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.