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At least 307 records · Page 17Linked to original sources
PubMed2006

Role of matrix metalloproteinases in intestinal inflammation.

Matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of MMPs (TIMPs), are produced in the gastrointestinal tract by several structural cells. The balance between MMPs and TIMPs is essential for many physiological processes in the gut. However, imbalance between MMPs and TIMPs plays an important role in the pathophysiology of diverse intestinal inflammatory conditions. We reviewed the role of the MMP/TIMP system in the pathogenesis of intestinal inflammatory diseases and pharmacologic perspectives for the use of compounds that restore the MMP/TIMP balance.

Animals↗
PubMed2001

Involvement of tachykinins in intestinal inflammation.

The tachykinins, substance P, neurokinin A and neurokinin B are small peptides expressed in the extrinsic primary afferent nerve fibers and enteric neurons of the gut. Tachykinins exert a variety of biological actions mediated by three distinct receptors, termed NK1, NK2 and NK3, and at the gastrointestinal level these peptides influence motility, electrolyte and fluid secretion and tissue homeostasis. Several intestinal disorders are associated with changes in the expression of the tachykinin system. Thanks to biological studies and receptor cloning, new selective tachykinins antagonists are now available and have been shown to be active in experimental gut disorders. Some of them are now under clinical trial in inflammatory bowel diseases and the irritable bowel syndrome. The body of preclinical data so far available seems to indicate that tachykinin antagonists might be a new therapeutic tool in the treatment of gut disorders.

Animals↗
PubMed2006

Growth factors as treatment options for intestinal inflammation.

On the basis of several studies that have been completed to date, some growth factors appear promising for the treatment of inflammatory bowel disease: keratinocyte-like growth factor-2 (KGF-2), epidermal growth factor (EGF) enemas used in combination with oral mesalamine, somatropin (human growth hormone), and sargramostim (recombinant human GM-CSF). The results of these studies are highlighted and suggest that new insights into the regulation of intestinal immunity may provide effective synergistic or single-agent treatment alternatives to immunosuppression for inflammatory bowel disease. These data focus on the reparative components of mucosal homeostasis.

Animals↗
PubMed2003

The dendritic cell: its role in intestinal inflammation and relationship with gut bacteria.

Dendritic cells are antigen presenting cells that are likely to be pivotal in the balance between tolerance and active immunity to commensal microorganisms that is fundamental to inflammatory conditions, including Crohn's disease and ulcerative colitis. Interactions between dendritic cells and microbial products are discussed and how they contribute to regulation of immune responses. The concept that interactions between dendritic cells and commensal organisms may be responsible for maintaining intestinal immune homeostasis is also explored.

Bacterial Infections↗
PubMed1998

Regulation of proliferation of human colonic subepithelial myofibroblasts by mediators important in intestinal inflammation.

An increase in myofibroblast number may be necessary for wound healing but may also lead to postinflammatory scarring. We have, therefore, studied the role of mediators important in inflammatory bowel disease in regulating proliferation of human colonic myofibroblasts. Using primary cultures of these cells, we have shown increases in [3H]thymidine incorporation in response to platelet-derived growth factor (EC50 = 14 ng/ml), basic fibroblast growth factor (EC50 = 2.2 ng/ml), and epidermal growth factor (EC50 = 1.1 ng/ml). Coulter counting of cell suspensions demonstrated increases in cell number with these growth factors along with insulin-like growth factor-I and -II. In addition the proinflammatory cytokines IL-1beta and TNF-alpha produced increases in [3H]thymidine incorporation. IL-1beta and platelet-derived growth factor together produced an increase in [3H]thymidine greater than either agonist alone; this effect was not, however, seen when we examined changes in cell numbers. Finally, we demonstrate a mechanism whereby these responses may be downregulated: vasoactive intestinal peptide (1 microM) elevates cyclic AwMP in these cells 4. 2-fold over control and produces a dose-related inhibition of platelet-derived growth factor-driven proliferation with a maximum inhibition of 33% at 1 microM.

