title: Toll-like receptor 4 is essential to preserving cardiac function and survival in low-grade polymicrobial sepsis.
abstract: BACKGROUND
  Toll-like receptor 4 (TLR4), the receptor for endotoxin, mediates hyperinflammatory response and contributes to high mortality during both endotoxin shock and severe sepsis. However, little is known about the role of TLR4 in the pathogenesis of low-grade polymicrobial sepsis, which is often associated with immunosuppression.
  
  
  METHODS
  Low-grade polymicrobial sepsis was generated by cecum ligation and puncture. Mortality was monitored in wild- type (C57BL/10ScSn) and TLR4def (C57BL/10ScCr) mice. Ex vivo heart and individual cardiomyocyte function were assessed in Langendorff (Hugo Sachs Elektronik; Harvard Apparatus, Holliston, MA) and IonOptix systems (IonOptix, Milton, MA), respectively. Serum chemistry was tested for liver and kidney injury. Cytokines were examined using a multiplex immunoassay. Neutrophil migratory and phagocytic functions were assessed using flow cytometry. Reactive oxygen species were measured using redox-sensitive dichlorodihydrofluorescein dye.
  
  
  RESULTS
  Following cecum ligation and puncture, wild-type mice developed bacterial peritonitis with mild cardiac dysfunction (n=3 in sham and n=8 in cecum ligation and puncture) and a mortality of 23% within 14 days (n=22). In comparison, septic TLR4def mice had deleterious cardiac dysfunction (n=6 in sham and n=10 in cecum ligation and puncture), kidney and liver injury (n=7), and much higher mortality at 81% (n=21). The deleterious effects observed in septic TLR4def mice were associated with increased local and systemic cytokine response, reduced neutrophil migratory and phagocytic function, increased reactive oxygen species generation in leukocytes, and impaired bacterial clearance.
  
  
  CONCLUSIONS
  TLR4 plays an essential role in host defense against low-grade polymicrobial sepsis by mediating neutrophil migratory/phagocytic functions, attenuating inflammation, reducing reactive oxygen species generation, and enhanced bacterial clearance.
authors.affiliation: From the Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts (M.Z., L.Z., Y.F., Y.-J.C., F.I., W.C.); and Department of Ultrasound Medicine, Second Xiangya Hospital, Xiangya School of Medicine, Changsha, China (M.Z., Q.Z.).
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Lin
authors.initials: L
authors.lastname: Zou
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Yu-Jung
authors.initials: YJ
authors.lastname: Chen
authors.forename: Qichang
authors.initials: Q
authors.lastname: Zhou
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
mesh_terms: D000818:Animals; D058491:Bacterial Load / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D005260:Female; D006321:Heart / Q000503:physiopathology*; D066298:In Vitro Techniques; D007674:Kidney Diseases / Q000503:physiopathology; D008107:Liver Diseases / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012518:Sarcomeres / Q000235:genetics; D018805:Sepsis / Q000000981:diagnostic imaging / Q000401:mortality / Q000503:physiopathology*; D012772:Shock, Septic / Q000000981:diagnostic imaging / Q000401:mortality / Q000503:physiopathology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D014463:Ultrasonography
chemical_list: D051197:Toll-Like Receptor 4; D002118:Calcium