Immune dysregulation and pathophysiology of alcohol consumption and alcoholic liver disease.

Alcoholic liver disease (ALD) is a clinical-pathologic entity caused by the chronic excessive consumption of alcohol. The disease includes a broad spectrum of anomalies at the cellular and tissual level that can cause acute-on-chronic (alcoholic hepatitis) or chronic (fibrosis, cirrhosis, hepatocellular cancer) injury, having a great impact on morbidity and mortality worldwide. Alcohol is metabolized mainly in the liver. During alcohol metabolism, toxic metabolites, such as acetaldehyde and oxygen reactive species, are produced. At the intestinal level, alcohol consumption can cause dysbiosis and alter intestinal permeability, promoting the translocation of bacterial products and causing the production of inflammatory cytokines in the liver, perpetuating local inflammation during the progression of ALD. Different study groups have reported systemic inflammatory response disturbances, but reports containing a compendium of the cytokines and cells involved in the pathophysiology of the disease, from the early stages, are difficult to find. In the present review article, the role of the inflammatory mediators involved in ALD progression are described, from risky patterns of alcohol consumption to advanced stages of the disease, with the aim of understanding the involvement of immune dysregulation in the pathophysiology of ALD.

Proinflammatory and anti-inflammatory cytokine profile in pediatric patients with irritable bowel syndrome.

BACKGROUND AND OBJECTIVES: There is evidence that patients with irritable bowel syndrome (IBS) have a low degree of inflammation in the intestinal mucosa. The aim of the study was to evaluate the profile of pro- and anti-inflammatory cytokines in plasma in Mexican pediatric patients with IBS. PATIENTS AND METHODS: Fifteen patients with IBS according to Rome III criteria for childhood and 15 healthy children, matched by age and sex, were included in the study. Plasma levels of tumoral necrosis factor alpha (TNF-α), interleukins 10 and 12 (IL-10, IL-12) and transforming growth factor beta (TGF-ß) were quantified and compared between groups. RESULTS: Plasma levels of IL-10 were lower in patients with IBS (86.07+21.3 pg/mL vs. 118.71+58.62 pg/mL: P=.045) and IL-12 levels were higher in patients with IBS compared to the control group of healthy children (1,204.2±585.9 pg/mL vs. 655.04±557.80 pg/mL; P=.011). The IL-10/IL-12 index was lower in patients with IBS (0.097±0.07 vs. 0.295±0.336; P=.025). Plasma concentration of TGF-ß was higher in patients with IBS (545.67±337.69 pg/mL vs. 208.48±142.21 pg/mL; P=.001). There was no difference in plasma levels of TNF-α between groups. CONCLUSIONS: This study suggests that children with IBS have a state of altered immune regulation. This is consistent with the theory of low-grade inflammatory state in these patients. Further studies are needed to elucidate the role played by these cytokines, specifically TGF-ß in the pathogenesis of IBS.

The role of oxidative stress in the development of alcoholic liver disease.

BACKGROUND: Alcohol is the most accepted addictive substance worldwide and its consumption is related to multiple health, economic, and social problems. The liver is the organ in charge of ethanol metabolism and it is susceptible to alcohol's toxic effects. OBJETIVOS: To provide a detailed review of the role of oxidative stress in alcoholic liver disease and the mechanisms of damage involved, along with current information on the hepatoprotective effectiveness of the molecules that have been studied. MATERIALS AND METHODS: A search of the PubMed database was conducted using the following keywords oxidative stress, alcoholic liver damage, alcoholic cirrhosis, and antioxidants. There was no time limit for gathering all available information on the subject at hand. RESULTS: According to the literature reviewed, oxidative stress plays an important role in the pathogenesis of alcoholic liver damage. Molecules such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), formed during ethanol metabolism, structurally and functionally modify organic molecules. Consequently, biologic processes are altered and hepatocytes are sensitized to the action of cytokines like tumor necrosis factor-α, as well as to the action of endotoxins, activating signaling pathways such as those controlled by nuclear factor kappa B, extracellular signal regulated kinases, and mitogen activated protein kinase. CONCLUSIONS: Oxidative stress plays an important role in the development of liver damage resulting from alcohol consumption. The molecules that have currently displayed a hepatoprotective effect in preclinical and clinical trials must be studied further so that their effectiveness can be confirmed and they can possibly be used as adjuvant treatments for this disease.

Effect of pentoxifylline on levels of pro-inflammatory cytokines during chronic hepatitis C.

The cellular and humoral natural immune response induced by hepatitis C virus (HCV) is commonly unable to eradicate the virus. HCV is a highly mutable, hepatotropic RNA virus that causes acute and chronic hepatitis, an infection that involves the production of various cytokines. The aim of the study is to analyse the expression of pro-inflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma and the chemokine CXCL8 (IL-8) in liver tissue and their expression and secretion in PBMC of patients with chronic hepatitis C (CHC), in response to pentoxyfilline (PTX). We studied six CHC patients, naive to treatment. Patients received PTX 400 mg twice a day/8 weeks. Pentoxyfilline resulted in decreased expression of mRNA of liver IL-1beta, TNF-alpha and IFN-gamma: 144.2 versus 83.5 molecules of IL-1beta (P < 0.05), TNF-alpha 194.3 versus 17.6 molecules (P = 0.03) and IFN-gamma 26.1 versus 0.5 molecules (P = 0.04). Following PTX, PBMC exhibited a decrease in IFN-gamma mRNA 12.2 versus 1.5 molecules (P = 0.028) and CXCL8 4.2 versus 2.5 molecules (P = 0.027). In PBMC, only the secretion of TNF-alpha was decreased 1109 versus 933.5 pg/ml, P = 0.046. Production of cytokines both locally (within the liver) and systemically (PBMC) may serve as biomarkers of the infection with hepatitis C. PTX inhibits the expression of several pro-inflammatory cytokines in the liver. These results indicate that it is worth exploring PTX in hepatitis in future clinical trials in nonresponders to antiviral treatment.