Effect of Catalase on Endotoxin-induced Acute Lung Injury in Unanesthetized Sheep

Abstract

Administration of endotoxin intravenously to unanesthetized sheep causes an acute lung injury characterized by increased microvascular barrier permeability and subsequent pulmonary edema. Endotoxin-induced sheep lung injury can be attenuated by leukocyte depletion, and may be mediated by toxic metabolites of oxygen. We studied effects of administering catalase, which catalyzes conversion of hydrogen peroxide to oxygen and water, to sheep subsequently infused with endotoxin to test the hypothesis that hydrogen peroxide plays a role in the pathogenesis of lung injury. We found that infusions of endotoxin (1 microgram/kg) into untreated sheep caused the expected biphasic response, a transient, early, marked pulmonary arterial hypertension followed by a prolonged increase in protein-rich lung lymph flow characteristic of increased microvascular permeability filtration in the lungs. Intraperitoneal injections of catalase (50 mg/kg) prior to infusing endotoxin in these same sheep resulted in substantial catalase activity in plasma and in lung lymph, and attenuated the expected changes in pulmonary arterial pressure, lung lymph flow, and arterial leukocyte counts and oxygen tension after endotoxin infusions. Furthermore, mechanical elevation of hydrostatic pressure in the lungs of a catalase-treated sheep infused with endotoxin resulted in increased lung lymph flow with a decreased protein concentration, indicating that the microvascular barrier to fluid and protein was functionally intact. Administration of catalase that was inactivated by reaction with hydrogen peroxide in the presence of aminotriazole or administration of the catalase vehicle, thymol, had no effects on the sheep responses to endotoxin. We conclude that hydrogen peroxide plays a role in the pathogenesis of endotoxin-induced acute lung injury in sheep.

Reactive Oxygen Species-Reducing Strategies Improve Pulmonary Arterial Responses to Nitric Oxide in Piglets with Chronic Hypoxia-Induced Pulmonary Hypertension

“…Either the cell-permeable PEG-CAT (250 U/ml) or cell-impermeable CAT (250 U/ml) was used as the H 2 O 2 -decomposing agent. To evaluate the effect of enzymatically inactive CAT, in some studies, we used CAT that was incubated with 3-amino-1,2,4-triazole [5 · 10 -2 M; (34,39)], a CAT inhibitor.…”

Influence of Fructose-1,6-Diphosphate on Endotoxin-Induced Lung Injuries in Sheep

“…Experimental models using oxyradical-generating systems or conditions do produce pulmonary injury. It is of particular importance to emphasize that interventions, such as oxygen free radical scavengers or inhibitors and leukocyte depletion, attenuate or prevent formation of noncardiogenic edema [35][36][37][38]. In the present study, there was a marked decline in leukocyte counts in the peripheral blood in both groups during and after endotoxin infusion.…”

Superoxide Dismutase and Catalase Do Not Affect the Pulmonary Hypertensive Response to Group B Streptococcus in the Lamb

“…The results of the present study are in direct opposition to our original hypothesis. Previous studies indicate that acutely administered SOD and CAT act by scavenging ROS in extracellular spaces (6,7,26). Data from our study indicate that ROS may not penetrate into extracellular spaces.…”

“…Several investigators have proposed that ROS are early mediators of pulmonary hypertension (4 -6). For example, pulmonary hypertension induced by endotoxin in the sheep is attenuated by catalase, indicating that hydrogen peroxide may participate in the generation of increased pulmonary arterial pressures (6,7). However, other studies have resulted in inconsistent responses (8 -11).…”

“…The use of SOD and CAT in other studies of ROS involvement in models of pulmonary hypertension have yielded inconsistent results (6,7,10,12,27). Possible reasons for the conflicting results could stem from the different doses of the antioxidants used or the time between administration of the antioxidant enzymes and the actual start of some of the experimental protocols.…”