Abstract
Sepsis is typically triggered by an overwhelming systemic inflammatory response to pathogens, and may lead to severe organ dysfunction and/or death. Sepsis consequently has a high mortality rate and a high rate of complications for survivors, despite modern medical advances. Therefore, drug identification and validation for the treatment of sepsis is of the utmost importance. As a selective phosphodiesterase-4 inhibitor, rolipram also exhibits the abilities of inhibiting multiple pro-inflammatory cytokines production in macrophages and toxin-induced inflammation in mice. However, this drug has never been studied as a sepsis treatment method. We found that rolipram significantly improves survival in mice challenged with gram-negative bacterium E. coli, CLP, or E. coli derived lipopolysaccharide. We have also found that rolipram inhibits organ damage, pro-inflammatory cytokine production, and intracellular migration of early-stage inflammatory elements. Our results also show that rolipram increases anti-inflammatory cytokine production. The protective effects of rolipram on septic mice may result from inhibition of the MAP kinase and NF-κB signaling pathways. Rolipram may therefore be a potential novel sepsis treatment, one that would bypass the time-consuming and costly drug-discovery process.
Highlights
Sepsis is triggered by an overwhelming systemic inflammatory response to pathogenic microorganisms, and may lead to multiple organ dysfunction syndrome (MODS) and death
To assess the protective effect of rolipram on sepsis induced by E. coli, CLP, or E. coli derived LPS, we investigated the effect of the drug on survival rate
We demonstrate that rolipram may protect against LPS-induced inflammation and shock in mice, likely through the inhibition of the NF-κB and MAPK signaling pathways
Summary
Sepsis is triggered by an overwhelming systemic inflammatory response to pathogenic microorganisms, and may lead to multiple organ dysfunction syndrome (MODS) and death. Sepsis is associated with high morbidity and mortality, even under optimal conditions of critical care It is the leading cause of death in non-coronary intensive care units[1]. LPS induces inflammation by binding to Toll-like receptor 4 on the host cell surface. Upon activation of this receptor, the adaptor protein MyD88 is recruited to the receptor, which in turn triggers a cascade of signaling events that leads to the transcription of the transcription factor NF-κB and the mitogen-activated protein (MAP) kinases. LPS-induced transcription and translation of inflammatory mediators leads to inflammatory reactions, organ damage, and shock in the host[12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
