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Biomedical subjects

D W Powell

Publications and source records attributed to D W Powell.

At least 37 records · Page 2Linked to original sources
PubMed1997

Phenotypic characterization of an intestinal subepithelial myofibroblast cell line.

Subepithelial myofibroblasts are located at the interface between the epithelium and lamina propria in most mucosal tissues. Their biological functions are largely unknown because a long-term cell culture model for these cells has not been available. In this report, we define the phenotypic properties of a human colonic cell line (18Co) that exhibits most of the known characteristics of intestinal subepithelial myofibroblasts in situ. These characteristics include 1) a cell shape that can be reversibly interconverted between a flattened discoid and stellate morphology, 2) intracellular organelles reminiscent of myofibroblasts and smooth muscle cells in situ, 3) expression of alpha-smooth muscle actin, 4) plasma membrane receptors for endothelins and natriuretic peptides, and 5) regulation of epithelial sensitivity to calcium-dependent secretagogues by paracrine secretion of prostaglandins. 18Co cells provide an exploitable model to begin defining the physiological and pathophysiological functions of intestinal subepithelial myofibroblasts at the molecular level.

Actins↗
PubMed1997

Platelet-activating factor contributes to immune cell and oxidant-mediated intestinal secretion.

The sensitivity of the Ussing-chambered rat colon to stimulation of Cl- secretion (as measured by the change in short-circuit current) by exogenous platelet-activating factor (PAF) was increased significantly by washing the colon in vitro with Ringer's solution containing fatty acid-free albumin. When the wash solution was extracted with chloroform/methanol and the lipid extract was added back to Ussing-chambered colons, inhibition of PAF-stimulated short-circuit current was observed, whereas short-circuit current responses to bradykinin or vasoactive intestinal peptide were not affected. Hypoxia appears to be an important trigger for the down-regulation of the PAF response. These data suggest that hypoxia releases PAF or an endogenous lipid PAF inhibitor that desensitizes PAF receptors on colonic epithelial or mucosal cells. The short-circuit current response of rabbit colon to the chemotactic peptide formyl-methionyl-leucyl-phenylalanine was not inhibited by any PAF antagonist devoid of cyclooxygenase inhibitory activity but was strongly inhibited by indomethacin. In contrast, anti-IgE- or H2O2-stimulated short-circuit current in rat colon was inhibited by specific PAF antagonists, and this inhibition was additive with indomethacin. Both anti-IgE and H2O2 significantly increased PAF production by rat colon. These data suggest that PAF plays an important role in oxidant (H2O2)- and anti-IgE-mediated colonic Cl- secretion but not in Cl- secretion mediated by formyl-methionyl-leucyl-phenylalanine-stimulated phagocytes.

Animals↗
PubMed1996

Gastroenterology workforce modeling.

OBJECTIVE: To examine the current supply and distribution of gastroenterologists and project future supply under various scenarios to provide a paradigm for workforce reform. DESIGN: An analysis of current practices and distribution of gastroenterologists and a demographic model, using the 1992 gastroenterology workforce as a baseline. MAIN OUTCOME MEASURE: Comparison of current supply, distribution, and practice profiles with past data and future projections, using analyses of data from the 1993 Area Resource File, 1992 Medicare Part B file, age- and sex-specific death and retirement rates from the Bureau of Health Professions, managed care staffing patterns, the National Survey of Internal Medicine Manpower, and the Bureau of the Census. RESULTS: Rapid growth in the number of US gastroenterologists has resulted in a gastroenterologist-to-population ratio double that used on average by health maintenance organizations. In addition, the work profile of gastroenterologists is shared significantly by primary care physicians and other specialists, with the exception of a few specific and uncommon procedures. CONCLUSIONS: Empirical evidence suggests that, even in the absence of detailed models to describe the desired supply/need balance for gastroenterology, the US health care system and clinicians may benefit from a reduction in gastroenterology training programs. The Gastroenterology Leadership Council endorsed a goal of 25% to 50% reduction in trainee numbers over 5 years, and recent National Resident Matching Program data indicate that a voluntary downsizing process is in full force. This study illustrates a paradigm for workforce planning that could be useful for other medical specialties.

Demography↗
PubMed1996

IL-1 stimulates intestinal myofibroblast COX gene expression and augments activation of Cl- secretion in T84 cells.

Because interleukin-1 (IL-1) is an important mediator in the inflamed intestine, its effects on enterocyte-subepithelial myofibroblast (SEMF) interaction were investigated in vitro. Acutely juxtaposing T84 cells with 18Co or P2JF SEMF preincubated with IL-1 alpha significantly enhanced T84 short-circuit current (Isc) responsiveness to secretagogues in comparison to SEMF not activated by IL-1 alpha. The sensitivity of T84 cell Isc to Ca(2+)-dependent, but not adenosine 3',5'-cyclic monophosphate-dependent, secretagogues was augmented by IL-1 alpha-treated SEMF. These effects of IL-1 alpha are directly correlated with SEMF prostaglandin E2 (PGE2) production. Both IL-1 alpha augmentation of Cl secretagogue responsiveness and PGE2 formation were inhibited by IL-1 receptor antagonist. Within 5 h, IL-1 alpha stimulated a 10-fold increase in cyclooxygenase (COX)-2 steady-state mRNA levels in 18Co cells. In contrast, COX-1 message levels increased more slowly to two- to threefold above control levels after 24 h incubation. These results demonstrate that the proinflammatory cytokine IL-1 alpha accentuates intestinal SEMF augmentation of enterocyte responsiveness to Ca(2+)-dependent CI-secretagogues. PGE2 is an important mediator of SEMF-enterocyte interaction. The effects of IL-1 alpha on SEMF PGE2 productions are, at least in part, due to stimulation of COX gene expression.

