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PubMed2001

Effect of L-arginine on the course of experimental colitis.

BACKGROUND AND AIMS: L-Arg is the substrate for nitric oxide, and also for L-ornithine which, in turn, is the precursor for the synthesis of collagen and polyamines. By these different metabolic pathways, L-Arg is involved in the mechanisms of inflammation, tissue repair and fibrosis. Thus, the aim of this study was to assess the effect of both different amounts of L-Arg supplementation and L-Arg-free diets upon colonic inflammatory damage and fibrosis in experimental colitis. METHODS: Sprague-Dawley rats with trinitrobenzene sulphonic acid (TNBS)-induced colitis received increasing doses of L-Arg (30, 100, 500 mg/day), or D-Arg (500 mg/day). In a second experiment, two L-Arg-free diets (one supplemented with L-Gly) were compared to a L-Arg diet. Nitrite/nitrate release in the lumen of the colon and colonic damage were evaluated. In the first experiment, tissue collagen levels and colonic mucosal proliferation were also assessed. RESULTS: In the acute phase of colitis, intracolonic nitrite/nitrate levels were significantly higher in the 100 and 500 mg supplemented L-Arg groups than in D-Arg group. However, only rats treated with 500 mg of L-Arg showed moderately higher inflammatory and fibrosis colonic scores than the D-Arg treated rats. There was no significant influence of L-Arg-free diets on the course of TNBS-induced colitis. However, L-Arg diet accelerated weight gain both pre- and post-TNBS. CONCLUSIONS: These results suggest that normal amounts of L-Arg in the diet are not harmful, whereas both absence of L-Arg or supplementation with high doses of this amino acid may be deleterious. In the former this might be due to a decrease of nitrogen retention in injured rats, whereas in the latter it may result from both nitric oxide-mediated tissue damage and collagen deposition.

Acute Disease↗
PubMed2001

Altered response of intestinal mucosal fibroblasts to profibrogenic cytokines in inflammatory bowel disease.

BACKGROUND AND AIMS: Fibrosis is a major complication of inflammatory bowel disease (IBD), which may be mediated by the intestinal fibroblast. Our aim was to isolate and characterize mucosal fibroblasts from histologically normal intestine (control), ulcerative colitis (UC), inflamed Crohn's disease (CD), and fibrosed CD intestine. METHODS: Fibroblasts were characterized by light and electron microscopy and immunohistochemistry. Fibroblast collagen secretion and proliferation were determined by 3H-proline and 3H-thymidine incorporation, and the effects of exposure to interleukin (IL)-1beta, basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta1, insulin-like growth factor (IGF)-1, and macrophage colony stimulating factor (M-CSF) were determined. RESULTS: No difference in doubling time was observed between the fibroblast populations from UC and CD intestine. All proliferated faster than fibroblasts from control intestine. Collagen secretion from IBD fibroblasts, independent of type, was increased compared with control fibroblasts and PDGF, bFGF, and TGF-beta1-induced collagen secretion from IBD fibroblasts. CONCLUSIONS: These results suggest the presence of an activated subpopulation of fibroblasts in both UC and CD tissue irrespective of the presence of tissue fibrosis or disease type.

Actins↗
PubMed2001

Inflammation location, but not type, determines the increase in TGF-beta1 and IGF-1 expression and collagen deposition in IBD intestine.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is frequently complicated by extracellular matrix (ECM) changes that may result in fibrosis. Transforming growth factor (TGF)-beta1 and insulin-like growth factor (IGF)-1 mediate numerous ECM changes. Our aim was to determine whether TGF-beta1 and IGF-1 are involved in intestinal ECM collagen regulation and what impact the inflammatory infiltrate has on their expression. METHODS: TGF-beta1 and IGF-1 mRNA and protein were assessed in fibrosed Crohn's disease (CD), inflamed CD, inflamed ulcerative colitis (UC), and control intestine using in situ hybridization and immunohistochemistry. Collagen types I and III were quantified by electron immunohistochemistry. RESULTS: In CD, increased TGF-beta1 and IGF-1 mRNA expression was transmural. In UC, the increase was confined to the lamina propria and submucosa. In both, distribution of TGF-beta1 and IGF-1 protein matched mRNA expression and coincided with the distribution of the inflammatory infiltrate. An increase in the collagen type III:I ratio in both CD and UC also coincided with the inflammatory infiltrate. CONCLUSIONS: These findings suggest that TGF-beta1 and IGF-1 are involved in intestinal ECM remodeling in IBD, and their enhanced expression depends on the presence and location of inflammatory infiltrates rather than the type of IBD.

