Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia.

To see whether circulating granulocytes are necessary for the lung vascular reaction to endotoxin, we measured the endotoxin response in chronically instrumented sheep before and after granulocyte depletion with hydroxyurea. Granulocyte depletion did not affect the pulmonary hypertension caused by endotoxin (peak mean pulmonary artery pressures = 38 +/- 2 cm H2O before depletion and 42 +/- 2 after depletion, P = NS). The late phase increase in lung lymph flow after endotoxin was significantly lower in the granulocytopenic animals as reflected by lung lymph flow (mean steady state lymph flow before depletion = 30.6 +/- 2.0 SE ml/h; mean steady state lymph flow after granulocyte depletion = 15.4 +/- 1.0; P less than 0.01) even though late phase pulmonary vascular pressures were similar before and after granulocyte depletion. Lung lymph protein clearance (lymph flow x lymph/plasma protein concentration) was also significantly lower after granulocyte depletion (mean steady state before depletion = 2.14 +/- 1.4 SE ml/h; and after depletion = 10.4 +/- 1.0; P less than 0.01). We conclude that circulating granulocytes are necessary for the development of increased lung vascular permeability to fluid and protein following endotoxin. The pulmonary vasopressor effects of endotoxin in sheep are independent of granulocytes.

Effects of endotoxemia on cyclic nucleotides in the unanesthetized sheep.

The effects of endotoxemia on hemodynamics, pulmonary fluid, and solute exchange and cGMP and cAMP concentrations in lung lymph and pulmonary artery and left atrial blood were studied in six unanesthetized sheep. Cyclic AMP levels increased early in the endotoxin reaction, reaching peak concentration 1 hr after endotoxemia (during the period of pulmonary hypertension). Cyclic GMP levels increased gradually during the endotoxin reaction, reaching peak concentrations 5 hr after endotoxemia (during the period of "increased pulmonary vascular permeability"). The changes observed in cyclic nucleotide levels in lung lymph and pulmonary artery and left atrial blood suggested pulmonary production of cGMP but not cAMP. Cyclic AMP concentrations correlated with PPA, Qlymph, and a drop in the L/P ratio, whereas lung lymph cGMP correlated with an increased clearance of protein in the lymph. These results further characterize the sheep endotoxin reaction and suggest a possible role for cyclic nucleotides in the pathogenesis of the changes in lung vascular function that follow endotoxin infusion in sheep.