Bosutinib mitigates inflammation in experimental sepsis.

Abstract

Background: Sepsis, a leading cause of death globally, lacks targeted and effective treatment. Its pathophysiology involves unbalanced inflammation, marked by a high release of inflammatory mediators, leukocyte recruitment, vascular changes and dysfunction of the nervous and respiratory systems. Src family tyrosine kinases (SFK) play a critical role in immune responses, and their inhibition can modulate excessive inflammation. This study investigates the potential of bosutinib, an SFK inhibitor, as a treatment for sepsis.

Methods: Clinical signs, survival rates, systemic and neuronal inflammatory responses, cell recruitment, lung function and cerebral microcirculation were analysed in mice treated with bosutinib (3 mg/kg) or DMSO/saline followed by cecal ligation and puncture (CLP)-induced sepsis.

Results: Bosutinib treatment reduced the severity of sepsis, improved survival rates and reduced the levels of pro-inflammatory cytokines and chemokines in peritoneal lavage, plasma and brain tissue. It also reduced cellular infiltration and bacterial growth at the infection site and protected lung function by reducing diffuse alveolar damage. Using intravital microscopy and laser speckle techniques, bosutinib improved capillary density and blood perfusion and reduced leukocyte recruitment and adhesion in the cerebral microcirculation of septic animals.

Conclusions: Bosutinib pretreatment attenuated dysregulated inflammatory responses and neurovascular changes in experimental sepsis.