Abstract 10: Toll-like Receptor 2 Signaling Contributes to Cardiac Dysfunction and High Mortality During Experimental Sepsis
INTRODUCTION: Sepsis has a prevalence of 750,000 cases each year in the US. In severe cases such as septic shock, the mortality reaches more than 40%. It is known that cardiac dysfunction represents a main feature of severe sepsis and contributes to its high mortality. Yet, our understanding of the molecular mechanisms controlling these critical events remains incomplete. The present study was to test the hypothesis that innate immune Toll-like receptor 2 (TLR2) plays a pivotal role in these critical events during sepsis.
METHODS: Polymicrobial peritonitis was generated by cecum ligation and puncture (CLP). The sham animals underwent laparotomy but without CLP. The cardiac function was assessed by
a pressure transducer in the isolated hearts, and
Ca2+transients and sarcomere shortening in cardiomyocytes.
TLR2 chimeric mice were generated by lethal irradiation and bone marrow (BM) reconstruction.
RESULTS: There was a progressive (12– 24 h) and severe reduction in LV function in WT mice subjected to CLP as demonstrated by in vivo serial echocardiography, by LV hemodynamic measurements in isolated hearts, and by sarcomere shortening and Ca2+transients in isolated cardiomyocytes. In comparison, TLR2−/− mice subjected to CLP had much better preserved LV contractile functions and better preserved sarcomere shortening, but not Ca2+transients. TLR2−/− mice also had reduced serum levels of pro-inflammatory cytokines (e.g., TNFá and IL-6) and significantly improved neutrophil mobility into the infectious peritoneal cavity. Moreover, CLP WT mice had a high mortality rate (64% at 48 h and 91% at 96 h), whereas TLR2−/− mice showed dramatic reduction in the mortality rate (22% at 48 h, 33% at 96 h, P<0.05). Compared to the WT→WT (Donor→Recipient) chimeric control mice, the KO→WT mice (WT mice lacking TLR2 in their BM cells) exhibited similar cytokine levels, similar cardiac dysfunction, and similar mortality rate within 14 days following CLP.
CONCLUSIONS: Taken together, these data suggest that TLR2 signaling, most likely that of parenchymal tissues mediates cardiac dysfunction and contributes to the high mortality induced by polymicrobial intra-abdominal sepsis.
This research has received full or partial funding support from the American Heart Association, Founders Affiliate (Connecticut, Maine, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Vermont).