title: The tyrosine kinase inhibitor imatinib prevents lung injury and death after intravenous LPS in mice.
abstract: Severe sepsis and septic shock are frequent causes of the acute respiratory distress syndrome, and important sources of human mortality. Lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls, plays a major role in the pathogenesis of severe sepsis and septic shock. LPS exposure induces the production of harmful reactive oxygen species, and the resultant oxidant injury has been implicated in the pathogenesis of both severe sepsis and ARDS. We previously showed that the tyrosine kinase inhibitor imatinib increases lung endothelial antioxidant enzymes and protects against pulmonary endothelial antioxidant injury. In the present study, we tested the hypothesis that imatinib would protect against lung injury and systemic inflammation caused by intravenous LPS in an intact mouse model of endotoxemia mimicking early sepsis. We found that intravenous LPS induced a significant increase in the activity of lung xanthine oxidoreductase (XOR), an enzyme which is a major source of reactive oxygen species and implicated in the pathogenesis of acute lung injury. Imatinib had no effect of LPS-induced XOR activity. However, pretreatment of mice with imatinib increased lung catalase activity and decreased intravenous LPS-induced lung oxidant injury as measured by γ-H2AX, a marker of oxidant-induced DNA damage, lung apoptosis, and pulmonary edema. Imatinib also attenuated systemic cytokine expression after intravenous LPS exposure. Finally, imatinib completely prevented mortality in an in vivo, intravenous LPS mouse model of endotoxemia and lung injury. These results support the testing of imatinib as a novel pharmacologic agent in the treatment of Gram-negative sepsis and sepsis-induced ARDS.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland rsteph13@jhmi.edu.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Stephens
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Laura
authors.initials: L
authors.lastname: Johnston
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Laura
authors.initials: L
authors.lastname: Servinsky
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Bo S
authors.initials: BS
authors.lastname: Kim
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Mahendra
authors.initials: M
authors.lastname: Damarla
keywords: Endotoxin; imatinib; lung injury; sepsis