Bosutinib protects against pulmonary vascular leakage by improving endothelial cell-matrix adhesion

Dysfunction of the endothelial barrier leads to uncontrolled fluid extravasation and vascular leak, yielding high morbidity and mortality. We previously demonstrated that Abl kinase inhibition protects against vascular leak. Since then, next generation AKIs were developed with broader kinase inhibition and better safety profiles. The current study aims to evaluate whether combined kinase inhibition as provided by next generation AKIs, provides novel therapy strategies against vascular leakage. A screen on second and third generation AKIs revealed that bosutinib (Bosulif®) has better protective effects on endothelial barrier, as compared to imatinib and other AKIs. Materials and results: Upon exposure to various inflammatory mediators, bosutinib reinforced vascular integrity through enhanced focal adhesion formation and adherens junction stabilization in primary human lung endothelial cells. Bosutinib treatment attenuated alveolar protein leakage and pulmonary edema in an acute lung injury mice model. We demonstrate that these protective effects of bosutinib resulted from combined inhibition of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) and Arg. MAP4K4 was identified as important novel regulator of focal adhesion turnover and combined inhibition of Arg and MAP4K4 completely mimicked the protective effect of bosutinib on barrier function. In conclusion, bosutinib shows a robust protective effect against inflammation-induced endothelial barrier disruption via combined inhibition of Arg and MAP4K4. Because bosutinib is a clinically available drug, reinforcement of cell-matrix adhesions by bosutinib may be a viable strategy against pulmonary vascular leakage syndromes.