Cell Line↗
PubMed1995

Neuroimmunophysiology of the gastrointestinal mucosa: implications for inflammatory diseases.

In conclusion, studies of the neuroimmunophysiology of the intestinal mucosa of the past 5-8 years have demonstrated an important role for the immune system in modulating water and electrolyte transport as well as intestinal motility in the gut. Activation of mast cells and phagocytes leads to heightened Cl- and water secretion, as well as changes in intestinal motility which leads to diarrheal states. These diarrheal responses are self-protective; they rid the intestine of offending microorganisms and antigens. Our investigation of this response has uncovered a new immune accessory cell Cz, the intestinal myofibroblast. This cell seems to play an important role in amplifying the immune signal. This cell is probably also important for the secretion of growth factors onto the epithelium and also the secretion of collagen which results in fibrosis under diseased states. These intestinal myofibroblasts are prolific prostaglandin producers, an important finding because prostaglandin synthesis inhibition has been shown to decrease the development of neoplasia in the gut. Thus, these intestinal myofibroblasts may have other important roles in addition to just modulating water and electrolyte secretion or gut motility. Our laboratory is now engaged in studying these intestinal myofibroblasts in some detail hoping to better understand the biology of these interesting cells.

Animals↗
PubMed1993

Prostanoids inhibit intestinal NaCl absorption in experimental porcine cryptosporidiosis.

BACKGROUND: Recent studies of piglet cryptosporidiosis have shown that impaired Na(+)-coupled glucose absorption is associated with a loss of two thirds of the villous absorptive surface and an inflammatory infiltration of the lamina propria. Because inflammatory cells release eicosanoids that may alter electrolyte transport, the present study examined the role of prostanoids on NaCl transport. METHODS: Ileal mucosa was stripped of its muscle layers and mounted in Ussing chambers in the presence or absence of indomethacin. Adjacent tissue was also frozen for subsequent extraction and radioimmunoassay of prostaglandin E2 (PGE2). RESULTS: Results showed that net Na+ absorption is inhibited and net Cl- secretion is induced in infected piglets. Indomethacin restored net Na+ and Cl- absorption to control levels and exogenous PGE reversed this effect. Radioimmunoassay of tissue extracts showed that PGE2 increased from 56.7 +/- 9.6 ng/cm2 in control to 134 +/- 16.8 ng/cm2 in infected ileum (P < 0.01). CONCLUSIONS: These data indicate that in addition to the Na-glucose malabsorption arising from structural damage, part of the diarrhea of these infected animals must be attributed to local prostanoid production.

Animals↗
PubMed1993

Studies on the effect of CL 306,293, a substituted quinoline carboxylic acid, on the clinical disease induced in mice with LP-BM5 virus.

CL 306,293, a substituted quinoline carboxylic acid, is a potent inhibitor of dihydroorotic acid dehydrogenase, an enzyme essential for the biosynthesis of pyrimidines. In mammalian cell culture, the agent exhibits antiproliferative properties that can be reversed by the addition of uridine. CL 306,293 inhibits the development of the clinical disease in a murine model of immunodeficiency induced by a mixture of LP-BM5 retroviruses. In infected mice, the agent prevents the development of hypergammaglobulinemia, lymphadenopathy, splenomegaly and induction of an IL-2 deficiency. The CD4/CD8 ratio and the number of B cells in the lymph nodes are decreased if the infected animals are treated with CL 306,293. CL 306,293 was more efficacious and potent than 3'-azido-3'-deoxythymidine. The beneficial effects of CL 306,293 observed in this model are most probably related to its antiproliferative properties.

AIDS-Related Complex↗
PubMed1993

Nonantibiotic therapy and pharmacotherapy of acute infectious diarrhea.

