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Neutrophil Toll-Like Receptor 9 Expression and the Systemic Inflammatory Response in Acetaminophen-Induced Acute Liver Failure

Manakkat Vijay, Godhev K. MPhil1; Ryan, Jennifer M. MBBS1,2,3; Abeles, Robin D. MRCP1,2; Ramage, Stephen MBBS1,2; Patel, Vishal MBBS1,2; Bernsmeier, Christine MD, PhD1; Riva, Antonio PhD3; McPhail, Mark J. W. PhD, MBBS1,4; Tranah, Thomas H. MBBS1; Markwick, Lee J. L. PhD1,3; Taylor, Nicholas J. MBBS1,2; Bernal, William MD, PhD1,2; Auzinger, Georg MD, PhD1,2; Willars, Chris MBBS, FRCA, FCIM2; Chokshi, Shilpa PhD3; Wendon, Julia A. MBBS1,2; Ma, Yun MD, PhD1; Shawcross, Debbie L. MBBS, PhD1,2

doi: 10.1097/CCM.0000000000001309
Clinical Investigations
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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.

1Institute of Liver Studies and Transplantation, King’s College London School of Medicine at King’s College Hospital, London, United Kingdom.

2Liver Intensive Care Unit, King’s College London School of Medicine at King’s College Hospital, London, United Kingdom.

3Foundation for Liver Research, London, United Kingdom.

4Hepatology and Gastroenterology, Liver and Antiviral Unit, St. Marys Hospital, Imperial College London, London, United Kingdom.

Drs. Ma and Shawcross contributed equally.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Supported, in part, by the Institute of Liver Studies Charitable Fund and the Foundation for Liver Research, United Kingdom. The infrastructure to support this study was provided by the Medical Research Council (MRC) Centre for Transplantation, King’s College London, United Kingdom (MRC grant no. MR/J006742/1) and the National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.

Mr. Manakkat Vijay was supported by a King’s College London International PhD studentship. He received support for article research from the Institute of Liver Studies Charitable Fund, Foundation for Liver Research, United Kingdom. Dr. Ryan received funding from Norgine (travel award to attend the International Liver Congress, European Association for the Study of the Liver, 2015). She received other support from the European Foundation for Alcohol Research (ERAB) (grant awarded for consumables for separate PhD project). Her institution received funding from National Institute for Health Research (NIHR) Doctoral Research Fellowship. Dr. Abeles was supported by a Department of Health NIHR Clinical Research PhD Fellowship for the duration of this study. He received support for article research from NIHR (United Kingdom). His institution received funding from NIHR Doctoral Research Fellowship. Dr. Patel disclosed that Norgine Ltd. have provided a travel bursary. His institution received funding from Norgine Ltd. Dr. Bernal received funding from Vital Therapiesand Ocera Therapeutics. Professor Wendon disclosed that the medical advisory board work in no way relates to the content of this article. She received funding from Excalenz and Pulsion (medical advisory board). Her institution received funding from Intensive Care Society grant (consumables only). Dr. Shawcross received honoraria from Norgine for consultancy and advisory board activities. Her institution received funding from the young investigator grant from the Royal Society in 2010 [RG2010/R2] and a Department of Health HEFCE Clinical Senior Lectureship awarded to Dr. Shawcross. Also she was supported by the Institute of Liver Studies Charitable Fund, Foundation for Liver Research, United Kingdom. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: debbie.shawcross@kcl.ac.uk

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