Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P10145 (IL-8)
 23,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-8 is a neutrophil chemoattractant that has been implicated in the pathogenesis of alcoholic hepatitis. The mechanism of ethanol-induced interleukin-8 production in liver is uncertain, although hepatocytes and Kupffer cells have both been proposed as sources of the chemokine. In this study we investigated whether short-term ethanol exposure stimulates production of rat interleukin-8 [cytokine-induced neutrophil chemoattractant (CINC)] by normal rat hepatocytes and Kupffer cells in primary culture. Initial experiments verified that hepatocytes and Kupffer cells produce CINC in response to cytokines or lipopolysaccharide. Ethanol, by contrast, failed to stimulate CINC secretion by either cell type even at concentrations as high as 100 mM. Although ethanol had no direct effect on liver cell CINC production, conditioned medium from ethanol-treated hepatocytes induced a threefold rise in CINC production by Kupffer cells. The increase was abrogated when hepatocytes were treated with ethanol and the metabolic inhibitor 4-methylpyrazole. The results suggest that the mechanism of ethanol-induced CINC production is indirect, involving ethanol oxidation and communication between hepatocytes and Kupffer cells.
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PMID:Rat hepatocytes and Kupffer cells interact to produce interleukin-8 (CINC) in the setting of ethanol. 748 3

Studies were performed to evaluate the role of interleukin 8 (IL-8) in the pathogenesis of alcoholic hepatitis. Using a recently developed sensitive and specific enzyme-linked immunosorbent assay, we measured serum IL-8 levels in patients with alcoholic hepatitis. The mean serum IL-8 level was increased significantly in patients with alcoholic hepatitis compared with normal controls (P < 0.05). It was of interest to note that serum IL-8 levels were increased transiently after abstinence from alcohol in patients with alcoholic hepatitis. These findings suggest that there may be a correlation between IL-8 and alcoholic hepatitis.
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PMID:Assay of serum interleukin 8 levels in patients with alcoholic hepatitis. 790 98

Patients with alcoholic hepatitis often have hepatic polymorphonuclear leukocyte infiltration and neutrophilia. Interleukin-8 is a cytokine that stimulates neutrophil chemotaxis and release of lysosomal enzymes. It is made by several types of cells, including fibroblasts, Kupffer cells and hepatocytes. In this study, serial plasma interleukin-8 concentrations were measured with enzyme-linked immunosorbent assay in 40 consecutive patients with moderate-to-severe alcoholic hepatitis over a 6-mo period. Two control groups included 10 patients without clinically important liver disease admitted for treatment of alcohol dependence and 12 healthy male volunteers. The mean plasma interleukin-8 level on admission was markedly increased: 695 +/- 146 pg/ml in the alcoholic hepatitis patients. The alcohol-dependent control group and the normal volunteer controls had mean interleukin-8 concentrations of 106 +/- 28 pg/ml and 10 +/- 5 pg/ml, respectively. Initially increased interleukin-8 levels in alcoholic hepatitis patients decreased to a mean of 182 +/- 42 pg/ml over the first month; levels had decreased further to 124 +/- 79 pg/ml after 6 mo. Increased interleukin-8 concentrations in patients with alcoholic hepatitis suggest a role for interleukin-8 in the neutrophilia and hepatic polymorphonuclear leukocyte infiltration of alcoholic hepatitis.
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PMID:Increased plasma interleukin-8 concentrations in alcoholic hepatitis. 835 98

Alcoholic liver disease is associated with three histologically distinct processes: steatosis (parenchymal fat accumulation), alcoholic hepatitis (characterized by parenchymal infiltration by neutrophil polymorphs), and alcoholic cirrhosis (in which chronic inflammation and fibrosis dominate). Chemokines are cytokines that promote subset-specific leukoycte recruitment to tissues and could therefore play a crucial role in determining which leukocyte subsets are recruited to the liver in alcoholic liver disease. This paper reports that chemokine expression is increased in the liver of patients with alcoholic liver disease and, moreover, that distinct patterns of chemokine expression are associated with the different inflammatory responses to alcohol. Interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 alpha (MIP-1 alpha), and MIP-1 beta were all detected in the parenchyma at sites of inflammation in alcoholic hepatitis, whereas in alcoholic cirrhosis, chemokines were restricted to inflammatory cells and endothelium in the fibrous septa and portal tracts. In alcoholic hepatitis, chemokine transcription was localized to sinusoidal cells, leukocytes, and fibroblasts in areas of parenchymal inflammation, but hepatocytes, despite staining strongly for chemokine protein, were negative. In alcoholic cirrhosis, chemokine mRNA was detected in portal tract endothelium, leukocytes, and fibroblasts. Thus, alcoholic hepatitis and alcoholic cirrhosis are associated with distinct patterns of chemokine expression that are likely to be important factors in determining whether a patient develops acute parenchymal inflammation and alcoholic hepatitis, or chronic septal inflammation and alcoholic cirrhosis.
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PMID:Distinct patterns of chemokine expression are associated with leukocyte recruitment in alcoholic hepatitis and alcoholic cirrhosis. 987 44

