14 - An inhibitor of NOX2 activation prevents lung injury following LPS administration

Abstract

We have identified a peptide (called PIP-2) that specifically inhibits the activation of NADPH oxidase, type 2 (NOX2). Mice (C57Bl/6) were administered intratracheal lipopolysaccharide (LPS derived from E.coli) at 5 μg/g body wt. Lungs from mice that were evaluated at 12, 16, or 24 hours after LPS showed inflammation (increased cells and protein in the lung lavage fluid), oxidative stress (increased TBARS, 8-isoprostanes, and protein carbonyls in the lung homogenate ), and lung edema (increased lung wet to dry weight ratio). These indices of acute lung injury (ALI) were stable through 24 hr with partial recovery at 48 hr after LPS. Treatment with PIP-2 at 0, 12, or 16 hr after LPS resulted in a complete resolution of the indices of lung injury when lungs were examined at 24 hr. We interpret these results as a reflection of ongoing injury and repair processes in the lung following LPS. In control LPS-treated lungs, ongoing injury and repair were essentially in balance so that the manifestations of acute lung injury remained constant between 12 and 24 hr after LPS administration. However, with administration of PIP-2 at 12 or 16 hr, inhibition of NOX2 activation allowed the lung to fully repair prior to its examination at 24 hr. Thus, inhibition of NOX2 activation can protect lungs against inflammatory lung injury associated with administration of LPS. The non-toxic PIP-2 peptide could be a useful therapeutic agent to prevent oxidative lung injury.