Mucosal injury and inflammation in a model of chronic granulomatous colitis in rats

Yamada, Tamaki; Sartor, R. Balfour; Marshall, Steven J.; Specian, Robert D.; Grisham, Matthew B.

doi:10.1016/0016-5085(93)91011-6

Cited by 166 publications

(92 citation statements)

References 28 publications

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“…These findings are further consistent with the current characterization of the pathophysiological development of IBD and its strong link to disruption of mucosal barrier function. For example, disruption of gut barrier permeability function elicits symptoms of inflammation and IBD-like responses in animals (Yamada et al, 1993;Hermiston and Gordon, 1995). Accordingly, a leaky gut is likely to be key in initiation and continuation of the IBD flare where mucosal inflammation leads to a vicious cycle of oxidative processes, barrier structural protein instability, and eventually mucosal injury.…”

Section: Discussionmentioning

confidence: 99%

“…For example, transgenic rodents with a hyperpermeable-intestinal-barrier exhibit intestinal mucosal inflammation (Hermiston and Gordon, 1995). Similarly, loss of intestinal barrier function induced by the injection of bacterial derivatives into the mucosa of rodents elicits IBD-like conditions (Yamada et al, 1993). Accordingly, investigating the molecular events underlying the alterations of gut barrier function is of fundamental biological and clinical value.…”

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confidence: 99%

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θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

Banan¹,

Zhang²,

Shaikh³

et al. 2005

J Pharmacol Exp Ther

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Using monolayers of intestinal Caco-2 cells, we discovered that the isoform of protein kinase C (PKC), a member of the "novel" subfamily of PKC isoforms, is required for monolayer barrier function. However, the mechanisms underlying this novel effect remain largely unknown. Here, we sought to determine whether the mechanism by which PKC-disrupts monolayer permeability and dynamics in intestinal epithelium involves PKC--induced alterations in claudin isotypes. We used cell clones that we recently developed, clones that were transfected with varying levels of plasmid to either stably suppress endogenous PKC-activity (antisense, dominant-negative constructs) or to ectopically express PKC-activity (sense constructs). We then determined barrier function, claudin isotype integrity, PKC-subcellular activity, claudin isotype subcellular pools, and claudin phosphorylation. Antisense transfection to underexpress the PKC-led to monolayer instability as shown by reduced 1) endogenous PKC-activity, 2) claudin isotypes in the membrane and cytoskeletal pools (2claud-1, 2claud-4 assembly), 3) claudin isotype phosphorylation (2 phospho-serine, 2 phospho-threonine), 4) architectural stability of the claudin-1 and claudin-4 rings, and 5) monolayer barrier function. In these antisense clones, PKC-activity was also substantially reduced in the membrane and cytoskeletal cell fractions. In wild-type (WT) cells, PKC-(82 kDa) was both constitutively active and coassociated with claudin-1 (22 kDa) and claudin-4 (25 kDa), forming endogenous PKC-/claudin complexes. In a second series of studies, dominant-negative inhibition of the endogenous PKC-caused similar destabilizing effects on monolayer barrier dynamics, including claudin-1 and -4 hypophosphorylation, disassembly, and architectural instability as well as monolayer disruption. In a third series of studies, sense overexpression of the PKC-caused not only a mostly cytosolic distribution of this isoform (i.e., Ͻ12% in the membrane ϩ cytoskeletal fractions, indicating PKC-inactivity) but also led to disruption of claudin assembly and barrier function of the monolayer. The conclusions of this study are that PKC-activity is required for normal claudin assembly and the integrity of the intestinal epithelial barrier. These effects of PKC-are mediated at the molecular level by changes in phosphorylation, membrane assembly, and/or organization of the subunit components of two barrier function proteins: claudin-1 and claudin-4 isotypes. The ability of PKC-to alter the dynamics of permeability protein claudins is a new function not previously ascribed to the novel subfamily of PKC isoforms.The epithelium of the intestinal mucosa is the largest interface between the body and the external environment. An important characteristic of this interface is its ability to maintain a highly selective permeability barrier that protects the internal milieu from hostile factors in the lumenal environment. Barrier permeability, which in general is maintained by epithelial tight-junctional proteins, pe...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

Banan¹,

Zhang²,

Shaikh³

et al. 2005

J Pharmacol Exp Ther

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“…The first model used for this purpose took advantage of the fact that PGN itself can induce colitis (21,22) and therefore we could test the effect of NOD2 over-expression on a colitis induced by a TLR ligand closely tied to NOD2-mediated negative regulation. In studies of PGN-colitis we administered 50% ethanol per rectum to both NOD2-Tg mice and littermate control mice alone or followed 8h later by soluble PGN (1mg) again per rectum and then characterized the ensuing colitis in the two mouse groups.…”

