Toll-like receptor 2 plays a critical role in cardiac dysfunction during polymicrobial sepsis
Zou L, Feng Y, Chen YJ, Si R, Shen S, Zhou Q, Ichinose F, Scherrer-Crosbie M, Chao W.
Crit Care Med May 2010;38(5):1335-42.
Reviewers: Vanessa G. Henke, MD and Theodore A. Alston, MD, PhD
Massachusetts General Hospital, Harvard Medical School
Myocardial dysfunction is depressed in inflammatory states, especially in the case of bacterial sepsis. Investigators at MGH induced sepsis in mice by cecal ligation and puncture. Myocardial depression was evident by echocardiography in vivo, by pressure measurements in isolated perfused hearts, and by calcium currents and contractions of isolated single cells. Compared to controls, the myocardial parameters were markedly preserved in animals genetically lacking toll-like receptor 2 (TLR2). Markers of inflammation were attenuated and 14-day survival was better (50 versus 10%). Accordingly, TLR2 can determine for whom the bell tolls.
In German, the word toll is akin to “fantastic.” The toll receptor was discovered in fruit flies and protects insects from microbial infection. Mammals were then found to have similar receptors for endotoxin and other microbial macromolecules. The receptors launch the so-called innate immune reactions. In contrast to the adaptive system, the innate system does not involve T cells and B cells and antibodies. Though TLRs evolved as defense molecules, the inflammatory cascades can prove excessive and deleterious, as demonstrated by the survival outcomes in these experiments.
L. Henry Edmunds describes CPB as “total body inflammation.” It is interesting to wonder whether the TLRs and innate immune system participate in undesirable inflammation associated with extracorporeal circulation. CPB is known to enhance translocation of endotoxin from the GI tract to the bloodstream (Tsunooka N, et al, Eur J Cardiothorac Surg 2004;25:275-80). Furthermore, the innate immune system is related to the blood coagulation system (Esmon CT, Br J Haematol 2005;131:417-30). Indeed, activation of a clotting enzyme (from horseshoe crab!) is classically and presently a routine laboratory method for the assay of endotoxin.
It is puzzling from a Darwinian standpoint that the inflammatory response to sepsis depresses myocardial function. Chemical analogs of endotoxin fragments are experimental inhibitors of TLR2 and TLR4 (Seyberth T, et al, J Med Chem 2006;49:1754-65; Tidswell M, et al, Crit Care Med 2010;38:72-83). The TLR4 blocker is in phase 2 clinical trials. Eventually, therapies targeted at TLRs to help modulate the inflammatory response associated with cardiac surgery may become an important addition to the therapeutic armamentarium for providers of cardiovascular anesthesia and critical care.