title: Imatinib attenuates inflammation and vascular leak in a clinically relevant two-hit model of acute lung injury.
abstract: 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.
authors.affiliation: University of Illinois Hospital and Health Sciences System, Division of Pulmonary, Critical Care, Sleep and Allergy, Chicago, Illinois; University of Illinois at Chicago, Department of Pharmacology, Chicago, Illinois;
authors.forename: Alicia N
authors.initials: AN
authors.lastname: Rizzo
authors.affiliation: University of Illinois Hospital and Health Sciences System, Division of Pulmonary, Critical Care, Sleep and Allergy, Chicago, Illinois;
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.affiliation: University of Illinois Hospital and Health Sciences System, Division of Pulmonary, Critical Care, Sleep and Allergy, Chicago, Illinois;
authors.forename: Adilene E
authors.initials: AE
authors.lastname: Esquinca
authors.affiliation: University of Illinois Hospital and Health Sciences System, Division of Pulmonary, Critical Care, Sleep and Allergy, Chicago, Illinois;
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.affiliation: Arizona Health Sciences Center, University of Arizona, Tucson, Arizona.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: University of Illinois Hospital and Health Sciences System, Division of Pulmonary, Critical Care, Sleep and Allergy, Chicago, Illinois;
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Letsiou
authors.affiliation: University of Illinois Hospital and Health Sciences System, Division of Pulmonary, Critical Care, Sleep and Allergy, Chicago, Illinois; University of Illinois at Chicago, Department of Pharmacology, Chicago, Illinois; sdudek@uic.edu.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
mesh_terms: D055371:Acute Lung Injury / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D008070:Lipopolysaccharides; D008168:Lung / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D011651:Pulmonary Artery / Q000473:pathology; D012121:Respiration, Artificial / Q000009:adverse effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D055397:Ventilator-Induced Lung Injury / Q000150:complications / Q000188:drug therapy / Q000473:pathology
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D020011:Protective Agents; D014409:Tumor Necrosis Factor-alpha; D000068877:Imatinib Mesylate
keywords: NF-κB; acute lung injury; acute respiratory distress syndrome; endothelium; imatinib; lipopolysaccharide; mechanical ventilation