The most important aspect of nonantibiotic treatment of diarrhea is to prevent or repair dehydration and thus prevent significant morbidity or death. Although intravenous fluid therapy is effective, it is expensive and requires personnel and equipment. ORT has saved millions of lives in emerging nations and should be more commonly used in developed countries. Although the simple concept of glucose-stimulated Na+ and fluid absorption remains the basic tenet of such ORT, grain-based solutions appear to have added efficacy and nutritional value. Mild, nondysenteric diarrheas can be safely and reasonably effectively treated either with loperamide or with bismuth subsalicylate compounds. Effective adjunctive therapy for severe secretory diarrheas has thus far escaped discovery. Somatostatin analogues such as octreotide have approximately 50% efficacy in reduction of the moderate secretory diarrheas such as those present in AIDS. There are pharmacologic leads that should be explored to develop more gut specific antisecretory forms of alpha 2-adrenergic agents, somatostatin, or phenothiazines. In addition, Cl- channel blockers still hold great theoretic promise. Effective antisecretory therapy has been sought for the past 20 years. It is disappointing that no effective new drugs have yet emerged. Undoubtedly, this speaks of our inexact understanding of the mechanisms that result in secretory diarrheas. Because of the continued loss of life from diarrhea in emerging nations, better understandings of these mechanisms and effective therapies remain appropriate goals for medical science.

Acute Disease↗
PubMed1992

Fibroblasts modulate intestinal secretory responses to inflammatory mediators.

Cultured colonic epithelial cells and fibroblasts were used to examine the interaction between these cell types during intestinal secretion. Secretory responses of T84 colonic epithelial cells, measured as changes in the short-circuit current in modified Ussing chambers to bradykinin, serotonin, hydrogen peroxide, and histamine, were enhanced in the presence of fibroblasts, either in cocultures or when separate cultures of fibroblasts were acutely juxtaposed with the T84 cultures. This effect was abolished by pretreatment with indomethacin and the fibroblasts were found to release prostaglandin E2 in response to these inflammatory mediators. Fibroblasts may exert a paracrine regulation on the secretory response of intestinal epithelial cells via the generation and release of cyclooxygenase products in response to inflammatory mediators. These studies suggest a novel function for the intestinal fibroblastic sheath: that of amplification of the inflammatory response through mesenchymal/epithelial interaction.

Animals↗
PubMed1990

Villous atrophy, crypt hyperplasia, cellular infiltration, and impaired glucose-Na absorption in enteric cryptosporidiosis of pigs.

Intestinal morphology and fluid and electrolyte transport were examined in a neonatal porcine model of cryptosporidiosis. Sections of jejunum, ileum, and colon were obtained for morphometric analysis on days 3, 6, 9, and 12 postinfection, and in vivo perfusion studies of jejunum and ileum were conducted on days 3 and 4 postinfection. The most severe morphologic lesion was seen in the ileum on day 3, and consisted of villous atrophy, crypt hyperplasia, and cellular infiltration. Villous surface area was reduced from 2.1 +/- 0.4 x 10(5) microns2 in control ileum to 0.8 +/- 0.1 x 10(5) microns2 in infected ileum, a result associated with enterocytes that were fewer in number and reduced in cross-sectional area. Conversely, the number of inflammatory cells in the lamina propria of the villus increased from 456 +/- 116 in control to 1014 +/- 187 in infected villus without a significant change in the volume of the lamina propria. At the height of infection, there was an approximate 1:2 ratio of both organisms and inflammatory cells to villous enterocytes. In contrast, organisms were not observed in the crypts, and the concentration of inflammatory cells in crypt lamina propria was unaltered. Disappearance of organisms and polymorphonuclear cells from the ileum was associated with restoration of normal structure and was complete by day 12. Although organisms were seen in the colon, the general architecture was not severely affected. On days 3 and 4 postinfection, there was a complete impairment of the glucose-stimulated Na and water absorption in both jejunum and ileum of infected pigs; however, absorption of electrolytes and water from a basic Ringer's solution, in the absence of glucose, was not significantly affected. These results are consistent with a malabsorptive diarrheal disease associated with the morphological damage and are very similar to those seen in enteric viral disease in pigs, except that the upper intestine is more severely affected in the latter.

Animals↗
PubMed1990

Hydrogen peroxide stimulates rat colonic prostaglandin production and alters electrolyte transport.

The changes in short circuit current (electrogenic Cl- secretion) of rat colon brought about by xanthine/xanthine oxidase in the Ussing chamber were inhibited by catalase and diethyldithiocarbamate, but not by superoxide dismutase. These results, the reproduction of the response with glucose/glucose oxidase and with exogenous H2O2, and the lack of effect of preincubation with deferoxamine or thiourea implicate H2O2, and not O2- or OH., as the important reactive oxygen metabolite altering intestinal electrolyte transport. 1 mM H2O2 stimulated colonic PGE2 and PGI2 production 8- and 15-fold, respectively, inhibited neutral NaCl absorption, and stimulated biphasic electrogenic Cl secretion with little effect on enterocyte lactic dehydrogenase release, epithelial conductance, or histology. Cl- secretion was reduced by cyclooxygenase inhibition. Also, the Cl- secretion, but not the increase in prostaglandin production, was reduced by enteric nervous system blockade with tetrodotoxin, hexamethonium, or atropine. Thus, H2O2 appears to alter electrolyte transport by releasing prostaglandins that activate the enteric nervous system. The change in short circuit current in response to Iloprost, but not PGE2, was blocked by tetrodotoxin. Therefore, PGI2 may be the mediator of the H2O2 response. H2O2 produced in nontoxic concentrations in the inflamed gut could have significant physiologic effects on intestinal water and electrolyte transport.

Animals↗