Section: Mice That Over-express Nod2 Are Resistant To the Developmentmentioning

confidence: 99%

NOD2 Transgenic Mice Exhibit Enhanced MDP-Mediated Down-Regulation of TLR2 Responses and Resistance to Colitis Induction

et al. 2007

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“…Recently, attention has been focused on the overproduction of nitric oxide (NO) in IBD (7,31,46,58). Several studies have identified increased levels of NO in the rectal dialysates (46), in the inflamed mucosa of patients with ulcerative colitis (UC) (3), and in animal models of colitis (26,37,60). The increased NO synthase (NOS) activity was identified predominantly as the inducible form of NOS (iNOS) (23).…”

mentioning

confidence: 99%

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

Vallance¹,

Dijkstra²,

Qiu³

et al. 2004

American Journal of Physiology-Gastrointestinal and Liver Physi

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The role of nitric oxide (NO) in inflammatory bowel diseases has traditionally focused on the inducible form of NO synthase (iNOS). However, the constitutive endothelial (eNOS) and neuronal (nNOS) isoforms may also impact on colitis, either by contributing to the inflammation or by regulating mucosal integrity in response to noxious stimuli. To date, studies examining the roles of the NOS isoforms in experimental colitis have been conflicting, and the mechanisms by which these enzymes exert their effects remain unclear. To investigate and clarify the roles of the NOS isoforms in gut inflammation, we induced trinitrobenzenesulfonic acid colitis in eNOS, nNOS, and iNOS knockout (KO) mice, assessing the course of colitis at early and late times. Both eNOS and iNOS KO mice developed a more severe colitis compared with wild-type mice. During colitis, iNOS expression dramatically increased on epithelial and lamina propria mononuclear cells, whereas eNOS expression remained localized to endothelial cells. Electron and fluorescence microscopy identified bacteria in the ulcerated colonic mucosa of eNOS KO mice, but not in wild-type, iNOS, or nNOS KO mice. Furthermore, eNOS KO mice had fewer colonic goblet cells, impaired mucin production, and exhibited increased susceptibility to an inflammatory stimulus that was subthreshold to other mice. This susceptibility was reversible, because the NO donor isosorbide dinitrate normalized goblet cell numbers and ameliorated subsequent colitis in eNOS KO mice. These results identify a protective role for both iNOS and eNOS during colitis, with eNOS deficiency resulting in impaired intestinal defense against lumenal bacteria and increased susceptibility to colitis. mucus; bacteria; inflammatory bowel diseases; goblet cells SEVERAL FACTORS HAVE BEEN implicated in the pathogenesis of human inflammatory bowel diseases (IBD) including an immunological intolerance to enteric microflora (10 -12, 43), as well as defects in mucosal barrier function (47). Recently, attention has been focused on the overproduction of nitric oxide (NO) in IBD (7,31,46,58). Several studies have identified increased levels of NO in the rectal dialysates (46), in the inflamed mucosa of patients with ulcerative colitis (UC) (3), and in animal models of colitis (26,37,60). The increased NO synthase (NOS) activity was identified predominantly as the inducible form of NOS (iNOS) (23). Whereas the two constitutive isoforms, neuronal (nNOS) and endothelial-derived (eNOS), modulate several aspects of intestinal physiology (6, 53), their contribution to the inflammatory response has received less attention.Despite considerable evidence that iNOS-derived NO contributes to tissue destruction in colitis and other inflammatory states (27), conflicting results have been obtained by using pharmacological inhibitors of NOS in animal models of IBD. Several studies have found that the nonspecific NOS inhibitor N G -nitro-L-arginine methyl ester reduced intestinal inflammation (17, 37, 45); other studies found little benefit (20) o...

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Mucosal injury and inflammation in a model of chronic granulomatous colitis in rats

Cited by 166 publications

References 28 publications

θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

θ Isoform of Protein Kinase C Alters Barrier Function in Intestinal Epithelium through Modulation of Distinct Claudin Isotypes: A Novel Mechanism for Regulation of Permeability

NOD2 Transgenic Mice Exhibit Enhanced MDP-Mediated Down-Regulation of TLR2 Responses and Resistance to Colitis Induction

Relative contributions of NOS isoforms during experimental colitis: endothelial-derived NOS maintains mucosal integrity

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