Methylprednisolone Prevention of Increased Lung Vascular Permeability following Endotoxemia in Sheep

Abstract

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.

Effects of a Leukotriene Antagonist on the Early Hemodynamic Manifestations of Group B Streptococcal Sepsis in Piglets

“…The initial phase of pulmonary hypertension is prevented by indomethacin given before and after the infusion of bacteria. The later phase is not affected by indomethacin, yet.is prevented by steroids (8,9). In addition, recent evidence suggests that the increase in pulmonary hypertension and PVR and the decrease in CO noted in this late phase of GBS sepsis are reversed by a leukotriene antagonist (2,10).…”

Thromboxane A2 mediates lung vasoconstriction but not permeability after endotoxin.

“…Increased Pw in the control experiments most likely resulted from a general vasoconstriction throughout the lung. Left heart failure was ruled out, since left atrial pressure has been found to be unchanged or reduced by endotoxin infusion (3,30). Inhibition of TxA2 synthesis by dazoxiben essentially prevented increased Ppa, Pw, and PVR after endotoxin infusion, even though the vasoconstrictor PGF2a concentration was elevated.…”

Modification by steroids of pulmonary oedema and prostaglandin E2 pharmacokinetics induced by endotoxin in rats

“…Lung oedema (dry: wet weight ratios) was more clearly reversed by the steroids. Such antagonism of the effects of endotoxin are well known for methylprednisolone (Al-Kaisi et al, 1977;Brigham et al, 1981;Borg et al, 1985b) and, although relatively less substantiated for budesonide (Ottosson et al, 1986), it would be expected from budesonide's generally anti-inflammatory profile of activities (Kallstrom et al, 1985).…”

“…there is considerable experimental evidence that corticosteroids antagonize or prevent lung injury due to endotoxaemia (Al-Kaisi et al, 1977;Hinshaw et al, 1980;Brigham et al, 1981;Schumer, 1981;Borg et al, 1985b), we have also looked at the effects of two synthetic corticosteroids, methylprednisolone and budesonide, on our model of endotoxin-induced lung injury. A preliminary account of some of this work has been given to the British Pharmacological Society (Izumi & Bakhle, 1987).…”