Interleukin-8 (IL-8), a cytokine produced by a host of cells including monocytes, macrophages, Kupffer cells and hepatocytes, can activate neutrophils. Peripheral neutrophilia and liver neutrophil infiltration are frequently noted in patients with alcoholic liver disease (ALD). Serum IL-8 levels are markedly elevated in patients with alcoholic hepatitis compared with those in patients with alcoholic cirrhosis, alcoholic fatty liver and non-alcoholic liver disease. The levels are also elevated in patients who die of hepatic failure and correlate with biochemical and histologic parameters and severity of liver injury. Patients with high serum IL-8 had a higher mortality rate than those with lower levels. In liver tissue from patients with ALD, local IL-8 levels also correlated with the degree of neutrophil infiltration. Serum IL-8 levels decreased gradually with abstinence from alcohol. Ethanol can increase plasma endotoxin, a potent inducer of tumor necrosis factor (TNF)-alpha and IL-1. Subsequently, TNF-alpha and IL-1, together with endotoxin, stimulate circulating and local IL-8 in ALD. Activated IL-8 then mediates neutrophil infiltration, a pivotal process in the pathogenesis of ALD. IL-8 levels might reflect the stage and severity of ALD and might serve as a predictor of survival in patients with alcoholic hepatitis. The development of agents with an anti-IL-8 effect is promising for the therapy of ALD.
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PMID:Interleukin-8 and alcoholic liver disease. 1041 75

Leukocyte infiltration in the liver is one of the most important features of alcoholic liver disease. However, in alcoholic hepatitis, the role of polymorphonuclear neutrophils (PMNs) in liver injury still remains to be fully elucidated. Furthermore, the migration of PMNs and their presence in the liver during alcoholic hepatitis have not been fully investigated. Up-regulation of chemokine secretion and adhesion molecule expression on effector cells (i.e., PMNs) and target cells (i.e., hepatocytes) are important factors in neutrophilic infiltration of the liver. The CXC chemokines--that is, interleukin (IL)-8 (in human beings), cytokine-induced neutrophil chemoattractant (CINC) (in rats), and KC (in mice)--are proneutrophilic agents. They are up-regulated during chronic--that is, several years of--alcohol use in human beings and in up to 30 weeks in experimental models of ethanol intoxication in mice and rats. Up-regulation of these chemokines in the circulation and tissues is also associated with enhanced neutrophilic infiltration in the liver. In the rat, the up-regulation of CXC chemokine production is time dependent. For example, after 16 weeks of feeding, up-regulation of CXC chemokine is observed, whereas after 32 weeks, CC chemokines are enhanced. Concomitantly, selective migration of PMNs and mononuclear cells is observed. In another model, in which both CXC and CC chemokines were enhanced after chronic ethanol use for 12 weeks in mice, neutrophilic and mononuclear/lymphocytic infiltrations were also seen. This model correlates closely with alcoholic hepatitis in human beings, characterized by increased IL-8, RANTES (regulated upon activation, normal T cell expressed and secreted), and macrophage inflammatory protein-1 (MIP-1) and profound increases in neutrophils and lymphocytes in the liver.
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PMID:Neutrophilic infiltration in alcoholic hepatitis. 1206 32

