BACKGROUND: Although toll-like receptor 4 (TLR4) activation has been demonstrated to play a key role in the induction of intrahepatic inflammation, leading to hepatocellular damage in liver ischemia/reperfusion injury (IRI), the nature of TLR4 ligands generated during tissue injury remains to be elucidated. We hypothesized that endogenous TLR4 ligands, rather than endotoxin (lipopolysaccharide [LPS]), are instrumental in the activation of liver TLR4 leading to local inflammation response that culminates in ultimate organ IRI. METHODS AND RESULTS: By using the LPS-neutralizing agent, recombinant bactericidal/permeability-increasing protein, we showed that the endotoxin blockade failed to protect mouse livers from warm IRI, as assessed by serum alanine aminotransferase levels, intrahepatic inflammatory gene induction profile, and liver pathology. The recombinant bactericidal/permeability-increasing protein did not cause any hepatocytoxicity by itself if injected into normal naive mice. Furthermore, we demonstrated that liver perfusates, generated by isolated liver perfusion system, contained LPS-independent, heat-sensitive protein molecules that activated macrophages to produce tumor necrosis factor (TNF)-alpha through TLR4 but not TLR2 pathway. CONCLUSION: This study provides a definitive evidence that endogenous TLR4 ligands are critical in the pathogenesis of liver IRI.
BACKGROUND: Although toll-like receptor 4 (TLR4) activation has been demonstrated to play a key role in the induction of intrahepatic inflammation, leading to hepatocellular damage in liver ischemia/reperfusion injury (IRI), the nature of TLR4 ligands generated during tissue injury remains to be elucidated. We hypothesized that endogenous TLR4 ligands, rather than endotoxin (lipopolysaccharide [LPS]), are instrumental in the activation of liver TLR4 leading to local inflammation response that culminates in ultimate organ IRI. METHODS AND RESULTS: By using the LPS-neutralizing agent, recombinant bactericidal/permeability-increasing protein, we showed that the endotoxin blockade failed to protect mouse livers from warm IRI, as assessed by serum alanine aminotransferase levels, intrahepatic inflammatory gene induction profile, and liver pathology. The recombinant bactericidal/permeability-increasing protein did not cause any hepatocytoxicity by itself if injected into normal naive mice. Furthermore, we demonstrated that liver perfusates, generated by isolated liver perfusion system, contained LPS-independent, heat-sensitive protein molecules that activated macrophages to produce tumor necrosis factor (TNF)-alpha through TLR4 but not TLR2 pathway. CONCLUSION: This study provides a definitive evidence that endogenous TLR4 ligands are critical in the pathogenesis of liver IRI.
Authors: Feng Ren; Zhongping Duan; Qiao Cheng; Xiuda Shen; Feng Gao; Li Bai; Jun Liu; Ronald W Busuttil; Jerzy W Kupiec-Weglinski; Yuan Zhai Journal: Hepatology Date: 2011-06-26 Impact factor: 17.425
Authors: Justin D Ellett; Carl Atkinson; Zachary P Evans; Zainab Amani; Edward Balish; Michael G Schmidt; Rick G Schnellmann; Kenneth D Chavin Journal: Liver Transpl Date: 2011-09 Impact factor: 5.799
Authors: Huihua Li; Xiaoli Su; Xuebin Yan; Karla Wasserloos; Wei Chao; A Murat Kaynar; Zhao-Qian Liu; George D Leikauf; Bruce R Pitt; Li-Ming Zhang Journal: Anesthesiology Date: 2010-09 Impact factor: 7.892
Authors: Yuan Zhai; Henrik Petrowsky; Johnny C Hong; Ronald W Busuttil; Jerzy W Kupiec-Weglinski Journal: Nat Rev Gastroenterol Hepatol Date: 2012-12-11 Impact factor: 46.802