Bβ15-42 Protects against Acid-induced Acute Lung Injury and Secondary Pseudomonas Pneumonia In Vivo

Rationale: Acute lung injury (ALI) is a serious condition in critically ill patients that predisposes to secondary bacterial pneumonia. Vascular leak is a hallmark in the pathogenesis of ALI. The fibrin-derived peptide B beta(15-42) was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of B beta(15-42) in ALI has not been addressed so far. Objectives: To investigate the therapeutic potential of B beta(15-42) in ALI and secondary pneumonia induced by Pseudomonas aeruginosa. Methods: The effect of the fibrin-derived peptide B beta(15-42) was studied in models of ALI, induced either by pulmonary administration of LPS or hydrochloric acid. Lung inflammation was analyzed by quantifying cell influx, cytokine levels, and oxidized lipids. Vascular leak was determined by Evans Blue extravasations and alveolar protein content. In subsequent two-hit studies, mice were infected with A aeruginosa 24 hours after induction of aspiration pneumonitis and effects of B beta(15-42) on inflammation, bacterial clearance, and survival were evaluated. Measurements and Main Results: After LPS or acid inhalation, proinflammatory cytokine levels, neutrophil influx, and vascular leak were found diminished in mice treated with B beta(15-42). Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received B beta(15-42) during acid aspiration and were subsequently challenged with bacteria displayed reduced inflammation, enhanced bacterial clearance, and ultimately improved survival. Conclusions: The fibrin-derived peptide B beta(15-42) exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginoso pneumonia.