Showing papers in "American Journal of Physiology-gastrointestinal and Liver Physiology in 2004"
TL;DR: Observations of mice genetically prone to inflammatory bowel disease also develop colorectal cancer especially in the presence of bacterial colonization offer compelling support for the role of inflammation in colon carcinogenesis.
Abstract: Patients with ulcerative colitis and Crohn's disease are at increased risk for developing colorectal cancer. To date, no known genetic basis has been identified to explain colorectal cancer predisp...
1,213 citations
TL;DR: Crohn's disease patients have an abnormal increase in intestinal epithelial permeability, and the defect in intestinal tight junction (TJ) barrier has been proposed as an important etiologic facto barrier.
Abstract: Crohn's disease (CD) patients have an abnormal increase in intestinal epithelial permeability. The defect in intestinal tight junction (TJ) barrier has been proposed as an important etiologic facto...
750 citations
TL;DR: Probiotics and protein(s) released by these organisms may functionally modulate the intestinal epithelium of the host by different mechanisms, including the competition of whole organisms for contact with the epithelial surface as well as stabilization of the cytoskeleton and barrier function and the induction of mucin expression.
Abstract: Clinical studies have suggested that so-called probiotic bacteria may be effective as therapy in inflammatory bowel disease. However, the molecular mechanisms of their interaction with the intestin...
422 citations
TL;DR: The role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy is discussed and some of the possible mechanisms involved are outlined.
Abstract: It is well established that cancer arises in chronically inflamed tissue, and this is particularly notable in the gastrointestinal tract. Classic examples include Helicobacter pylori-associated gastric cancer, hepatocellular carcinoma, and inflammatory bowel disease-associated colorectal cancer. There is growing evidence to suggest that this association is not coincidental but may indeed be causal. In this review, we discuss the role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy and outline some of the possible mechanisms involved.
355 citations
TL;DR: Among the range of gastrointestinal peptides released by ingested nutrients is the brain/gut peptide CCK, which plays a variety of roles in coordinating gastrointestinal activity and has been demonstrated to be an important mediation for the control of meal size.
Abstract: During a meal, ingested nutrients accumulate in the stomach, with a significant portion passing on to the small intestine. The gastrointestinal presence of ingested nutrients initiates a range of physiological responses that serve to facilitate the overall digestive process. Thus peptides and transmitters are released, and various neural elements are activated that coordinate gastrointestinal secretion and motility and can eventually lead to meal termination or satiety. Among the range of gastrointestinal peptides released by ingested nutrients is the brain/gut peptide CCK. CCK plays a variety of roles in coordinating gastrointestinal activity and has been demonstrated to be an important mediator for the control of meal size.
333 citations
TL;DR: A significant body of evidence indicates that endotoxemia and endotoxin-mediated hepatocellular damage play a crucial role in the pathogenesis of alcoholic liver disease.
Abstract: A significant body of evidence indicates that endotoxemia and endotoxin-mediated hepatocellular damage play a crucial role in the pathogenesis of alcoholic liver disease. A close correlation between endotoxemia and the severity of alcohol-induced liver injury is supported by a number of clinical and experimental studies. Elevated intestinal permeability appears to be the major factor involved in the mechanism of alcoholic endotoxemia and the pathogenesis of alcoholic liver disease. Ethanol and its metabolic derivatives, acetaldehyde in particular, alter intracellular signal-transduction pathways leading to the disruption of epithelial tight junctions and an increase in paracellular permeability to macromolecules. Studies addressing the mechanisms of such epithelial disruption and the protective factors that prevent ethanol and acetaldehyde-mediated disruption of epithelial tight junctions are critically important in the investigations toward the search of preventive and therapeutic strategies for alcoholic liver disease.
314 citations
TL;DR: An overview is presented of those signals generated by the gastrointestinal (GI) tract during meals that interact with the central nervous system to create a sensation of fullness and satiety, with CCK being the most investigated.
