PDF《Hepatitis, not for Septic Shock》

Am J Respir Crit Care Med Vol 159.

pp 1308C1315,

1999 Internet address: www.atsjournals.org LPS Challenge in D-galactosamineCSensitized Mice Accounts for Caspase-dependent Fulminant Hepatitis, not for Septic Shock ALEXANDRE MIGNON, NICOLAS ROUQUET, MONIQUE FABRE, SYLVIE MARTIN, JEAN CHRISTOPHE PAG?S, JEAN FRAN?OIS DHAINAUT, AXEL KAHN, PASCALE BRIAND, and VIRGINIE JOULIN INSERM U

129 ICGM;

INSERM U

380 ICGM;

Service d'

Anatomopathologie, Hopital du Kremlin-Bicêtre;

INSERM U 294, Faculté Xavier Bichat;

and Service de Réanimation, Hopital Cochin, Paris, France Experimental models of sepsis using endotoxin challenges, including studies with sensitized animals with D-galactosamine, have largely contributed to the basic rationale for innovative clinical trials in human septic shock, which have, to date, failed. The ability of these models to reproduce human dis- ease has been highly discussed. We report here that the widely used D-galactosamine/LPS model does not account for septic shock. Treatment with YVAD-CMK, a potent tetrapeptide inhibitor of caspases of the interleukin (IL)-1? converting enzyme (ICE) family, protects from LPS-induced liver apoptosis and mortality in D-galactosamineCsensitized mice when administered either before or up to

2 h after the lethal challenge. This curative effect is related to complete inhibition of caspase-3 ac- tivity in the liver. However, YVAD-CMK does not affect LPS-induced release of IL-1? and does not protect from a lethal dose of LPS in unsensitized mice. These experiments demonstrate the differ- ence between these two widely recognized experimental models of sepsis. LPS toxicity in D-galac- tosamineCtreated mice, leading to blocked gene transcription, results from tumor necrosis factor (TNF)-?-induced caspase-3Cdependent liver injury, not from the systemic inflammatory response. These results provide evidence that inhibitors of the ICE caspase family can prevent or even over- come the ongoing hepatic injury induced by TNF-? during sepsis, ischemiaCreperfusion, or severe hepatitis. Mignon A, Rouquet N, Fabre M, Martin S, Pagès JC, Dhainaut JF, Kahn A, Briand P, Joulin V. LPS challenge in D-galactosamineCsensitized mice accounts for caspase-dependent fulminant hepatitis, not for septic shock. AM J RESPIR CRIT CARE MED 1999;

159:1308C1315. Sepsis is the leading cause of death in intensive care units, af- fecting approximately 400,000 patients in the United States annually, and its incidence continues to increase. Despite a better understanding of its pathophysiology, mortality of sep- sis remains severe (1). Numerous experimental data have pro- vided a solid rationale for innovative therapies and clinical tri- als, which have to date not improved the outcome of the syndrome. Differences that exist between animal studies and human disease probably explain why novel agents are efficient in animals, yet fail in clinical trials of sepsis. Experimental models of sepsis are largely based on animal exposure to en- dotoxin (LPS). Since rodents are constitutively resistant to LPS, Galanos and coworkers (2) demonstrated nearly

20 years ago that mice treated with D-galactosamine (D-GalN) were dramatically sensitized to LPS, allowing reduction of more than 2,500-fold the lethal dose of endotoxin. Based on this ob- servation, several recent studies have been designed and pub- lished in prestigious journals using the LPS/D-GalN model (3C7). However, we addressed the question of whether these studies were relevant to septic shock. Leist and colleagues (8) indeed suggested that LPS in D-GalN-sensitized mice was due to tu- mor necrosis factor alpha (TNF-?) toxicity under conditions of blocked gene transcription, and that accounted for TNF-?- mediated liver apoptosis and acute liver failure. Recently, considerable interest has been focused on the TNF-? apoptotic pathway, especially because of the involve- ment of the cysteine protease of the interleukin (IL)-1? con- verting enzyme (ICE) family referred to as caspases. ICE, re- ferred to as caspase-1, was first described as the enzyme that cleaves inactive pro-IL-1? to mature IL-1? (9). ICE and ICE- related proteases have been further identified as cysteine pro- teases involved in several, if not all, apoptotic pathways, in- cluding the Fas (CD95) and the TNF pathway (10, 11). Eleven caspases have been identified to date in human and in mouse, and allocated into three subgroups with respect to their diver- gent substrate specificity. Reminiscent of the coagulation or (Received in original form December 2,