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.
Highlights
ACUTE LUNG INJURY/ACUTE RESPIRATORY DISTRESS SYNDROME (ALI/ ARDS) is a devastating disease process characterized by severe pulmonary inflammation and vascular leak that causes hypoxemic respiratory failure in critically ill patients [51]
There are no effective therapies to protect endothelial cell (EC) barrier function, recent work from several groups has demonstrated that imatinib, an FDA-approved tyrosine kinase inhibitor, attenuates vascular leak induced by multiple inflammatory stimuli [5, 10, 27, 45]
A recent series of case reports suggests that imatinib may reduce vascular permeability in certain conditions in humans [4, 8, 36], suggesting that imatinib may have therapeutic potential in patients with inflammatory vascular leak syndromes
Summary
ACUTE LUNG INJURY/ACUTE RESPIRATORY DISTRESS SYNDROME (ALI/ ARDS) is a devastating disease process characterized by severe pulmonary inflammation and vascular leak that causes hypoxemic respiratory failure in critically ill patients [51]. Recent reports indicate that imatinib attenuates the vascular leak induced by diverse stimuli including thrombin, histamine, VEGF, LPS, and reactive oxygen species (ROS) [5, 10, 27, 29, 45] These studies have indicated that multiple targets of imatinib, including c-Abl, Arg, and PDGFR, are involved in regulating the cytoskeletal rearrangements that mediate vascular permeability. Contrary to its barrier-protective effects, imatinib has well-established side effects of periorbital and subcutaneous edema, as well as pleural and pericardial effusions in patients, suggesting that it can worsen vascular leak in certain clinical contexts [17, 23, 41] Consistent with this potential for imatinib to exert both barrier-protective and edemagenic effects, we recently reported that imatinib attenuates LPS-induced lung injury but exacerbates VILI both in vitro and in vivo [29]. Our data indicate that imatinib has potent anti-inflammatory effects, in addition to its previously described effects on EC permeability, and further support its potential use as a therapeutic option for inflammatory vascular leak syndromes
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