Cell Division↗
PubMed2004

Corticotropin-releasing hormone (CRH) requirement in Clostridium difficile toxin A-mediated intestinal inflammation.

Clostridium difficile, the causative agent of antibiotic-associated colitis, mediates inflammatory diarrhea by releasing toxin A, a potent 308-kDa enterotoxin. Toxin A-induced inflammatory diarrhea involves many steps, including mucosal release of substance P (SP) corticotropin-releasing hormone (CRH) and neutrophil transmigration. Here we demonstrate that, compared with wild type, mice genetically deficient in CRH (Crh(-/-)) have dramatically reduced ileal fluid secretion, epithelial cell damage, and neutrophil transmigration 4 h after intraluminal toxin A administration. This response is associated with diminished mucosal activity of the neutrophil enzyme myeloperoxidase compared with that of wildtype mice. In wild-type mice, toxin A stimulates an increase in intestinal SP content compared with buffer administration. In contrast, toxin A administration in Crh(-/-) mice fails to result in an increased SP content. Moreover, immunohistochemical experiments showed that CRH and SP are colocalized in some enteric nerves of wild-type mice, and this colocalization is more evident after toxin A administration. These results provide direct evidence for a major proinflammatory role for CRH in the pathophysiology of enterotoxin-mediated inflammatory diarrhea and indicate a SP-linked pathway.

Animals↗
PubMed1997

Imbalance of the interleukin 1 system in colonic mucosa--association with intestinal inflammation and interleukin 1 receptor antagonist [corrected] genotype 2.

BACKGROUND: Interleukin 1 (IL-1) alpha and beta are potent cytokines which play key roles in inflammation. They are controlled by IL-1 receptor antagonist (IL-1ra). AIMS: To investigate the influence of mucosal inflammation and IL-1ra genotype on the IL-1ra:IL-1 balance. PATIENTS AND METHODS: IL-1 alpha, IL-1 beta, and IL-1ra were measured by enzyme linked immunosorbent assay (ELISA) in biopsy specimens taken from inflamed and non-inflamed colon of 60 patients with Crohn's disease (CD), 34 with ulcerative colitis (UC), 15 inflammatory controls, and 103 non-inflamed controls. IL-1ra genotype was determined by polymerase chain reaction and gel electrophoresis. RESULTS: IL-1 alpha and IL-1 beta were significantly increased in inflamed mucosa in inflammatory bowel disease (IBD) (CD: 53.5 (22.4) and 409.9 (118.7) pg/mg protein, respectively; UC: 18.9 (6.8) and 214.5 (78.2) pg/mg, respectively) and non-IBD patients (19.2 (7.4) and 281.4 (121.0) pg/mg, respectively; p < 0.0001) compared with normal controls (2.8 (0.6) and 30.6 (5.6) pg/mg, respectively). In CD IL-1 alpha and beta were also significantly increased in non-inflamed mucosa (6.1 (1.3) pg/mg and 88.7 (17.4) pg/mg, respectively; p < 0.0012). IL-1ra:(IL-1 alpha+beta) ratios were significantly decreased in inflamed mucosa of patients with CD (182 (45); p < 0.0001), UC (425 (136); p = 0.0018) and without IBD (221 (76); p < 0.0001), and in non-inflamed mucosa in CD (369 (149); p < 0.0001) compared with normal controls (1307 (245); p < 0.0001). Patients with IL-1ra genotype 2 had slightly but significantly reduced mucosal IL-1ra concentrations (p = 0.003). The greatest difference was seen in colonic biopsy specimens from patients with inflamed Crohn's disease. CONCLUSION: Mucosal inflammation can modulate the balance of the IL-1:IL-1ra system in colonic mucosa.

Adult↗
PubMed1997

Oxidants, transcription factors, and intestinal inflammation.