Collagen↗
PubMed1998

Significance of diminished factor XIII in Crohn's disease.

OBJECTIVE: Coagulation factor XIII is a plasma transglutaminase involved in crosslinking of fibrin, the last step of the coagulation system and a connective tissue factor contributing to the wound healing process. It circulates as a heterotetrameric molecule consisting of two identical proenzyme subunits (factor XIIIA) and two carrier protein subunits (factor XIIIS). The aim of this study was to determine the disease features associated with the diminution of factor XIII in Crohn's disease. METHODS: Factor XIIIA and factor XIIIS levels were assessed in patients presenting with Crohn's disease, ulcerative colitis, infectious colitis, or diverticulitis, in patients with rheumatoid arthritis, and in control subjects. Prothrombin fragment 1 + 2 assay, as a marker of the generation of thrombin and measurement of C-terminal telopeptide of type I collagen as an estimate of degradation of collagen type I, were performed. RESULTS: Factor XIIIA was significantly decreased in Crohn's disease, in ulcerative colitis, and in infectious colitis by comparison with subjects presenting with diverticulitis, normal, and rheumatoid subjects p = 0.0001). Factor XIIIS was unmodified in patients with Crohn's disease by comparison with controls but was reduced in those presenting with intestinal bleeding (p = 0.0002). In Crohn's disease, the lowest level of factor XIIIA was observed in patients with intestinal bleeding (p = 0.0003). Factor XIIIA was correlated with the Van Hees index (r = -0.5661; p = 0.0001) and with the C-terminal telopeptide of type I collagen (r = -0.4110; p = 0.0011) but not with prothrombin fragment 1 + 2. The multiple regression analysis showed that only Van Hees index and intestinal bleeding were independent variables for explaining the diminution of Factor XIIIA in Crohn's disease. CONCLUSIONS: Factor XIIIA subunit is an indicator of Crohn's disease activity. Our study suggests that a low factor XIIIA level is related to the presence of intestinal lesions and might be linked to intestinal repair mechanisms; loss in intestinal lumen could be also involved, especially in patients with intestinal bleeding.

Adolescent↗
PubMed2002

Polyunsaturated phosphatidylcholine lowers collagen deposition in a rat model of corrosive esophageal burn.

Esophageal strictures are characterized by excess deposition of collagen in the esophageal wall. Polyunsaturated phosphatidyl-choline (PPC) stimulates collagen breakdown in experimental models of liver cirrhosis and colitis. This study was done in order to investigate the therapeutical effect of PPC in preventing esophageal strictures due to alkali-induced esophageal burns in rats. Fifty-five albino rats were divided into four groups as follows: control group (Group A, 10 rats), rats with sham operation and treated with saline (Group B, 15 rats), rats with esophageal burns only (Group C, 15 rats), and PPC-fed rats with esophageal burns (Group D, 15 rats). A standard esophageal burn was produced as described by Gehanno. PPC was administered orally to Group D rats in doses of 100 mg/day for four weeks. All animals were sacrificed on the 28th day of the experiment. Hydroxyproline levels in esophageal tissue was determined in each rat, and histopathologic evaluation was performed for each group. Hydroxyproline levels were significantly lower in the PPC-fed rats than in the rats with pure esophageal burns (p < 0.001). Histopathologically, collagen deposition in the submucosa and tunica muscularis was lower in Group D rats (PPC-fed rats with esophageal burn) than Group C rats (pure esophageal burn) (p < 0.05). As a result of our study, we concluded that PPC has an ameliorating effect on stricture formation after alkali-induced corrosive esophageal burns in rats.

Animals↗
PubMed2000

Increased urinary N-telopeptide cross-linked type 1 collagen predicts bone loss in patients with inflammatory bowel disease.

