Blood concentrations of mediators released from activated neutrophils are related to the severity of alcohol-induced liver damage

Background Immune dysregulation and neutrophil infiltration are hallmarks of alcohol-related liver disease (ALD). Our objective was to evaluate the blood profile of neutrophil-derived mediators [neutrophil elastase (NE), myeloperoxidase (MPO), alpha1-antitrypsin (A1AT)], and their potential relevance in ALD. Methods 62 patients with ALD /47 males, and 15 females, aged 49,2 ± 9,9/ were prospectively recruited and distributed according to their 1/ gender, 2/ severity of liver dysfunction (by Child-Turcotte-Pugh, MELD scores, and mDF) 3/ presence of complications of ALD complications, and followed for 90 days. 24 age- and sex-matched healthy volunteers served as the control group. Neutrophil-derived biomarkers were quantified using enzyme-linked immunosorbent assays (ELISAs). Results Blood concentrations of MPO and NE were significantly higher in ALD patients in comparison with controls. A1AT levels were not different. There were no gender-related differences in the studied biomarker levels. Both NE and MPO correlated with routine markers of inflammation, while NE with MELD and mDF scores. Patients with a severe ALD course i.e. MELD>20 or mDF>32, presented with significantly higher NE blood concentrations. Conclusions Our results point out the critical role of neutrophils in the pathogenesis of ALD. NE and MPO correlated with the intensity of inflammation, and NE was related to the severity of liver dysfunction.

[1]  James H. Conigrave,et al.  More than three times as many Indigenous Australian clients at risk from drinking could be supported if clinicians used AUDIT-C instead of unstructured assessments , 2022, Addiction Science & Clinical Practice.

[2]  B. Geller,et al.  Prognostic value of neutrophil-to-lymphocyte ratio in cirrhosis patients undergoing transjugular intrahepatic portosystemic shunt. , 2021, European journal of gastroenterology & hepatology.

[3]  Guohong Deng,et al.  Baseline Neutrophil-to-Lymphocyte Ratio Is Independently Associated With 90-Day Transplant-Free Mortality in Patients With Cirrhosis , 2021, Frontiers in Medicine.

[4]  Yao Liu,et al.  Neutrophil–lymphocyte ratio and the risk of hepatocellular carcinoma in patients with hepatitis B-caused cirrhosis , 2021, European journal of gastroenterology & hepatology.

[5]  Douglas A. Simonetto,et al.  Urinary NGAL as a Diagnostic and Prognostic Marker for Acute Kidney Injury in Cirrhosis: A Prospective Study , 2021, Clinical and translational gastroenterology.

[6]  Hongyang Wang,et al.  The Roles of Neutrophils in the Pathogenesis of Liver Diseases , 2021, Frontiers in Immunology.

[7]  Yulan Liu,et al.  Neutrophil-Induced Liver Injury and Interactions Between Neutrophils and Liver Sinusoidal Endothelial Cells , 2021, Inflammation.

[8]  G. Szabo,et al.  Two Faces of Neutrophils in Liver Disease Development and Progression , 2020, Hepatology.

[9]  R. Xu,et al.  Neutrophils in liver diseases: pathogenesis and therapeutic targets , 2020, Cellular & Molecular Immunology.

[10]  S. Kottilil,et al.  Abnormal Innate Immunity in Acute-on-Chronic Liver Failure: Immunotargets for Therapeutics , 2020, Frontiers in Immunology.

[11]  K. So,et al.  Liver regeneration and alcoholic liver disease , 2020, Annals of translational medicine.

[12]  C. Rosales.  Neutrophils at the crossroads of innate and adaptive immunity , 2020, Journal of leukocyte biology.

[13]  Qin-Si Wan,et al.  Fluid Biomarkers for Predicting the Prognosis of Liver Cirrhosis , 2020, BioMed research international.

[14]  F. DeLeo,et al.  The Role of Neutrophils in the Immune System: An Overview. , 2019, Methods in molecular biology.

[15]  Paul L. Martin,et al.  Bacterial Infection in Patients with Cirrhosis: Don’t Get Bugged to Death , 2019, Digestive Diseases and Sciences.

[16]  M. Bartneck,et al.  Therapeutic Targeting of Neutrophil Granulocytes in Inflammatory Liver Disease , 2019, Front. Immunol..

[17]  P. Hayes,et al.  Baseline neutrophil‐to‐lymphocyte ratio predicts response to corticosteroids and is associated with infection and renal dysfunction in alcoholic hepatitis , 2019, Alimentary pharmacology & therapeutics.

[18]  W. Jiménez,et al.  Neutrophil Gelatinase‐Associated Lipocalin for Assessment of Acute Kidney Injury in Cirrhosis: A Prospective Study , 2019, Hepatology.

[19]  Ning Wang,et al.  Recent Insights Into the Role of Immune Cells in Alcoholic Liver Disease , 2019, Front. Immunol..

[20]  A. Mari,et al.  Neutrophil-to-lymphocyte ratio is independently associated with inflammatory activity and fibrosis grade in nonalcoholic fatty liver disease. , 2019, European journal of gastroenterology & hepatology.

[21]  Yi Liu,et al.  Different Faces for Different Places: Heterogeneity of Neutrophil Phenotype and Function , 2019, Journal of immunology research.

