A B S T R A C T To see whether methylprednisolone would affect the pulmonary vascular response to endotoxemia, we studied responses to endotoxemia in the presence and absence of methylprednisolone in the same chronically instrumented, unanesthetized sheep. Infusion of Escherichia coli endotoxin (0.70-1.33,g/ kg) caused an initial period of marked pulmonary hypertension followed several hours later by a long period of increased vascular permeability when pulmonary vascutlar presstures were niear base linie (baseline pulmonary artery pressure (PPa) = 21+1 cm H2O SE, left atrial pressure (Pla) = 1+3; experimental PPa = 20±3, Pla = 3±4; P = NS), lung lymph flow (Qlym) was high (base-line Qlym = 7.2±0.2 ml/h; experimental Olym = 23.2+1.0; P < 0.05) and lymph/ plasma protein conceintration (L/P) was high (base-line L/P = 0.65±0.04; experimental L/P = 0.79±0.05; P < 0.05). When methylprednisolone (1.0 g + 0.5 g/h i.v.) was begtuni 30 min before the same dose of endotoxin was infused, the initial ptilmonary hypertension was less and the late phase increase in lutng vascutlar permeability was prevented (experimental PPa = 24± 1, Pla = 1± 1, Olym = 10.0 ± 0.4; L/P = 0.56 ± 0.03). Olym and L/P were significantly (P < 0.05) lower than with endotoxin alone. Methylprednisolone began duiring the initial putlmonary hypertensive response to endotoxin also prevented the late phase increase inl lutiig vasecular permeability, but the druLg had no effect once vascutlar permeability was increased. We conclude that large doses of methylprednisolone given before or sooIn after endotoxemia prevent the increase in luing vasctular permeability that endotoxin cauises, but do not reverse the abnormality once it occurs.

A B S T R A C T Pulmonary diffusing capacity and arterial blood Po2 decrease in humans when 10% fat emulsion is infused. To study its effects on the pulmonary circulation and lung fluid balance, we infused 0.25 g/kg x h of a 10% fat emulsion (Intralipid, Cutter Laboratories, Inc., Berkeley, Calif.) into an awake sheep lung lymph preparation. The emulsion caused a sustained increase in pulmonary artery pressure to approximately twice base line with little change in left atrial pressure. Pa02 decreased an average 13 torr and lung lymph flow increased two-to threefold. Lymph/ plasma total protein concentration fell as lymph flow increased; the magnitude of the lymph/plasma protein decrease was similar to that reported previously when lung vascular pressures were mechanically elevated. Heparin infusion (loading dose = 4,000 U, maintenance dose = 2,000 U/h) cleared the serum of triglycerides but did not alter the response to fat emulsion. Indomethacin infusion (loading dose = 5 mg/kg, maintenance dose = 3 mg/kg x h) blocked the rise in pulmonary artery pressure, the increase in lung lymph flow, and the fall in Pao0. Neither extravascular lung water nor [14C]urea lung vascular permeability surface area products were altered by fat emulsion infusion. We conclude that fat emulsion infusion in sheep increases lung microvascular filtration by increasing vascular pressures, but has no effect on vascular permeability. Since the effects are blocked by indomethacin, they may be prostaglandin mediated.

Because, in sheep, histamine-induced increased lung vascular permeability is prevented by diphenhydramine, we tested the effects of diphenhydramine on the sheep lung vascular response to endotoxin. We infused E. coli endotoxin (0.40-1.00 micrograms/kg) with and without diphenhydramine (3.0 mg/kg bolus + 1.5 mg . kg-1 . h-1) in the same unanesthetized sheep while measuring pulmonary arterial (Ppa) and left atrial (Pla) pressures, lung lymph flow (Qlym) and lymph (L) and plasma (P) protein concentrations. Endotoxin caused pulmonary hypertension soon after infusion (base-line Ppa = 22 +/- 3 (SE) cmH2O; after endotoxin Ppa = 40 +/- 2; P less than 0.05, n = 6) and after several hours an increase in permeability reflected in high flow of protein-rich lymph (base-line; Qlym = 7.5 +/- 1.4 (SE) ml/h, L/P protein concentration = 0.60 +/- 0.02: after endotoxin; Qlym = 21.4 +/- 3.1, P less than 0.05; L/P = 0.66 +/- 0.03, P less than 0.05). In the presence of diphenhydramine, endotoxin caused identical pressure changes but Qlym was lower during the period of increased permeability (16.7 +/- 3.0 (SE) ml/h, P less than 0.05 compared to endotoxin alone) and L/P protein concentration was similar (0.68 +/- 0.04, P = NS). We conclude that endogenous histamine may be partly responsible for the increase in lung vascular permeability after endotoxemia, but that histamine probably is not the sole mediator of the permeability change.

Pulmonary edema frequently accompanies acute myocardial infarction (MI). We measured pulmonary arterial (PAP), left atrial (LAP), and aortic pressures (AP),lung lymph flow (QL), and clearance of total serum protein and each of eight protein fractions in five anesthetized sheep before and after coronary artery ligation. After a stable base line of 1 h, ligation produced significant increases in LAP, QL, and clearance of total protein and four protein fractions, but no significant changes in PAP, AP, or lymph-to-plasma total protein concentration ratio (CSL/CSP). Variables returned to pre-MI levels within 2 h after occlusion. The ratio of wet to dry lung weight measured 2 h after ligation was within normal limits. Two sheep in which the time course of postligation LAP was duplicated by left atrial balloon inflation showed no change in QL. The QL changes seen cannot be caused by LAP increase alone without substantial decrease in CSL/CSP. Increased QL with high CSL/CSP is typical of increased lung vascular permeability, which is a plausible explanation of our results.

No abstract