Cimetidine reduces hyperoxic lung injury in lambs

Area of Science:

• Pulmonary Medicine
• Toxicology
• Biochemistry

Background:

• Acute oxygen toxicity poses a significant risk during hyperbaric oxygen therapy and mechanical ventilation.
• Endotoxin pretreatment was previously shown to reduce acute pulmonary oxygen toxicity in lambs.
• Cytochrome P-450 mono-oxygenation reactions are implicated in the production of toxic oxygen species.

Purpose of the Study:

• To investigate whether inhibiting cytochrome P-450 activity with cimetidine could protect lambs against acute oxygen toxicity.
• To determine if P-450-mediated oxygen radical production contributes to hyperoxic lung injury.

Main Methods:

• Nine lambs received cimetidine before exposure to >95% oxygen; six control lambs received only oxygen.
• Gas exchange, lung water accumulation, and microvascular permeability were monitored.
• Postmortem antioxidant enzyme levels and glutathione redox state (GSH/GSSG ratio) were analyzed.
• Cytochrome P-450 activity was measured in lung microsomes.

Main Results:

• Cimetidine-treated lambs maintained normal gas exchange longer and accumulated less lung water compared to controls.
• Microvascular permeability remained normal in cimetidine-treated lambs after 72 hours of oxygen exposure.
• The reduced to oxidized glutathione ratio (GSH/GSSG) was significantly higher in cimetidine-treated lambs, indicating reduced oxidative stress.

Conclusions:

• Inhibition of cytochrome P-450 activity by cimetidine confers protection against acute pulmonary oxygen toxicity in lambs.
• Reduced oxidative stress, evidenced by an elevated GSH/GSSG ratio, is a key mechanism of this protection.
• Ranitidine, a non-P-450 inhibitor, did not provide similar protection, further supporting the role of P-450 inhibition.