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

• Published in: American journal of physiology. Lung cellular and molecular physiology 2015-12, Vol.309 (11), p.L1294-L1304
• Main Authors: Rizzo, Alicia N, Sammani, Saad, Esquinca, Adilene E, Jacobson, Jeffrey R, Garcia, Joe G N, Letsiou, Eleftheria, Dudek, Steven M
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - complications; Acute Lung Injury - drug therapy; Acute Lung Injury - pathology; Animals; Bronchoalveolar Lavage Fluid; Call for Papers; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cells; Disease Models, Animal; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Humans; Imatinib Mesylate - pharmacology; Imatinib Mesylate - therapeutic use; Inflammation - complications; Inflammation - drug therapy; Inflammation - pathology; Lipopolysaccharides; Lung - blood supply; Lung - metabolism; Lung - pathology; Lung diseases; Male; Mice, Inbred C57BL; Models, Biological; NF-kappa B - metabolism; Patients; Phosphorylation - drug effects; Protective Agents - pharmacology; Protective Agents - therapeutic use; Pulmonary Artery - pathology; Respiration, Artificial - adverse effects; Respiratory distress syndrome; Rodents; Tumor Necrosis Factor-alpha - biosynthesis; Ventilation; Ventilator-Induced Lung Injury - complications; Ventilator-Induced Lung Injury - drug therapy; Ventilator-Induced Lung Injury - pathology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00031.2015

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.