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Bβ_15–42 Protects against Acid-induced Acute Lung Injury and Secondary Pseudomonas Pneumonia In Vivo

¹ Research Center for Molecular Medicine of the Austrian Academy of Sciences (CeMM), Vienna, Austria; ² Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, ³ Ludwig Boltzmann Cluster for Cardiovascular Research, Department of Biomedical Research, ⁴ Department of Pathology, ⁵ Institute of Vascular Biology and Thrombosis Research, Center for Biomolecular Medicine and Pharmacology, ⁶ Department of Medical and Chemical Laboratory Diagnostics, and ⁸ Department of Dermatology, Division of General Dermatology, Medical University Vienna, Vienna, Austria; and ⁷ Fibrex Medical Research and Development GmbH, Vienna, Austria

Correspondence and requests for reprints should be addressed to Sylvia Knapp, M.D., Ph.D., Research Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, and Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria. E-mail: sylvia.knapp{at}meduniwien.ac.at

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 Bβ_15–42 was shown to preserve endothelial barriers, thereby reducing vascular leak. The potential therapeutic role of Bβ_15–42 in ALI has not been addressed so far.

Objectives: To investigate the therapeutic potential of Bβ_15–42 in ALI and secondary pneumonia induced by Pseudomonas aeruginosa.

Methods: The effect of the fibrin-derived peptide Bβ_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 P. aeruginosa 24 hours after induction of aspiration pneumonitis and effects of Bβ_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 Bβ_15–42. Acid aspiration impaired macrophage functions and rendered mice more susceptible to subsequent P. aeruginosa infection, whereas mice that received Bβ_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 Bβ_15–42 exerted protective effects during ALI, resulting in diminished lung injury and preserved antibacterial properties of macrophages, which improved outcome during subsequent P. aeruginosa pneumonia.

Key Words: acute lung injury • inflammation • pneumonia • Pseudomonas aeruginosa

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Vascular leak and neutrophil migration are hallmarks of acute lung injury (ALI). Despite high mortality rates, specific therapies to prevent lung injury and inflammation are not available. What This Study Adds to the Field The fibrin-derived peptide Bβ15–42 prevents vascular leak and protects mice from ALI and secondary Pseudomonas aeruginosa pneumonia in vivo.