Journal
CRITICAL CARE MEDICINE
Volume 44, Issue 1, Pages 43-53Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/CCM.0000000000001309
Keywords
acute liver failure; encephalopathy; neutrophil; toll-like receptor 9
Categories
Funding
- Institute of Liver Studies Charitable Fund
- Foundation for Liver Research, United Kingdom
- Medical Research Council (MRC) Centre for Transplantation, King's College London, United Kingdom [MR/J006742/1]
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust
- King's College London
- King's College London International PhD studentship
- Institute of Liver Studies Charitable Fund, Foundation for Liver Research, United Kingdom
- Norgine
- European Foundation for Alcohol Research (ERAB)
- National Institute for Health Research (NIHR) Doctoral Research Fellowship
- Department of Health NIHR Clinical Research PhD Fellowship
- NIHR (United Kingdom)
- NIHR Doctoral Research Fellowship
- Norgine Ltd.
- Vital Therapies
- Ocera Therapeutics
- Excalenz
- Pulsion
- Intensive Care Society
- Royal Society [RG2010/R2]
- Department of Health HEFCE Clinical Senior Lectureship
- Medical Research Council [MR/J006742/1] Funding Source: researchfish
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Objectives: There is a marked propensity for patients with acetaminophen-induced acute liver failure to develop sepsis, which may culminate in multiple organ failure and death. Toll-like receptors sense pathogens and induce inflammatory responses, but whether this is protective or detrimental in acetaminophen-induced acute liver failure remains unknown. Design, Setting, and Patients: We assessed Toll-like receptor expression on circulating neutrophils and their function in 24 patients with acetaminophen-induced acute liver failure and compared with 10 healthy controls. Interventions: Neutrophil Toll-like receptor 2, -4, and -9 expression and cytokine production and function were studied ex vivo at baseline and following stimulation with lipopolysaccharide, oligodeoxynucleotides, ammonium chloride, and interleukin-8. To examine the influence of acetaminophen-induced acute liver failure plasma and endogenous DNA on Toll-like receptors-9 expression, healthy neutrophils were incubated with acetaminophen-induced acute liver failure plasma with and without deoxyribonuclease-I. Measurements and Main Results: Circulating neutrophil Toll-like receptor 9 expression was increased in acetaminophen-induced acute liver failure on day 1 compared with healthy controls (p = 0.0002), whereas Toll-like receptor 4 expression was decreased compared with healthy controls (p < 0.0001). Toll-like receptor 2 expression was unchanged. Neutrophil phagocytic activity was decreased, and spontaneous oxidative burst increased in all patients with acetaminophen-induced acute liver failure compared with healthy controls (p < 0.0001). Neutrophil Toll-like receptor 9 expression correlated with plasma interleukin-8 and peak ammonia concentration (r = 0.6; p < 0.05) and increased with severity of hepatic encephalopathy (grade 0-2 vs 3/4) and systemic inflammatory response syndrome score (0-1 vs 2-4) (p < 0.05). Those patients with advanced hepatic encephalopathy (grade 3/4) or high systemic inflammatory response syndrome score (2-4) on day 1 had higher neutrophil Toll-like receptor 9 expression, arterial ammonia concentration, and plasma interleukin-8 associated with neutrophil exhaustion. Healthy neutrophil Toll-like receptor 9 expression increased upon stimulation with acetaminophen-induced acute liver failure plasma, which was abrogated by preincubation with deoxyribonuclease-I. Intracellular Toll-like receptor 9 was induced by costimulation with interleukin-8 and ammonia. Conclusion: These data point to neutrophil Toll-like receptor 9 expression in acetaminophen-induced acute liver failure being mediated both by circulating endogenous DNA as well as ammonia and interleukin-8 in a synergistic manner inducing systemic inflammation, neutrophil exhaustion, and exacerbating hepatic encephalopathy.
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