At present, the relation between alcoholic consumption and the development of hepatic injury is clearly defined. However, the influence of genetic factors, the existence of associated pathologies, and the concomitant use of other hepatotoxic agents should also be considered.During chronic drunkenness, great quantities of oxygen free radicals are produced, redox balance is disturbed, and the defensive capacity of natural antioxidants is exceeded. All these factors originate an "oxidative stress," that totally distorts the hepatocellular function. Llkewise, an increase in the acetaldehyde intracellular concentration modifies several cellular proteins, deteriorating even more the hepatic activity. The importance of the "neo-antigens" between cellular components and acetaldehyde is still undefined, as well as their role in the formation of the Mallory Bodies.On the other hand, the complex network of intercellular and intracellular communications that includes cytokines, adherence molecules and membrane receptors are essential elements to be considered in the alcoholic liver disease genesis. The endotoxin, the TNF-a, the IL-8, as well as the ROIs production seem to be the most important factors.With reference to Alcoholic Hepatitis, the development of an exaggerated inflammatory response with the existence of neutrophiles may be the main mechanism of hepatocellular injury (82, 167, 168.)The final diagnosis of Alcoholic Hepatitis is histological. This also enables to measure the injury severity and to determine the presence of fibrosis and/or cirrhosis, in which case prognosis is more uncertain.Should a history of exaggerated alcoholic ingestion exist, diagnosis could be clinically determined. There is a great variability of clinical symptoms, and some patients present chronic liver disease complications frequently. Those who develop severe liver insufficiency will present leukocytosis, icterus and fever. In these cases, mortality can be as high as 80 per cent. There is no relationship between the alteration of liver function tests and the injury severity.The usefulness of antioxidants in cirrhosis has been demonstrated in animal modeis and in some studies made in human voluntarles. However, their role as therapy within the context of Alcoholic Hepatitis has not been yet defined.In conclusion, several therapeutic approaches have been investigated and from all of them, only steroids have proven to be effective on patients properly selected. The discriminative function (DF) benefit has been confirmed in certain studies. Should a patient have a DIF of more than 93, he/she may receive corticosterold treatment. Contral ndicati ons are a bsol ute when the patientpresents infection, renal insufficiency or gastrointestinal bleeding.Once the patient has been compensated, ABSTINENCE is essential. Likewise, an appropriate nutritional support is an important part of the treatment.Where the possibility of Liver Transplant exists, this should be planned if there is a deterioration of the patient's general condition or if he/she compiles with the necessary criteria, since the survival rate in these cases is similar to those who received a transpiant due to other causes.
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PMID:[ALCOHOLIC HEPATITIS] 1221 43

Ethanol toxicity on liver is a function of duration of alcoholism, amount of daily intake of alcohol and patient's nutrition. The threshold of alcohol toxicity on the liver is about 40 g of ethanol daily in men and 20-30 g in women, however liver cirrhosis develops in no more than 8-20% of patients exceeding this values. Ethanol is oxidized in the liver to acetaldehyde--a compound considerably more toxic than ethanol itself. Despite small amount of alcohol dehydrogenase (ADH) found in gastric mucosa, the metabolism of ethanol in this site may have an important hepatoprotective effect. The oxidation of ethanol is associated with a change of hepatocyte redox homeostasis, which leads to a number of metabolic disorders such as lactic acidosis, hyperlipidaemia and hyperuricaemia. Chronic ethanol consumption does not influence ADH activity, but has a profound stimulatory effect on microsomal enzymes, in particular cytochrome CYP2E1. This fact is responsible for development in alcoholic liver associated with rise of oxygen consumption, excessive production of free radicals and increased metabolism of ethanol, vitamin A and testosterone. Ethanol and acetaldehyde have a deleterious effect, both the direct and indirect, on hepatocytes e.g., generating radical oxygen species and damaging intestinal mucosal barrier. Cellular oxidative stress that is caused by both an excess of free radicals and the antioxidatives' deficiency (glutathion, vitamin E, phosphatidylcholine), may be the principal factor responsible for progression of alcoholic liver disease. Among other factors accelerating alcohol-related liver lesion there are certain drugs, high fat diet, infection with HCV and genetic factors (female sex, enzymatic polymorphic forms of ADH and ALDH, hemochromatosis). Great importance in pathogenesis of necrotic and inflammatory hepatic events is being attributed to portal endotoxaemia and cytokines induced within the liver, in particular TNF-alpha and interleukin 8. These cytokines play a key role in development of alcoholic hepatitis, which clinical severity ranges from subclinical to fatal forms. Apart from abstinence, the treatment of alcohol liver disease is based on hyperalimentation, since alcoholism is generally associated with protein malnutrition. In severe forms of alcohol hepatitis corticosteroids are recommended.
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PMID:[Alcoholic liver disease]. 1290 Dec 71