Abstract: An overview is presented of those signals generated by the gastrointestinal (GI) tract during meals that interact with the central nervous system to create a sensation of fullness and satiety. Although dozens of enzymes, hormones, and other factors are secreted by the GI tract in response to food in the lumen, only a handful are able to influence food intake directly. Most of these cause meals to terminate and hence are called satiety signals, with CCK being the most investigated. Only one GI signal, ghrelin, that increases meal size has been identified. The administration of exogenous CCK or other satiety signals causes smaller meals to be consumed, whereas blocking the action of endogenous CCK or other satiety signals causes larger meals to be consumed. Satiety signals are relayed to the hindbrain, either indirectly via nerves such as the vagus from the GI tract or else directly via the blood. Most factors that influence how much food is eaten during individual meals act by changing the sensitivity to satiety signals. This includes adiposity signals as well as habits and learning, the social situation, and stressors.
305 citations
TL;DR: Findings show that butyrate is able to upregulate colonic mucins at the transcriptional level and even better when it is the major energy source of the cells.
Abstract: The mucus layer covering the gastrointestinal mucosa is considered the first line of defense against aggressions arising from the luminal content. It is mainly composed of high molecular weight glycoproteins called mucins. Butyrate, a short-chain fatty acid produced during carbohydrate fermentation, has been shown to increase mucin secretion. The aim of this study was to test 1) whether butyrate regulates the expression of various MUC genes, which are coding for protein backbones of mucins, and 2) whether this effect depends on butyrate status as the major energy source of colonocytes. Butyrate was provided at the apical side of human polarized colonic goblet cell line HT29-Cl.16E in glucose-rich or glucose-deprived medium. In glucose-rich medium, butyrate significantly increased MUC3 and MUC5B expression (1.6-fold basal level for both genes), tended to decrease MUC5AC expression, and had no effect on MUC2 expression. In glucose-deprived medium, i.e., when butyrate was the only energy source available, MUC3 and MUC5B increase persisted, whereas MUC5AC expression was significantly enhanced (3.7-fold basal level) and MUC2 expression was strikingly increased (23-fold basal level). Together, our findings show that butyrate is able to upregulate colonic mucins at the transcriptional level and even better when it is the major energy source of the cells. Thus the metabolism of butyrate in colonocytes is closely linked to some of its gene-regulating effects. The distinct effects of butyrate according to the different MUC genes could influence the composition and properties of the mucus gel and thus its protective function.
285 citations
TL;DR: The results demonstrate the development of an obese/diabetic experimental model for NASH in db/db mice and suggest an important role for Ob-Ra and OPN in the pathogenesis of NASH.
Abstract: Obesity and type 2 diabetes are associated with nonalcoholic steatohepatitis (NASH), but an obese/diabetic animal model that mimics human NASH remains undefined. We examined the induction of steato...
275 citations
TL;DR: The phenotypic features of liver sinusoidal endothelial cells (SEC), such as open fenestrae in sieve plates and lack of a basement membrane, are lost with capillarization as mentioned in this paper.
Abstract: The phenotypic features of liver sinusoidal endothelial cells (SEC), open fenestrae in sieve plates and lack of a basement membrane, are lost with capillarization. The current study examines locali...
255 citations
TL;DR: Studies in animal models support an etiologic role for cytokines in the liver injury of ALD, and multiple new strategies are under investigation to modulate cytokine metabolism as a form of therapy for ALD.
Abstract: Alcoholic liver disease (ALD) remains a leading cause of death from liver disease in the United States for which there is no FDA-approved therapy. Abnormal cytokine metabolism is a major feature of ALD. Elevated serum concentration levels of TNF-α and TNF-α-inducible cytokines/chemokines, such as IL-6, -8, and -18, have been reported in patients with alcoholic hepatitis and/or cirrhosis, and levels correlated with markers of the acute phase response, liver function, and clinical outcome. Studies in animal models support an etiologic role for cytokines in the liver injury of ALD. Cytokines, such as transforming growth factor-β, play a critical role in the fibrosis of ALD. Multiple new strategies are under investigation to modulate cytokine metabolism as a form of therapy for ALD.
