American journal of physiology. Gastrointestinal and liver physiology
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Am. J. Physiol. Gastrointest. Liver Physiol. · Jun 2001
Production of MDC/CCL22 by human intestinal epithelial cells.
The intestinal mucosa contains a subset of lymphocytes that produce Th2 cytokines, yet the signals responsible for the recruitment of these cells are poorly understood. Macrophage-derived chemokine (MDC/CCL22) is a recently described CC chemokine known to chemoattract the Th2 cytokine producing cells that express the receptor CCR4. The studies herein demonstrate the constitutive production of MDC/CCL22 in vivo by human colon epithelium and by epithelium of human intestinal xenografts. ⋯ In addition, tumor necrosis factor-alpha-induced MDC/CCL22 secretion was differentially modulated by Th1 and Th2 cytokines. Supernatants from the basal, but not apical, side of polarized epithelial cells induced a MDC/CCL22-dependent chemotaxis of CCR4-positive T cells. These studies demonstrate the constitutive and regulated production by intestinal epithelial cells of a chemokine known to function in the trafficking of T cells that produce anti-inflammatory cytokines.
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Am. J. Physiol. Gastrointest. Liver Physiol. · May 2001
Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats.
Sepsis is the leading cause of death in surgical intensive care units. Although both mild sepsis secondary to cecal ligation and single puncture (CLP) and fulminant, double puncture CLP (2CLP) may provoke hepatocyte death, we hypothesize that regeneration compensates for cell death after CLP but not 2CLP. In male Sprague-Dawley rats, hepatic necrosis, as determined by serum alpha-glutathione S-transferase (alpha-GST) levels, was significantly but equally elevated over time after both CLP and 2CLP. ⋯ To further substantiate impaired regeneration, steady-state levels of mRNAs encoding JunB, LRF-1, and cyclin D1 were determined. After 2CLP, the absence of JunB, LRF-1, and cyclin D1 mRNAs confirmed failed activation of the mitogen-activated protein kinase-linked proliferative pathway and progression through the cell cycle. Therefore, failed hepatocyte regeneration may be a manifestation of hepatic dysfunction in fulminant sepsis.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Feb 2001
ReviewStress and the gastrointestinal tract III. Stress-related alterations of gut motor function: role of brain corticotropin-releasing factor receptors.
Alterations of gastrointestinal (GI) motor function are part of the visceral responses to stress. Inhibition of gastric emptying and stimulation of colonic motor function are the commonly encountered patterns induced by various stressors. Activation of brain corticotropin-releasing factor (CRF) receptors mediates stress-related inhibition of upper GI and stimulation of lower GI motor function through interaction with different CRF receptor subtypes. CRF subtype 1 receptors are involved in the colonic and anxiogenic responses to stress and may have clinical relevance in the comorbidity of anxiety/depression and irritable bowel syndrome.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Apr 2000
ReviewPathobiology of visceral pain: molecular mechanisms and therapeutic implications. II. Genetic approaches to pain therapy.
New analgesic drugs are necessary because a number of pain states are untreatable. Genetic approaches to the identification of analgesic drug targets include mapping genes involved in human pain perception (e.g., trkA involved in hereditary neuropathies), identifying regulators of sensory neuron function in simple multicellular organisms and then investigating the activity of their mammalian homologs (e.g., POU domain transcription factors that specify sensory cell fate), as well as difference, expression, and homology cloning of receptors, ion channels, and transcription factors present in sensory neurons. After target validation through the construction of null mutant mice, high-throughput cell-based screens can be used to identify potential drug candidates. As a result of these approaches, a number of receptors and ion channels present in sensory neurons such as voltage-gated sodium channels [sensory neuron specific (SNS) and Na channel novel] and ATP-gated (P2X3), capsaicin-gated [vanilloid receptor 1(VR1)], and proton-gated [acid-sensing ion channel (ASIC)] channels are now under investigation as potential new analgesic drug targets.
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Am. J. Physiol. Gastrointest. Liver Physiol. · Jan 2000
ReviewLessons from genetically engineered animal models. VII. Apoptosis in intestinal epithelium: lessons from transgenic and knockout mice.
Apoptosis plays an important role in homeostasis of intestinal epithelia and is also a stress response to toxic stimuli. Transgenic and knockout mice have provided insights into the regulation of intestinal epithelial apoptosis that could not have been obtained by cell culture techniques. Two broad types of apoptosis have been characterized: spontaneous apoptosis, which occurs continuously at low levels in the normal, unstressed intestine, and stress-induced apoptosis, which occurs after genotoxic insult such as exposure to gamma radiation or DNA-damaging drugs. ⋯ The cumulative effect of stress-induced apoptosis on tissue architecture is not straightforward, and cell cycle arrest also plays a critical role. Nevertheless, p53 is an important determinant of the histopathological damage induced by 5-fluorouracil in murine intestinal epithelium. These studies have important implications for the development of more effective treatment for inflammatory bowel disease and cancer.