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.

Surviving Deadly Lung Infections: Innate Host Tolerance Mechanisms in the Pulmonary System

“…This work found that administration of imatinib reduced multiple measures of vascular permeability including cellular infiltration and total protein and pro-inflammatory cytokine concentrations in the bronchoalveolar lavage fluid. Imatinib was found to act in this model by reducing NF-κB activity, and reduced the symptoms of ALI, even when administered prophylactically (221). A similar effect of imatinib on edema and neutrophil influx was observed in a rat model of ischemia/reperfusion injury (222).…”

Lipopolysaccharide-induced endotoxemia in corn oil-preloaded mice causes an extended course of lung injury and repair and pulmonary fibrosis: A translational mouse model of acute respiratory distress syndrome

“…In addition, our novel model could be developed furthermore by combining corn oil/LPS treatment with mechanical ventilation, i.e. in a so-called “2-hit” scenario that may be more clinically relevant than currently available models [34]. …”

The pulmonary endothelium in acute respiratory distress syndrome: insights and therapeutic opportunities

“…Despite imatinib's association with peripheral oedema,106 case reports have suggested clinical improvements in idiopathic vascular leak107 and bleomycin-induced lung injury 108. Supporting these clinical observations these clinical observations, imatinib attenuated thrombin and histamine-induced barrier dysfunction in vitro109 and pulmonary vascular leak in clinically relevant murine models 105 109. Given its multiple sites of action (table 2), further mechanistic work is required to progress imatinib as a potential therapy in ARDS.…”

“…The pleiotropic effects of the tyrosine kinase inhibitor imatinib, particularly in attenuation of vascular permeability induced by a broad range of mediators (discussed in105), have stimulated study into its efficacy as a barrier-enhancing agent in ARDS. Despite imatinib's association with peripheral oedema,106 case reports have suggested clinical improvements in idiopathic vascular leak107 and bleomycin-induced lung injury 108.…”