TL;DR: Treatment of ethanol-fed mice with a PPARalpha agonist can reverse fatty liver even in the face of continued ethanol consumption, providing new therapeutic targets to reverse alcoholic fatty liver.
Abstract: Alcohol has long been thought to cause fatty liver by way of altered NADH/NAD(+) redox potential in the liver, which, in turn, inhibits fatty acid oxidation and the activity of tricarboxylic acid cycle reactions. More recent studies indicate that additional effects of ethanol both impair fat oxidation and stimulate lipogenesis. Ethanol interferes with DNA binding and transcription-activating properties of peroxisome proliferator-activated receptor-alpha (PPARalpha), as demonstrated with cultured cells and in ethanol-fed mice. Treatment of ethanol-fed mice with a PPARalpha agonist can reverse fatty liver even in the face of continued ethanol consumption. Ethanol also activated sterol regulatory element binding protein 1, inducing a battery of lipogenic enzymes. These effects may be due in part to inhibition of AMP-dependent protein kinase, reduction in plasma adiponectin, or increased levels of TNF-alpha in the liver. The understanding of these ethanol effects provides new therapeutic targets to reverse alcoholic fatty liver.
TL;DR: The hypothesis that apoptosis could be a favorable response to acinar cells and that interventions that favor induction of apoptotic, as opposed to necrotic, acinar cell death might reduce the severity of an attack of acute pancreatitis is proposed.
Abstract: Acute pancreatitis is a disease of variable severity in which some patients experience mild, self-limited attacks, whereas others manifest a severe, highly morbid, and frequently lethal attack. The...
TL;DR: It is concluded that most damage after hepatic ischemia occurs during reperfusion and can be blocked by A(2A)AR activation.
Abstract: Ischemia-reperfusion (I/R) injury occurs as a result of restoring blood flow to previously hypoperfused vessels or after tissue transplantation and is characterized by inflammation and microvascular occlusion. We report here that 4-[3-[6-amino-9-(5-ethylcarbamoyl-3,4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester (ATL146e), a selective agonist of the A(2A) adenosine receptor (A(2A)AR), profoundly protects mouse liver from I/R injury when administered at the time of reperfusion, and protection is blocked by the antagonist ZM241385. ATL146e lowers liver damage by 90% as assessed by serum glutamyl pyruvic transaminase and reduces hepatic edema and MPO. Most protection remains if ATL146e treatment is delayed for 1 h but disappears when delayed for 4 h after the start of reperfusion. In mice lacking the A(2A)AR gene, protection by ATL1465e is lost and ischemic injury of short duration is exacerbated compared with wild-type mice, suggesting a protective role for endogenous adenosine. I/R injury causes induction of hepatic transcripts for IL-1alpha, IL-1beta, IL-1Ra, IL-6, IL-10, IL-18, INF-beta, INF-gamma, regulated on activation, normal T cell expressed, and presumably secreted (RANTES), major intrinsic protein (MIP)-1alpha, MIP-2, IFN-gamma-inducible protein (IP)-10, and monocyte chemotactic protein (MCP)-1 that are suppressed by administering ATL146e to wild-type but not to A(2A)AR knockout mice. RANTES, MCP-1, and IP-10 are notable as induced chemokines that are chemotactic to T lymphocytes. The induction of cytokines may contribute to transient lymphopenia and neutrophilia that occur after liver I/R injury. We conclude that most damage after hepatic ischemia occurs during reperfusion and can be blocked by A(2A)AR activation. We speculate that inhibition of chemokine and cytokine production limits inflammation and contributes to tissue protection by the A(2A)AR agonist ATL146e.
TL;DR: The process of mutation accumulation and clonal expansion that is required for development of invasive pancreatic adenocarcinoma must be accelerated in chronic pancreatitis to account for the high incidence of pancreatic cancer in patients.
