Acute deletion of the extracellular superoxide dismutase leads to severe lung injury. A novel mouse model replicating ARDS‐like lung injury.

The extracellular SOD (ecSOD) is highly expressed in vessels and the lung. Mice with an embryonic knockout of ecSOD are phenotypically normal but develop lung disease when given 100% oxygen and augmented hypertension when treated with angiotensin II. Given the fact that there are multiple antioxidant defenses that could compensate for embryonic deletion of ecSOD these effects might not reveal the true role of the ecSOD in adult animals. To address this question, we examined the effect of acute systemic ecSOD reduction in adult animals using Cre‐Lox technology and tamoxifen (tam) inducible Cre. Remarkably, the acute decrease in ecSOD caused by tam injection in led to 85% mortality in due to severe lung injury histologically similar to the acute respiratory distress syndrome (ARDS). This was associated with an increase in the alveolar‐arterial gradient (from 78±20 to 211±62 mmHG; p<0.05), respiratory acidosis and a 5‐fold increase in lung O 2 − levels as measured by electron spin resonance. Moreover, acute reduction of ecSOD increased lung CD45+ leukocytes an increase in CD8+ T cells suggesting that the loss of ecSOD triggers a CD8+ T cell dependent immune reaction. These data show that the ecSOD is essential for survival in the presence of ambient oxygen. The ecSOD can be oxidatively inactivated, and it is possible that its acute loss via this mechanism leads to worsening lung injury in the clinical situation.