It is now well appreciated that chronic gut inflammation is characterized by enhanced production of reactive metabolites of oxygen and nitrogen. Some of these oxidants are known to modulate the expression of a variety of genes that are involved in the immune and inflammatory responses. For example, certain oxidants are known to activate the nuclear transcription factor kappa B, which regulates the expression of a variety of different adhesion molecules, cytokines, and enzymes. Oxidants are also known to activate another transcription factor, activator protein-1. This transcription factor is composed of products from the fos and jun proto-oncogene family and is believed to be important in regulating cell growth and proliferation. Finally, oxidants are believed to promote intestinal epithelial cell apoptosis, and the B-cell lymphoma/leukemia-2 gene product is believed to inhibit this phenomenon in an antioxidant-dependent manner. Taken together, these observations suggest that nontoxic concentrations of reactive metabolites of oxygen and nitrogen play an important role in regulating the expression of genes involved in the inflammatory response and in modulating apoptosis.

Animals↗
PubMed1994

Rabbit interleukin-1 receptor antagonist. Cloning, expression, functional characterization, and regulation during intestinal inflammation.

Genomic and cDNA clones for rabbit interleukin-1 receptor antagonist (IL-1ra) were isolate based on homology with the human, mouse, and rat IL-1ra gene. A partial genomic clone, obtained by screening a rabbit genomic library, contained coding sequences for the carboxyl-terminal 108 amino acids of rabbit IL-1ra. Two classes of cDNA for rabbit IL-1ra were obtained using RNA from inflamed rabbit colon tissue. One class of cDNA coded for a secreted form of IL-1ra, whereas the other coded for a putative intracellular form of rabbit IL-1ra. The latter form is similar to that isolated from human epithelial cells. A partially synthetic rabbit IL-1ra gene was constructed and expressed in Escherichia coli. The recombinant rabbit IL-1ra was purified to homogeneity by ion exchange chromatography. Its affinity was similar to that of human IL-1ra for the human and mouse type I IL-1 receptor. From the cDNA clone and the purified recombinant protein, specific probes were developed for measuring levels of rabbit IL-1ra mRNA and protein in normal and inflamed rabbit tissues. Unlike IL-1 alpha and IL-1 beta, IL-1RA mRNA and protein were present at detectable levels in normal rabbit colon. During the development of an experimental formalin-immune complex colitis, rabbit IL-1 alpha showed a dramatic increase in tissue levels, consistent with previous results; IL-1ra also increased 3-4-fold. Treatment of colitis rabbits with corticosteroids significantly suppressed neutrophil infiltration, corticosteroid treatment suppressed IL-1ra but not IL-1 alpha mRNA steady-state levels. Our observations demonstrate that IL-1 and IL-1ra synthesis is differentially regulated in healthy and inflamed intestinal tissue.

Amino Acid Sequence↗
PubMed1998

High expression of inducible nitric oxide synthase correlates with intestinal inflammation of interleukin-2-deficient mice.

Severely inflamed colonic sections of IL-2 (-/-) mice showed up to 19-fold increased iNOS mRNA levels. The level of iNOS protein expression corresponded to the increased iNOS mRNA levels as detected by means of Western blot analysis. There was a clear, positive relationship between the level of iNOS expression and the degree of inflammation in the colonic tissue of IL-2 (-/-) and wild-type mice. Our data suggest that iNOS may play a key role in the pathogenesis of ulcerative colitis-like disease in IL-2 (-/-) mice. Further investigation should elucidate the impact of NO on the regulation of the inflammatory process in this model and might contribute to a better understanding of the role iNOS expression in human immune-mediated diseases.

Animals↗
PubMed2006

Chitinase 3-like-1 exacerbates intestinal inflammation by enhancing bacterial adhesion and invasion in colonic epithelial cells.