Abstract: Pancreatic inflammation appears to increase the risk of pancreatic cancer. This observation is striking in the hereditary pancreatitis kindreds but also occurs in alcoholic, idiopathic, and tropical chronic pancreatitis and cystic fibrosis. However, the mutations associated with hereditary pancreatitis or cystic fibrosis are not found in sporadic pancreatic adenocarcinomas, suggesting that the effects are indirect by causing recurrent pancreatitis and chronic inflammation. The process of mutation accumulation and clonal expansion that is required for development of invasive pancreatic adenocarcinoma must therefore be accelerated in chronic pancreatitis to account for the high incidence of pancreatic cancer in these patients.
TL;DR: The results reveal that TRP channels are present in subsets of vagal afferent neurons that project to the stomach and may confer temperature sensitivity on these cells.
Abstract: A number of transient receptor potential (TRP) channels has recently been shown to mediate cutaneous thermosensitivity. Sensitivity to warm and cool stimuli has been demonstrated in both human and animal gastrointestinal tract; however, the molecular mechanisms that underlie this have not been determined. Vagal afferent neurons with cell bodies in the nodose ganglion are known to mediate nonnociceptive sensation from the upper gut. In this study, isolated cultured nodose ganglion from the mouse neurons showed changes in cytoplasmic-free Ca(2+) concentrations over a range of temperatures, as well as to icilin (a TRPM8 and TRPN1 agonist) and capsaicin (a TRPV1 agonist). RT-PCR was used to show the presence of six temperature-sensitive TRP channel transcripts (TRPV1-4, TRPN1, and TRPM8) in whole nodose ganglia. In addition, RT-PCR of single nodose cell bodies, which had been retrogradely labeled from the upper gut, detected transcripts for TRPV1, TRPV2, TRPV4, TRPN1, and TRPM8 in a proportion of cells. Immunohistochemical labeling detected TRPV1 and TRPV2 proteins in nodose ganglia. The presence of TRP channel transcripts and proteins was also detected in cells within several regions of the gastrointestinal tract. Our results reveal that TRP channels are present in subsets of vagal afferent neurons that project to the stomach and may confer temperature sensitivity on these cells.
TL;DR: This review considers the anorectic peptides PYY, PP, GLP-1, and oxyntomodulin, which decrease appetite and promote satiety in both animal models and humans.
Abstract: Many peptides are synthesized and released from the gastrointestinal tract and pancreas, including pancreatic polypeptide (PP) and the products of the gastrointestinal L cells, glucagon-like peptide 1 (GLP-1), oxyntomodulin, and peptide YY (PYY). Whereas their roles in regulation of gastrointestinal function have been known for some time, it is now evident that they also influence eating behavior. This review considers the anorectic peptides PYY, PP, GLP-1, and oxyntomodulin, which decrease appetite and promote satiety in both animal models and humans.
TL;DR: Homozygous, PIZZ α1-antitrypsin (α1-AT) deficiency is associated with chronic liver disease and hepatocellular carcinoma resulting from the toxic effects of mutant α 1-anti-trypsin Z (α 1-ATZ) protei...
Abstract: Homozygous, PIZZ alpha(1)-antitrypsin (alpha(1)-AT) deficiency is associated with chronic liver disease and hepatocellular carcinoma resulting from the toxic effects of mutant alpha(1)-anti-trypsin Z (alpha(1)-ATZ) protein retained in the endoplasmic reticulum (ER) of hepatocytes. However, the exact mechanism(s) by which retention of this aggregated mutant protein leads to cellular injury are still unknown. Previous studies have shown that retention of mutant alpha(1)-ATZ in the ER induces an intense autophagic response in hepatocytes. In this study, we present evidence that the autophagic response induced by ER retention of alpha(1)-ATZ also involves the mitochondria, with specific patterns of both mitochondrial autophagy and mitochondrial injury seen in cell culture models of alpha(1)-AT deficiency, in PiZ transgenic mouse liver, and in liver from alpha(1)-AT-deficient patients. Evidence for a unique pattern of caspase activation was also detected. Administration of cyclosporin A, an inhibitor of mitochondrial permeability transition, to PiZ mice was associated with a reduction in mitochondrial autophagy and injury and reduced mortality during experimental stress. These results provide evidence for the novel concept that mitochondrial damage and caspase activation play a role in the mechanism of liver cell injury in alpha(1)-AT deficiency and suggest the possibility of mechanism-based therapeutic interventions.
