Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.

TitleImatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.
Publication TypeJournal Article
Year of Publication2015
AuthorsRizzo AN, Sammani S, Esquinca AE, Jacobson JR, Garcia JGN, Letsiou E, Dudek SM
JournalAm J Physiol Lung Cell Mol Physiol
Volume309
Issue11
PaginationL1294-304
Date Published2015 Dec 01
ISSN Number1522-1504
KeywordsAcute Lung Injury, Animals, Bronchoalveolar Lavage Fluid, Cell Nucleus, Disease Models, Animal, Endothelial Cells, Humans, Imatinib Mesylate, Inflammation, Lipopolysaccharides, Lung, Male, Mice, Inbred C57BL, Models, Biological, NF-kappa B, Phosphorylation, Protective Agents, Pulmonary Artery, Respiration, Artificial, Tumor Necrosis Factor-alpha, Ventilator-Induced Lung Injury
Abstract

<p>Acute lung injury/acute respiratory distress syndrome (ALI/ARDS), an illness characterized by life-threatening vascular leak, is a significant cause of morbidity and mortality in critically ill patients. Recent preclinical studies and clinical observations have suggested a potential role for the chemotherapeutic agent imatinib in restoring vascular integrity. Our prior work demonstrates differential effects of imatinib in mouse models of ALI, namely attenuation of LPS-induced lung injury but exacerbation of ventilator-induced lung injury (VILI). Because of the critical role of mechanical ventilation in the care of patients with ARDS, in the present study we pursued an assessment of the effectiveness of imatinib in a "two-hit" model of ALI caused by combined LPS and VILI. Imatinib significantly decreased bronchoalveolar lavage protein, total cells, neutrophils, and TNF-α levels in mice exposed to LPS plus VILI, indicating that it attenuates ALI in this clinically relevant model. In subsequent experiments focusing on its protective role in LPS-induced lung injury, imatinib attenuated ALI when given 4 h after LPS, suggesting potential therapeutic effectiveness when given after the onset of injury. Mechanistic studies in mouse lung tissue and human lung endothelial cells revealed that imatinib inhibits LPS-induced NF-κB expression and activation. Overall, these results further characterize the therapeutic potential of imatinib against inflammatory vascular leak.</p>

DOI10.1152/ajplung.00031.2015
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID26432864
PubMed Central IDPMC4669340
Grant ListF30 HL121982 / HL / NHLBI NIH HHS / United States
F30HL121982 / HL / NHLBI NIH HHS / United States
HL058064 / HL / NHLBI NIH HHS / United States