BACKGROUND & AIMS: Dysregulated host/microbial interactions appear to play a central role in the development of inflammatory bowel disease (IBD). However, molecular events leading to the dysregulation have not yet been defined fully. Studies were designed to characterize a key molecule that is involved in the dysregulation. METHODS: Colonic mucosal RNA from C57BL/6 mice on days 4 and 8 with administration of 4% dextran sulfate sodium for 5 days were subjected to DNA microarray analysis. Chitinase 3-like-1 (CHI3L1) messenger RNA and protein expressions were examined by reverse-transcription polymerase chain reaction and immunohistochemistry. A gentamicin protection assay of Salmonella typhimurium was performed using epithelial cell lines that are engineered genetically to overexpress or lack mouse CHI3L1. To examine the functional role of CHI3L1 in vivo, anti-CHI3L1 antibody was administered into the dextran sulfate sodium colitis model. RESULTS: Microarray analysis identified that CHI3L1 is up-regulated specifically in inflamed mucosa. The expression of CHI3L1 protein clearly was detectable in lamina propria and colonic epithelial cells (CECs) in several murine colitis models and ulcerative colitis and Crohn's disease patients but absent in normal controls. The gentamicin protection assays using intracellular bacteria showed that CHI3L1 is required for the enhancement of adhesion and internalization of these bacteria in CEC. In vivo neutralization experiments showed that CHI3L1 contributes to the facilitation of bacterial invasion into the intestinal mucosa and the development of acute colitis. CONCLUSIONS: CHI3L1 plays a pathogenic role in colitis, presumably by enhancing the adhesion and invasion of bacteria on/into CEC. Inhibition of CHI3L1 activity would be a novel therapeutic approach for IBD.

Animals↗
PubMed2005

Defining the role of T cell-derived leptin in the modulation of hepatic or intestinal inflammation in mice.

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin-signalling is associated with protection were employed: the model of ConA-induced hepatitis and the CD4(+)CD45Rb(high) transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin-deficient (ob/ob) CD4(+) T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFalpha, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4(+)CD45Rb(high) cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL-6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNgamma release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell-derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune-modulating effects of leptin.

Animals↗
PubMed1995

Influence of intestinal inflammation (IBD) and small and large bowel length on fecal short-chain fatty acids and lactate.

Treatment with short-chain fatty acids (SCFAs) seems promising in ulcerative colitis and changes in colonocyte oxidation of butyrate have been suggested to be of importance for the development of this disease. The influence of small and large bowel length after surgery on SCFAs is only partly known. SCFAs and lactate were measured in consecutive fecal samples from 300 patients with ulcerative colitis (103), Crohn's disease (127), and noninflammatory bowel disease (70); 205 had had surgery, 52 had short bowels (< 200 cm). Lactate (mainly the L-isomer) was elevated in ulcerative colitis patients with pancolitis (mean +/- SEM, 17 +/- 5 mmol/liter) and proctitis (12 +/- 3 mmol/liter) compared with quiescent ulcerative colitis (3 +/- 1 mmol/liter, P < 0.01), and correlated with the index of Truelove (R = 0.52, P < 0.0005). Lactate was also increased in Crohn's colitis (21 +/- 8 mmol/liter), but not in isolated ileitis (4 +/- 2 mmol/liter), compared with quiescent Crohn's disease (7 +/- 2 mmol/liter, P < 0.02), but did not correlate with the activity index (CDAI; R = 0.18, P = 0.12). In contrast to earlier reports, SCFAs (including butyrate) did not correlate with inflammatory activity or localization in either ulcerative colitis or Crohn's disease. The length of the small bowel had no influence on SCFAs and lactate in patients with either no colonic function (ileostomies), or with > 50% and < 50% preserved colorectal length, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2005

Neuropeptide neurotensin stimulates intestinal wound healing following chronic intestinal inflammation.