TL;DR: It is shown that posttranscriptional mechanisms play a more prominent role in LPS-induced regulation of human MRP2 and BSEP compared with the rat transporter proteins.
Abstract: Endotoxin-induced cholestasis in rodents is caused by hepatic downregulation of transporters, including the basolateral Na+-dependent taurocholate transporter (ntcp) and the canalicular bile salt e
TL;DR: An upregulation of OPN expression early in the development of steatohepatitis is demonstrated and an important role for OPN in signaling the onset of liver injury and fibrosis in experimental NASH is suggested.
Abstract: The pathogenesis of nonalcoholic steatohepatitis (NASH) is poorly defined. Feeding mice a diet deficient in methionine and choline (MCD diet) induces experimental NASH. Osteopontin (OPN) is a Th1 c...
TL;DR: This review will highlight recent experiments demonstrating a role for the innate immune response in the initiation and progression of alcohol-induced liver hepatitis and subsequent organ damage.
Abstract: Ethanol consumption is known to cause significant acute liver damage resulting in hepatic fibrosis and eventual cirrhosis when consumed chronically. The mechanism(s) by which ethanol exerts its damaging effects on the liver are not well understood; however, recent scientific investigation has begun to delineate the earliest events in alcoholic liver disease. From these studies, it is apparent that components of the innate immune system and, in particular, Kupffer cells, play a significant role in this process. It is also becoming clear that other parts of the immune system including T cells may also be responsible for mediating the devastating effects of chronic alcohol consumption on the liver. This review will highlight recent experiments demonstrating a role for the innate immune response in the initiation and progression of alcohol-induced liver hepatitis and subsequent organ damage.
TL;DR: It is demonstrated that IFN-γ/STAT1 plays an essential role in concanavalin A (ConA)-induced T cell hepatitis via activation of apoptotic signaling pathways.
Abstract: We have previously shown that IFN-γ/STAT1 plays an essential role in concanavalin A (ConA)-induced T cell hepatitis via activation of apoptotic signaling pathways. Here we demonstrate that IFN-γ/ST...
TL;DR: Investigation of gene expression in the CF mouse small intestine demonstrates that the CF intestine exhibits an inflammatory state with upregulation of components of the innate immune system.
Abstract: The CFTR null mouse [cystic fibrosis (CF) mouse] has a severe intestinal phenotype that serves as a model for CF-related growth deficiency, meconium ileus, and distal intestinal obstructive syndrom...
TL;DR: Findings indicate that TJ protein expression and cellular localization in Caco-2 cell monolayers rely on GLN, and this mechanism may similarly relate to GLN-mediated modulation of intestinal barrier function in stressed animals and humans.
Abstract: Intestinal epithelial tight junction (TJ) barrier dysfunction may lead to inflammation and mucosal injury. Glutamine (GLN) plays a role in maintenance of intestinal barrier function in various animal models and critically ill humans. Recent evidence from intestinal cell monolayers indicates that GLN maintains transepithelial resistance and decreases permeability. The mechanisms of these effects remain undefined. We hypothesized that GLN affects proteins involved in the intercellular junctional complex. GLN availability was controlled in Caco-2 monolayers by addition to the medium and treatment with methionine sulfoximine (MSO) to inhibit glutamine synthetase (GS). Expression of TJ proteins, claudin-1, occludin, and zonula occluden (ZO)-1 was measured by immunoblotting. Localization of TJ proteins was evaluated by immunofluorescence light microscopy. Structure of TJ was determined by transmission electron microscopy (TEM). Deprivation of GLN decreased claudin-1, occludin, and ZO-1 protein expression and caused a disappearance of perijunctional claudin-1 and a reduction of occludin but had no effect on ZO-1. TEM revealed that MSO-treated cells in the absence of GLN formed irregular junctional complexes between the apical lateral margins of adjoining cells. These findings indicate that TJ protein expression and cellular localization in Caco-2 cell monolayers rely on GLN. This mechanism may similarly relate to GLN-mediated modulation of intestinal barrier function in stressed animals and humans.