Our retrospective analysis of 105 patients with alcoholic liver injury confirmed that patients with severe alcoholic hepatitis (SAH) showed severe hyperbilirubinemia, reduced hepatic biosynthetic capacity, and marked acute inflammatory reactions, and developed multiple organ failure (MOF). Multivariate analysis using the Cox proportional hazards model showed serum C-reactive protein and DIC as significant independent prognostic factors among SAH, LC+AH, and AH groups. Improved assay showed an increase of plasma endotoxin with the progression of alcoholic liver injury. In most survivors, plasma Et levels decreased in the recovery phase. Serum interleukin (IL)-6 and IL-8 levels in the acute phase were high in patients with AH and LC+AH, especially in non-survivors and in patients with SAH. In the recovery phase, these cytokine levels in survivors tended to decrease, but in non-survivors, IL-6 remained high, and IL-8 further increased. Serum levels of HDL and albumin, which are protective against endotoxicity by inhibiting endotoxin uptake and TNF production by macrophages, were decreased with the progression of alcoholic liver injury. Animal experiments supported that the increase in endotoxin-binding capacity of HDL and albumin may serve as a protective mechanism against endotoxin in chronic ethanol-loaded rats and that an addition of high-dose ethanol to these rats may lead to impaired binding and inactivation of endotoxin. Lipopolysaccharide-binding protein (LBP) which enhances endotoxin uptake and TNF production by macrophages, was generally increased in patients with alcoholic liver injury. This imbalance among endotoxin binding proteins in the blood may induce overproduction of cytokines by macrophages in patients with severe alcoholic liver injury. Our animal experiments further revealed that an additional administration of a high-dose ethanol to chronic alcohol-fed rats led to decrease of endotoxin clearance, increased extrahepatic accumulation of endotoxin and elevation of plasma TNF. The splenic macrophages and pulmonary alveolar macrophages are demonstrated to be important for endotoxin uptake, and excessive production of TNF in rats given large amounts of alcohol. An in vitro culture experiment in the presence of rat LBP suggested a role of these macrophages in excessive production of TNF-alpha. When the functions of various macrophages were compared in rats given alcohol, maximum TNF-alpha secretion was noted in alveolar macrophages, In conclusion, endotoxemia and its effects on extrahepatic macrophages may play key roles in the progression of severe alcoholic liver injury and MOF.
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PMID:Relation of endotoxin, endotoxin binding proteins and macrophages to severe alcoholic liver injury and multiple organ failure. 1634 5

Alcoholic liver disease (ALD) remains an important complication and cause of morbidity and mortality from alcohol abuse. Major developments in our understanding of the mechanisms of ALD over the past decade are now being translated into new forms of therapy for this disease process which currently has no FDA approved treatment. Cytokines are low molecular weight mediators of cellular communication, and the pro-inflammatory cytokine tumor necrosis factor (TNF) has been shown to play a pivotal role in the development of experimental ALD. Similarly, TNF levels are elevated in the serum of alcoholic hepatitis patients. Abnormal methionine metabolism is well documented in patients with ALD, with patients having elevated serum methionine levels, but low S-adenosylmethionine levels in the liver. On the other hand, S-adenosylhomocysteine and homocysteine levels are elevated in ALD. Recent studies have documented potential interactions between homocysteine and S-adenosylhomocysteine with TNF in the development of ALD. Altered proteasome function also is now well documented in ALD, and decreased proteasome function can cause hepatocyte apoptosis. Recently it has been shown that decreased proteasome function can also act synergistically to enhance TNF hepatotoxicity. Hepatocytes dying of proteasome dysfunction release pro-inflammatory cytokines such as Interleukin-8 to cause sustained inflammation. This article reviews the interactions of cytokines, altered methionine metabolism, and proteasome dysfunction in the development of ALD.
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PMID:Dysregulated cytokine metabolism, altered hepatic methionine metabolism and proteasome dysfunction in alcoholic liver disease. 1634 6


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