Association between reactive oxygen species production in neutrophils and liver fibrosis in the general population

Fibrosis, induced by reactive oxygen species (ROS) production in neutrophils, has harmful effects on the liver and various other organs. However, little is known about the association between liver fibrosis and ROS levels in neutrophils in the general population. This large-scale epidemiological study aimed to determine the association between liver fibrosis and neutrophil-generated ROS levels according to age and sex in the general population. This cross-sectional study included 1,000 participants from a district health promotion project. Participants were grouped based on sex (male; female) and age (young, <65 years; old, ≥65 years). The four groups were as follows: male, young (n = 289); male, old (n = 100); female, young (n = 425); and female, old (n = 186). Liver fibrosis was assessed using the fibrosis 4 (FIB-4) index, aspartate aminotransferase-to-platelet ratio index (APRI), and non-alcoholic fatty liver disease (NAFLD) fibrosis score (NFS). Basal and stimulated ROS were considered in the analysis. Multiple linear analyses showed (1) significant positive correlations between all liver fibrosis scores and basal ROS in the young groups, and (2) significant negative correlations between NFS and stimulated ROS in females. Preventing liver fibrosis through neutrophil-related immune system enhancement may avert the development of lifestyle-related diseases and infections.

[1]  K. Chayama,et al.  Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis 2020 , 2021, Journal of Gastroenterology.

[2]  Lanman Xu,et al.  The relationship between obesity and the severity of non-alcoholic fatty liver disease: systematic review and meta-analysis , 2018, Expert review of gastroenterology & hepatology.

[3]  The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases , 2018, Clinical liver disease.

[4]  A. Lonardo,et al.  Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? , 2018, Journal of hepatology.

[5]  V. Wong,et al.  Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta‐analysis , 2017, Hepatology.

[6]  A. Yoshimura,et al.  Adiponectin Enhances Antibacterial Activity of Hematopoietic Cells by Suppressing Bone Marrow Inflammation. , 2016, Immunity.

[7]  H. Toyoda,et al.  Long-term prognosis of patients with chronic hepatitis C who did not receive interferon-based therapy: causes of death and analysis based on the FIB-4 index , 2016, Journal of Gastroenterology.

[8]  Mats Fredrikson,et al.  Fibrosis stage is the strongest predictor for disease‐specific mortality in NAFLD after up to 33 years of follow‐up , 2015, Hepatology.

[9]  Takanori Ito,et al.  FIB-4 index for assessing the prognosis of hepatocellular carcinoma in patients with Child-Pugh class A liver function , 2015, Journal of Cancer Research and Clinical Oncology.

[10]  G. V. Lutsenko,et al.  ROS production, intracellular HSP70 levels and their relationship in human neutrophils: effects of age , 2014, Oncotarget.

[11]  C. Nathan,et al.  Beyond oxidative stress: an immunologist's guide to reactive oxygen species , 2013, Nature Reviews Immunology.

[12]  Meinrad Lindschinger,et al.  Oxidative stress increases continuously with BMI and age with unfavourable profiles in males , 2012, The aging male : the official journal of the International Society for the Study of the Aging Male.

[13]  T. Saibara,et al.  Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population , 2011, BMC Gastroenterology.

[14]  N. Hayashi,et al.  Thrombocytopenia exacerbates cholestasis-induced liver fibrosis in mice. , 2010, Gastroenterology.

[15]  B. Neuschwander‐Tetri,et al.  Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. , 2010, The New England journal of medicine.

[16]  S. Nakaji,et al.  Effects of rugby sevens matches on human neutrophil-related non-specific immunity , 2006, British Journal of Sports Medicine.

[17]  J. Donohue.  Ageing, smoking and oxidative stress , 2006, Thorax.

[18]  M. Heineman,et al.  Sex hormones and the immune response in humans. , 2005, Human reproduction update.

[19]  S. Parthasarathy,et al.  Estrogen, neutrophils and oxidation. , 2004, Life sciences.

