C‐Abl Inhibition Exacerbates Mechanical Ventilation‐Induced Lung Injury In A Murine Model

Abstract

Endothelial cytoskeleton is a contractile structure responsible for cellular responses to external stimuli and mechanical stress. Nonmuscle myosin light chain kinase (nmMLCK), a critical actin‐binding protein is required for trafficking of inflammatory cellsand alterations in permeability. c‐Abl kinase plays an essential role in barrier regulation via posttranslational modification of nmMLCK. Abl tyrosine kinase phosphorylates nmMLCK and regulates endothelial barrier function. We hypothesized that tyrosine kinase inhibitor imatinib, an anticancer agent, can exacerbate lung injury induced by mechanical ventilation (MV). To explore the role of c‐Abl in lung injury in vivo, mice were tested in our ventilation‐induced acute lung injury (VILI) model after imatinib. Mice were harvested 4h after MV. Imatinib significantly increased bronchoalveolar lavage protein levels (825ug/ml) and total inflammatory cell counts (1.07 × 10□) compared to sham (571ug/ml, 0.75 × 10μ) (p<0.05). These preliminary results indicate that imatinib exacerbates VILI‐injury, likely via c‐Abl blockade. These studies have clinical relevance given the extensive use of imatinib as an anticancer agent and support an important functional role for c‐Abl in lung permeabilityFunded by: NIH grant: P01 HL58064