Doughty Lesley, Clark Robert S B, Kaplan Sandra S, Sasser Howell, Carcillo Joseph
Department of Pediatrics, Rhode Island Hospital, Providence, Rhode Island 02903, USA.
Pediatr Res. 2002 Dec;52(6):922-7. doi: 10.1203/00006450-200212000-00018.
The Fas-Fas ligand system is important for apoptosis of activated immune cells. Perturbation of this system occurs in diseases with dysregulated inflammation. Increased soluble Fas (sFas) occurs in systemic inflammatory response syndrome (SIRS) and can block apoptosis. Increased shedding of FasL (sFasL) occurs in viral infection and hepatitis. Although dysregulated inflammation is associated with sepsis-induced multiple organ failure (MOF) in children, a role for Fas has not been established. We hypothesize that 1) sFas will be increased in children with severe and persistent sepsis-induced MOF and will correlate with inflammatory markers suggesting a role for sFas in inflammatory dysregulation in severe sepsis, and 2) sFasL will be increased when viral sepsis or sepsis-induced liver failure-associated MOF is present in children. Plasma sFas, sFasL, IL-6, IL-10, nitrite + nitrates, and organ failure scores were measured on d 1 and d 3 in 92 children with severe sepsis and 12 critically ill control children. sFas levels were increased in severe sepsis, continued to increase in persistent MOF and nonsurvivors, and were correlated with serum inflammatory markers (IL-6, IL-10, nitrite + nitrate levels). In contrast, sFasL was not increased in severe sepsis and did not correlate with inflammation. sFasL was, however, increased in liver failure-associated MOF and in nonsurvivors, and was associated with viral infection. At autopsy, hepatocyte destruction and lymphocyte infiltration were associated with increased sFas and sFasL levels. sFas may interfere with activated immune cell death and contribute to dysregulation of inflammation, worsening outcome from severe sepsis. sFasL may contribute to hepatic injury and the development of liver failure-associated MOF.
Fas-Fas配体系统对活化免疫细胞的凋亡很重要。该系统的紊乱发生在炎症失调的疾病中。可溶性Fas（sFas）增加见于全身炎症反应综合征（SIRS），并可阻断细胞凋亡。Fas配体（sFasL）的脱落增加见于病毒感染和肝炎。虽然炎症失调与儿童脓毒症诱导的多器官功能衰竭（MOF）有关，但Fas的作用尚未明确。我们假设：1）在患有严重持续性脓毒症诱导的MOF的儿童中，sFas会升高，并与炎症标志物相关，提示sFas在严重脓毒症炎症失调中起作用；2）当儿童出现病毒性脓毒症或脓毒症诱导的肝衰竭相关MOF时，sFasL会升高。对92例严重脓毒症患儿和12例危重症对照患儿在第1天和第3天测定血浆sFas、sFasL、白细胞介素-6（IL-6）、白细胞介素-10（IL-10）、亚硝酸盐+硝酸盐以及器官功能衰竭评分。严重脓毒症时sFas水平升高，在持续性MOF和非存活者中持续升高，并与血清炎症标志物（IL-6、IL-10、亚硝酸盐+硝酸盐水平）相关。相比之下，严重脓毒症时sFasL未升高，且与炎症无关。然而，sFasL在肝衰竭相关MOF和非存活者中升高，并与病毒感染有关。尸检时，肝细胞破坏和淋巴细胞浸润与sFas和sFasL水平升高有关。sFas可能干扰活化免疫细胞死亡，并导致炎症失调，使严重脓毒症的预后恶化。sFasL可能导致肝损伤和肝衰竭相关MOF的发生。