[20]  J. Coll,et al.  VP22-mediated and light-activated delivery of an anti-c-raf1 antisense oligonucleotide improves its activity after intratumoral injection in nude mice. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[21]  M. Sheridan-Pereira,et al.  Sex-specific alterations in neutrophil apoptosis: the role of estradiol and progesterone. , 2003, Blood.

[22]  P. Greenwel,et al.  Role of hydrogen peroxide and oxidative stress in healing responses , 2002, Cellular and Molecular Life Sciences CMLS.

[23]  E. Sapey,et al.  Senescence in innate immune responses: reduced neutrophil phagocytic capacity and CD16 expression in elderly humans , 2001, Journal of leukocyte biology.

[24]  L. N. Valenti,et al.  Hyperferritinemia, iron overload, and multiple metabolic alterations identify patients at risk for nonalcoholic steatohepatitis , 2001, American Journal of Gastroenterology.

[25]  I. Rusyn,et al.  Diphenyleneiodonium sulfate, an NADPH oxidase inhibitor, prevents early alcohol-induced liver injury in the rat. , 2001, American journal of physiology. Gastrointestinal and liver physiology.

[26]  K. Burnand,et al.  Induced expression of adipophilin mRNA in human macrophages stimulated with oxidized low‐density lipoprotein and in atherosclerotic lesions , 1999, FEBS letters.

[27]  A. Rothman,et al.  Iron and chronic viral hepatitis , 1997, Hepatology.

[28]  John A. Smith.  Neutrophils, host defense, and inflammation: a double‐edged sword , 1994, Journal of leukocyte biology.

[29]  M. Uehara,et al.  Impaired ability of neutrophils to produce oxygen‐derived free radicals in patients with chronic liver disease and hepatocellular carcinoma , 1994, Hepatology.

[30]  C. Burgaleta,et al.  Effect of granulocyte-macrophage colony-stimulating factor on leukocyte function in cirrhosis. , 1993, Gastroenterology.

[31]  S. Friedman.  The Cellular Basis of Hepatic Fibrosis -- Mechanisms and Treatment Strategies , 1993 .

[32]  H. Jaeschke,et al.  Neutrophil and Kupffer cell-induced oxidant stress and ischemia-reperfusion injury in rat liver. , 1991, The American journal of physiology.

[33]  R. Hernández-Muñoz,et al.  Impaired oxygen utilization. A new mechanism for the hepatotoxicity of ethanol in sub-human primates. , 1989, The Journal of clinical investigation.

[34]  S. Weiss.  Tissue destruction by neutrophils. , 1989, The New England journal of medicine.

[35]  D. Komlos.  European Association for the Study of the Liver (EASL) - 56th International Liver Congress. Virtual - June 23-26, 2021 , 2021, Drugs of the Future.

[36]  N. Kawada,et al.  Expression of perilipin and adipophilin in nonalcoholic fatty liver disease; relevance to oxidative injury and hepatocyte ballooning. , 2009, Journal of atherosclerosis and thrombosis.

[37]  J. Plevris.  Localization of oxidized phosphatidylcholine in nonalcoholic fatty liver disease : Impact on disease progression , 2006 .

[38]  Katsuhiko Suzuki,et al.  Neutrophil activation, antioxidant supplements and exercise-induced oxidative stress. , 2004, Exercise immunology review.

[39]  J. Dayer,et al.  Cytokines, acute-phase proteins, and hormones: IL-1 and TNF-alpha production in contact-mediated activation of monocytes by T lymphocytes. , 2002, Annals of the New York Academy of Sciences.

[40]  J. Cannon,et al.  Gender differences in host defense mechanisms. , 1997, Journal of psychiatric research.

[41]  J. Sowers,et al.  Clinical review 91: Female sex hormones and cardiovascular disease in women. , 1997, The Journal of clinical endocrinology and metabolism.

[42]  R. Thurman,et al.  Antibiotics prevent liver injury in rats following long-term exposure to ethanol. , 1995, Gastroenterology.