Sepsis remains a major cause of death in critically ill patients. New therapeutic strategies are needed to treat this devastating disease. Excessive inflammatory responses, which lead to inflammatory tissue injury, contribute to the pathogenesis of multiple organ failure in sepsis. Recent studies have demonstrated that JAK3 is a promising target against various inflammatory diseases. However, the regulation and function of JAK3 in sepsis have not been studied. In our preliminary studies, we demonstrated that JAK3 expression is highly up-regulated during sepsis. Selective JAK3 inhibition by JAK3 inhibitors, including a FDA-approved inhibitor Tofacitinib, blocked endothelial inflammatory signaling and inflammatory lung injury during sepsis. Furthermore, we demonstrated that JAK3 expression is controlled by HDAC6, a histone deacetylase that modulates nuclear and non-nuclear protein function through deacetylation. HDAC6 knockdown or inhibition prevented TNF-? induced endothelial JAK3 expression, STAT1 activation, and leukocyte adhesion molecule ICAM-1 expression. In a mouse model of polymicrobial sepsis, HDAC6 inhibition blocked sepsis-induced JAK3 expression. In the proposed studies, we will conduct a serial of experiments to assess the therapeutic potential of JAK3 inhibition against sepsis-induced inflammatory lung injury, and to investigate the regulation of JAK3 by HDAC6 during sepsis.
Successful completion of the proposed studies will reveal a novel role of JAK3 in sepsis-induced inflammatory signaling. The studies will validate the therapeutic potential of JAK3 inhibition against inflammatory injury in sepsis. The proposed studies will provide important information for future clinical trials.
