Baricitinib protects mice from sepsis-induced cardiac dysfunction and multiple-organ failure.

Sepsis is one of the major complications of surgery resulting in high morbidity and mortality, but there are no specific therapies for sepsis-induced organ dysfunction. Data obtained under Gene Expression Omnibus accession GSE131761 were re-analyzed and showed an increased gene expression of Janus Kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3) in the whole blood of post-operative septic patients. Based on these results, we hypothesized that JAK/STAT activation may contribute to the pathophysiology of septic shock and, hence, investigated the effects of baricitinib (JAK1/JAK2 inhibitor) on sepsis-induced cardiac dysfunction and multiple-organ failure (MOF). In a mouse model of post-trauma sepsis induced by midline laparotomy and cecal ligation and puncture (CLP), 10-week-old male (n=32) and female (n=32) C57BL/6 mice received baricitinib (1mg/kg; i.p.) or vehicle at 1h or 3h post-surgery. Cardiac function was assessed at 24h post-CLP by echocardiography in vivo, and the degree of MOF was analyzed by determination of biomarkers in the serum. The potential mechanism underlying both the cardiac dysfunction and the effect of baricitinib was analyzed by western blot analysis in the heart. Trauma and subsequent sepsis significantly depressed the cardiac function and induced multiple-organ failure, associated with an increase in the activation of JAK2/STAT3, NLRP3 inflammasome and NF- κß pathways in the heart of both male and female animals. These pathways were inhibited by the administration of baricitinib post the onset of sepsis. Moreover, treatment with baricitinib at 1h or 3h post-CLP protected mice from sepsis-induced cardiac injury and multiple-organ failure. Thus, baricitinib may be repurposed for trauma-associated sepsis.

RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis.

Sepsis is caused by systemic infection and is a major health concern as it is the primary cause of death from infection. It is the leading cause of mortality worldwide and there are no specific effective treatments for sepsis. Gene deletion of the neutral solute channel Aquaporin 9 (AQP9) normalizes oxidative stress and improves survival in a bacterial endotoxin induced mouse model of sepsis. In this study we described the initial characterization and effects of a novel small molecule AQP9 inhibitor, RG100204, in a cecal ligation and puncture (CLP) induced model of polymicrobial infection. In vitro, RG100204 blocked mouse AQP9 H2O2 permeability in an ectopic CHO cell expression system and abolished the LPS induced increase in superoxide anion and nitric oxide in FaO hepatoma cells. Pre-treatment of CLP-mice with RG100204 (25 mg/kg p.o. before CLP and then again at 8 h after CLP) attenuated the hypothermia, cardiac dysfunction (systolic and diastolic), renal dysfunction and hepatocellular injury caused by CLP-induced sepsis. Post-treatment of CLP-mice with RG100204 also attenuated the cardiac dysfunction (systolic and diastolic), the renal dysfunction caused by CLP-induced sepsis, but did not significantly reduce the liver injury or hypothermia. The most striking finding was that oral administration of RG100204 as late as 3 h after the onset of polymicrobial sepsis attenuated the cardiac and renal dysfunction caused by severe sepsis. Immunoblot quantification demonstrated that RG100204 reduced activation of the NLRP3 inflammasome pathway. Moreover, myeloperoxidase activity in RG100204 treated lung tissue was reduced. Together these results indicate that AQP9 may be a novel drug target in polymicrobial sepsis.