Novel Treatments Targeting the Dysregulated Cell Signaling Pathway during Sepsis.

Abstract

Previously characterized as a purely immune mediated disease, sepsis is now recognized as a dysregulated multisystem response against a pathogen. Recognition of the infectious agent by pathogen recognition receptors (PRRs) can initiate activation of the NF-κB signaling pathway and promote the secretion of proinflammatory cytokines. During sepsis, the activation of NF-κB is dysregulated and results in cytokine storm, or the pathologic release of cytokines. Current treatments for sepsis rely on broad spectrum antimicrobial medications and fluid replacement therapy, to neutralize the inciting pathogen and maintain adequate blood pressure. The addition of vasopressor therapy is also utilized when sepsis progresses to septic shock, which is defined by treatment resistant hypotension. Even though modern treatment guidelines have improved clinical outcomes, the mortality rate of sepsis and septic shock is still 15-20% and 20-50%, respectively. To reduce mortality, recent sepsis treatment research has focused on investigating novel therapeutics that can attenuate the dysregulated NF-κB signaling pathway. Antioxidants, such as Retinoic acid and Oxytocin, can reduce activation of the NF-κB pathway by neutralizing stimulatory reactive oxygen species (ROS). Likewise, anti-inflammatory agents can also affect the NF-κB pathway by decreasing the secretion of proinflammatory cytokines, such as TNFα and IL-6. Novel anti-inflammatory cytokines, such as IL-37 and IL-38, have recently been characterized and shown to reduce inflammation in mice with bacterial sepsis. Separately, antioxidants and anti-inflammatory cytokines show promise as potential therapies for sepsis, however, a combined therapy including both agents may prove more beneficial in further improving clinical outcomes.