TL;DR: Neutrophils relevant for the aggravation of acute cholestatic liver injury in BDL mice accumulate in hepatic sinusoids, extravasate into the tissue dependent on ICAM-1, and cause cell damage involving reactive oxygen formation.
Abstract: Cholestasis-induced liver injury during bile duct obstruction causes an acute inflammatory response. To further characterize the mechanisms underlying the neutrophil-induced cell damage in the bile...
TL;DR: It is suggested that colitis alters trkA-positive neurons to preferentially increase slow TTX-R Na+ (Nav1.8) Na+ current, which is associated with increased slow TTx-R (Nav 1.8), which is implicated in inflammatory pain.
Abstract: The composition of Na+ currents in dorsal root ganglia (DRG) neurons depends on their neuronal phenotype and innervation target. Two TTX-resistant (TTX-R) Na+ currents [voltage-gated Na channels (N...
TL;DR: This work investigated the signaling pathways mediating NF-κB activation in pancreatic acinar cancer by exploring the mechanisms underlying its activation and found that these pathways are related to EMT and “cell reprograming”.
Abstract: Although NF-κB plays an important role in pancreatitis, mechanisms underlying its activation remain unclear. We investigated the signaling pathways mediating NF-κB activation in pancreatic acinar c...
TL;DR: It is demonstrated that GLP-2 alone, without enteral feeding, stimulates indexes of intestinal adaptation and villus hypertrophy associated with adaptation was predominantly due to an increase in CCP and not to changes in apoptotic rates.
Abstract: Glucagon-like peptide-2 (GLP-2) is an intestinal trophic enteroendocrine peptide that is associated with intestinal adaptation following resection. Herein, we investigate the effects of GLP-2 in a ...
TL;DR: Changes in enteroendocrine cell populations and 5-HT availability could contribute to the altered motility and secretion associated with intestinal inflammation by disrupting mucosal signaling to enteric nerves involved in peristaltic and secretory reflexes.
Abstract: Enteroendocrine cells act as sensory transducers, releasing 5-HT and numerous peptides that are involved in regulating motility, secretion, and gut sensation. The action of mucosal 5-HT is terminat...
TL;DR: It is found that the recruitment of the STAT-JAK complex by EGFR is responsible for keratinocyte migration that, in turn, might be mediated by MMP-1 activation.
Abstract: The epidermal growth factor receptor (EGFR) activates several signaling cascades in response to epidermal growth factor stimulation. One of these signaling events involves tyrosine phosphorylation of signal transducer and activator of transcription (STAT), whereas another involves activation of the phosphatidylinositol 3-OH kinase pathway. Two possibilities for STAT activation exist: a janus kinase (JAK)-dependent and a JAK-independent mechanism. Herein, we demonstrate that EGFR overexpression in primary esophageal keratinocytes activates STAT in a JAK-dependent fashion with the functional consequence of enhanced cell migration, which can be abolished by use of a JAK-specific inhibitor, AG-490. We determined the mechanisms underlying the signal transduction pathway responsible for increased cell migration. Stimulation of EGFR induces Tyr701 phosphorylation of STAT1 and initiates complex formation of STAT1 and STAT3 with JAK1 and JAK2. Thereafter, the STATs translocate to the nucleus within 15 min. In addition, we found that activation of this signaling pathway results in matrix metalloproteinase-1 (MMP-1) activity. By contrast, Akt activation does not impact the EGFR-STATs-JAKs complex formation and nuclear translocation of the STATs with subsequent MMP-1 activity, although Akt activation may contribute to cell migration through an independent mechanism. Taken together, we find that the recruitment of the STAT-JAK complex by EGFR is responsible for keratinocyte migration that, in turn, might be mediated by MMP-1 activation.