Because neurotensin (NT) and its high-affinity receptor (NTR1) modulate immune responses, chloride secretion, and epithelial cell proliferation, we sought to investigate their role in the repair process that follows the development of mucosal injuries during a persistent inflammation. Colonic NT and NTR1, mRNA, and protein significantly increased only after dextran sodium sulfate (DSS)-induced inflammatory damage developed. Colitis-induced body weight loss, colonic myeloperoxidase activity, and histological damage were significantly enhanced by SR-48642 administration, a nonpeptide NTR1 antagonist, whereas continuous NT infusion ameliorated colitis outcome. To evaluate the NT and NTR1 role in tissue healing, mucosal inflammatory injury was established administering 3% DSS for 5 days. After DSS discontinuation, mice rapidly gained weight, ulcers were healed, and colonic NT, NTR1, and cyclooxygenase (COX)-2 mRNA levels were upregulated, whereas SR-48642 treatment caused a further body weight loss, ulcer enlargement, and a blunted colonic COX-2 mRNA upregulation. In a wound-healing model in vitro, NT-induced cell migration in the denuded area was inhibited by indomethacin but not by an antitransforming growth factor-beta neutralizing antibody. Furthermore, NT significantly increased COX-2 mRNA levels by 2.4-fold and stimulated PGE(2) release in HT-29 cells. These findings suggest that NT and NTR1 are part of the network activated after mucosal injuries and that NT stimulates epithelial restitution at least, in part, through a COX-2 dependent pathway.

Animals↗
PubMed2005

MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis.

BACKGROUND: Gut commensal microbes affect the development and activation of the mucosal and systemic immune systems. However, the exact molecular mechanism of these microbes that is involved in the development of colitis remains unclear. METHODS: The present study was conducted to determine the distinct role of the innate immune system in the development of a dextran sulfate sodium (DSS) colitis model in MyD88(-/-) mice, because myeloid differentiation protein (MyD88) is a major adaptor molecule essential for signaling via Toll-like receptors (TLRs). To this end, MyD88(-/-) and wild-type (WT) mice received sterile distilled water containing 1.2% DSS for 8 days. The survival rate, total clinical score (body weight loss, stool consistency, and rectal bleeding), colon length, and histological score were assessed. The expression of surface markers (F4/80 and CD4) on infiltrating lamina propria mononuclear cells was analyzed immunohistochemistrically. RESULTS: MyD88(-/-) mice exhibited increased susceptibility to DSS-induced colitis, as reflected by significantly higher lethality and higher clinical and histological scores, and more severe colonic shortening compared to WT mice. Immunohistochemical analysis revealed a significant increase of both F4/80+ macrophages and CD4+ T cells in the inflamed mucosa in DSS-fed MyD88(-/-) mice compared to DSS-fed WT mice. CONCLUSIONS: These findings suggest that, via MyD88 signaling, the innate immune system in the gut plays an important protective role in colitis.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Cytokines, NF-kappaB, microenvironment, intestinal inflammation and cancer.

Inflammation and cancer have been viewed as closely linked for many years. This link is not merely a loose association but causative. In colorectal cancer (CRC), chronic inflammation as observed in inflammatory bowel (IBD) disease is a key predisposing factor and IBD-associated CRC comprises five percent of all CRCs. Although the molecular mechanisms linking IBD with CRC are not well understood, recent results obtained in preclinical models point to the transcription factor NF-kappaB as a central player. On the one hand, NF-kappaB regulates the expression of various cytokines and modulates the inflammatory processes in IBD. On the other, NF-kappaB stimulates the proliferation of tumor cells and enhances their survival through the regulation of anti-apoptotic genes. Furthermore, it has been clearly established that most carcinogens and tumor promoters activate NF-kappaB, while chemopreventive agents generally suppress this transcription factor. Actually, several lines of evidence suggest that activation of NF-kappaB may cause cancer. These include the finding that NF-kappaB genes can be oncogenes, and that this transcription factor controls apoptosis, cell-cycle progression and proliferation, and possibly also cell differentiation.

Apoptosis↗
PubMed2003

Gene therapy in the treatment of intestinal inflammation.

BACKGROUND: Local expression of anti-inflammatory or immunoregulatory genes may offer an alternative treatment of gastrointestinal inflammation. DISCUSSION: We review the basic requirements for gene therapy, the possible routes of delivery, and the different strategies for specific targeting focusing on gastrointestinal inflammation.

Gastroenteritis↗