma concentrations of thromboxane B2 (TxB2), prostaglandin (PG)F2 alpha, and 6-keto-PGF1 alpha. These phase I effects were attenuated or blocked by SRI 63-675 (10 mg/kg before endotoxin + 3 mg.kg-1.h-1 during endotoxemia). During phase II endotoxemia (i.e., 2-4 h), the PAF receptor antagonist blocked endotoxin-induced pulmonary edema and hypoxemia and increased relative permeability index of the alveolar-capillary membrane. SRI 63-675 also blocked the endotoxin-induced increases in plasma and bronchoalveolar lavage fluid concentrations of leukotriene B4 (LTB4). Ex vivo stimulation of whole blood with calcium ionophore caused large increases in plasma concentrations of TxB2 and LTB4. These increases were not significantly modified in blood derived from pigs treated with SRI 63-675, indicating no inhibition of cyclooxygenase or 5-lipoxygenase and suggesting that the in vivo effects were PAF receptor mediated. We conclude that PAF plays an important role in the release of eicosanoids during endotoxemia and in mediating, either directly or indirectly, endotoxin-induced lung injury in anesthetized pigs.
Olson
N C
NC
Department of Anatomy, College of Veterinary Medicine, North Carolina State University, Raleigh 27606.
Joyce
P B
PB
Fleisher
L N
LN
D000818:Animals; D001834:Body Water / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D015777:Eicosanoids / Q000502:physiology*; D004731:Endotoxins / Q000097:blood; D004926:Escherichia coli; D006321:Heart / Q000187:drug effects; D007975:Leukotriene B4 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D010974:Platelet Aggregation / Q000187:drug effects; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000098:blood supply; D011804:Quinolines / Q000494:pharmacology; D013552:Swine
D015777:Eicosanoids; D004731:Endotoxins; D010972:Platelet Activating Factor; D011804:Quinolines; C053130:SRI 63-675; D007975:Leukotriene B4; D000001:Calcimycin; D011451:Prostaglandin-Endoperoxide Synthases