The use of agents to inhibit the production of
reactive oxygen species (ROS) has been proposed for the treatment of
Acute Lung Injury (ALI). However, this approach also inhibits the bactericidal activity of polymorphonuclear leucocytes (PMN) and other cells, raising the possibility of aggravating
lung injury in ALI associated with
bacterial infection. We used the cecal
ligation and
puncture (CLP) model of ALI associated with
sepsis to investigate the effect of inhibiting
NADPH oxidase 2 (NOX2)-derived ROS production, the main source of ROS in lungs. A
phospholipase A2 inhibitor called
peroxiredoxin 6 inhibitory peptide-2 (PIP-2) was used to inhibit NOX2 activation; the
peptide prevents liberation of Rac, a necessary NOX2 co-factor. At 18 h after intravenous treatment with 2 µg PIP-2 /gram
body weight (wt), the number of colony-forming bacteria in lungs and peritoneal fluid of mice with CLP was approximately doubled as compared to untreated mice. Treatment with 10 µg PIP-2/g body wt resulted in 100% mortality within 18 h.
Antibiotic treatment abolished both the increase in lung bacteria with low dose PIP-2 and the increased mortality with high dose PIP-2. Treatment with PIP-2 plus
antibiotics resulted in significantly improved lung histology, decreased PMN infiltration, decreased lung fluid accumulation, and decreased oxidative
lung injury compared to
antibiotics alone. We conclude that the administration of PIP-2 provides partial protection against
lung injury in a model of ALI due to
bacterial infection, while concurrent
antibiotic treatment abolishes the deleterious effects of PIP-2 on lung bacterial clearance. These results suggest that addition of PIP-2 to the
antibiotic regimen is beneficial for treatment of ALI associated with
bacterial infection.