[22]  M. Lucey.  Alcohol-Associated Cirrhosis. , 2019, Clinics in liver disease.

[23]  P. Lescuyer,et al.  Biomarkers for acute kidney injury in decompensated cirrhosis: A prospective study , 2019, Nephrology.

[24]  K. Kodys,et al.  Abnormal neutrophil traps and impaired efferocytosis contribute to liver injury and sepsis severity after binge alcohol use. , 2018, Journal of hepatology.

[25]  S. Baik,et al.  Impact of sarcopenia on prognostic value of cirrhosis: going beyond the hepatic venous pressure gradient and MELD score , 2018, Journal of cachexia, sarcopenia and muscle.

[26]  D. Rockey,et al.  Predictors of clinical outcomes in cirrhosis patients , 2018, Current opinion in gastroenterology.

[27]  H. Cortez‐Pinto,et al.  EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. , 2018, Journal of hepatology.

[28]  R. Bataller,et al.  Clinical Guideline : Alcoholic Liver Disease , 2018 .

[29]  Kathryn Prame Kumar,et al.  Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease , 2018, Cell and Tissue Research.

[30]  Z. Granot,et al.  Neutrophil, quo vadis? , 2017, Journal of leukocyte biology.

[31]  J. Byun,et al.  Hepatic Immune Microenvironment in Alcoholic and Nonalcoholic Liver Disease , 2017, BioMed research international.

[32]  G. Hirschfield,et al.  EASL Clinical Practice Guidelines: The diagnosis and management of patients with primary biliary cholangitis. , 2017, Journal of hepatology.

[33]  D. Shawcross,et al.  Dysfunctional neutrophil effector organelle mobilization and microbicidal protein release in alcohol-related cirrhosis. , 2017, American journal of physiology. Gastrointestinal and liver physiology.

[34]  Mengwei Zang,et al.  Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression. , 2017, Journal of hepatology.

[35]  Tieshan Teng,et al.  Neutrophils and Immunity: From Bactericidal Action to Being Conquered , 2017, Journal of immunology research.

[36]  A. Segal,et al.  The NADPH Oxidase and Microbial Killing by Neutrophils, With a Particular Emphasis on the Proposed Antimicrobial Role of Myeloperoxidase within the Phagocytic Vacuole. , 2016, Microbiology spectrum.

[37]  R. Moreau,et al.  Impaired intracellular signaling, myeloperoxidase release and bactericidal activity of neutrophils from patients with alcoholic cirrhosis. , 2016, Journal of hepatology.

[38]  E. Albano,et al.  The role of immune mechanisms in alcoholic and nonalcoholic steatohepatitis: a 2015 update , 2016, Expert review of gastroenterology & hepatology.

[39]  E. Kalaitzakis,et al.  Bacterial infections in alcoholic and nonalcoholic liver cirrhosis , 2015, European journal of gastroenterology & hepatology.

[40]  T. Thévenot,et al.  New prognostic markers in liver cirrhosis. , 2015, World journal of hepatology.

[41]  Philip Wong,et al.  Hepatic encephalopathy in chronic liver disease: 2014 Practice Guideline by the American Association for the Study Of Liver Diseases and the European Association for the Study of the Liver , 2014, Hepatology.

[42]  Jing Wang,et al.  Regulation of immune responses by neutrophils , 2014, Annals of the New York Academy of Sciences.

[43]  Zheng Zhang,et al.  The role of neutrophils in the development of liver diseases , 2014, Cellular and Molecular Immunology.

[44]  Y. Solak,et al.  Blood neutrophil-to-lymphocyte ratio independently predicts survival in patients with liver cirrhosis , 2013, European journal of gastroenterology & hepatology.

[45]  D. C. Cara,et al.  Chemokines and mitochondrial products activate neutrophils to amplify organ injury during mouse acute liver failure , 2012, Hepatology.

[46]  R. Jalan,et al.  Evidence of neutrophil functional defect despite inflammation in stable cirrhosis. , 2011, Journal of hepatology.

[47]  Ying Sun,et al.  Imbalanced Intrahepatic Cytokine Expression of Interferon-γ, Tumor Necrosis Factor-α, and Interleukin-10 in Patients With Acute-on-Chronic Liver Failure Associated With Hepatitis B Virus Infection , 2009, Journal of clinical gastroenterology.

[48]  R. Jalan,et al.  Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts the outcome , 2007, Hepatology.

[49]  C. Müller.  Liver, Alcohol and Gender , 2006, Wiener Medizinische Wochenschrift.

[50]  B. Grant,et al.  Effectiveness of the derived Alcohol Use Disorders Identification Test (AUDIT-C) in screening for alcohol use disorders and risk drinking in the US general population. , 2005, Alcoholism, clinical and experimental research.

[51]  M. Ziol,et al.  Clinical and biological relevance of hepatocyte apoptosis in alcoholic hepatitis. , 2001, Journal of hepatology.

[52]  K. Hoppo,et al.  Plasma endotoxin and serum cytokine levels in patients with alcoholic hepatitis: relation to severity of liver disturbance. , 2000, Alcoholism, clinical and experimental research.

[53]  D. Kivlahan,et al.  The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. , 1998, Archives of internal medicine.