OBJECTIVE: Reduced bone mineral density (BMD) is common in patients with inflammatory bowel disease (IBD), but the factors associated with its longitudinal rate of change have not been established. We prospectively assessed the rate of change in BMD, and its association with biochemical markers of bone turnover. METHODS: Twenty-two patients with Crohn's disease and 14 ulcerative colitis patients age 37.1 +/- 11.6 yr were followed for 2 yr. Lumbar spine (L2-L4) and femoral neck BMD were measured by dual x-ray absorptiometry at baseline and 24 months. Bone-specific alkaline phosphatase, osteocalcin, urinary N-telopeptide crosslinked type 1 collagen (NTx), parathyroid hormone, and 25-hydroxyvitamin-D were determined at baseline. RESULTS: At baseline, 59% of Crohn's patients and 43% of ulcerative colitis patients were osteoporotic, with spine or femoral neck BMD T-score < -2.5. Spine BMD, and spine and femoral neck T-scores were lower and disease duration was longer in nine patients with ileal resection compared with nonoperated patients (0.84 +/- 0.15 g/cm2 vs 0.96 +/- 0.11 g/cm2, -3.0 +/- 1.5 vs -1.7 +/- 1.3, -3.2 +/- 1.5 vs -2.2 +/- 1.0, respectively; all p < 0.05). At 24 months, 13/36 (36%) and 14/36 (39%) patients experienced spinal and femoral neck bone loss, respectively, with mean annual percent BMD changes of -2.0% and -1.5%, respectively. NTx, a bone resorption marker, inversely correlated with spinal BMD rate of change (r = -0.4, p < 0.05). Using quartiles analysis, patients with the highest NTx (Q4) experienced the greatest decrease in spine BMD compared with patients with the lowest NTx (Q1). CONCLUSIONS: Spine and femoral neck bone loss continues over time in more than one-third of IBD patients. Increased NTx level predicts spinal bone loss in IBD patients.

Absorptiometry, Photon↗
PubMed2005

Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells.

OBJECTIVE: Regulatory T cells play an important role in the prevention of autoimmunity and have been shown to be effective in the treatment of experimental colitis, a T cell-mediated and organ-specific disease. We previously demonstrated that intrinsic CD25+ regulatory T cells modulate the severity of collagen-induced arthritis (CIA), which, in contrast to colitis, is a systemic antibody-mediated disease and an accepted model of rheumatoid arthritis. We undertook this study to determine whether regulatory T cells have the potential to be used therapeutically in arthritis. METHODS: We transferred CD4+,CD25+ T cells into mice exhibiting arthritis symptoms, both immunocompetent mice and mice subjected to lethal irradiation and rescued with syngeneic bone marrow transplantation. RESULTS: A single transfer of regulatory T cells markedly slowed disease progression, which could not be attributed to losses of systemic type II collagen-specific T and B cell responses, since these remained unchanged after adoptive transfer. However, regulatory T cells could be found in the inflamed synovium soon after transfer, indicating that regulation may occur locally in the joint. CONCLUSION: Our data indicate that CD25+ regulatory T cells can be used for the treatment of systemic, antibody-mediated autoimmune diseases, such as CIA.

Adoptive Transfer↗
PubMed2005

[Synthetic glycolipid ligands as novel therapeutics for multiple sclerosis].

Our previous works indicate that regulatory cells such as natural killer (NK) cells and NKT cells could play an active role in maintaining the remission state of MS. We have therefore adopted a strategy for developing the future MS therapy by targeting NKT cells. The unique glycolipid-reactive lymphocytes are known to produce a large quantity of Th2 cytokines such as IL-4 when encountering their ligands like alpha-galactosylceramide (alpha-GC). Whereas most of the NKT ligands so far described would stimulate both Th1 and Th2 cytokine production by NKT cells, the synthetic compound OCH, an analogue of alpha-GC with a shorter lipid tail, is the one which selectively induces IL-4 production. Given this property, oral or intraperitoneal OCH administration would prohibit the development of a variety of Th1-meediated pathology, including EAE, collagen-induced arthritis, type 1 diabetes, DSS-induced colitis and acute GVHD by inducing Th2 bias. This review paper summarizes the recent publications and our unpublished results related to the efficacy of OCH and to the molecular mechanism accounting for the Th2 inducing property of OCH.

Animals↗
PubMed2002

Part II: beneficial effects of the peroxynitrite decomposition catalyst FP15 in murine models of arthritis and colitis.

BACKGROUND: Peroxynitrite is a reactive oxidant species produced from nitric oxide and superoxide, which has been indirectly implicated in the pathogenesis of many inflammatory conditions including arthritis and colitis. Here, using a novel peroxynitrite decomposition catalyst, FP15, we directly investigate the role of peroxynitrite in the pathogenesis of arthritis and colitis in rodent models. METHODS: Arthritis was induced in mice by intradermal collagen injection; incidence and severity of arthritis was monitored using a macroscopic scoring system. At the end of the experiment paws were taken for determination of neutrophil infiltration (myeloperoxidase [MPO] activity), oxidative stress (malondialdehyde [MDA] level), and cytokine/chemokine levels. Colitis was induced in mice by 5% dextran sodium sulfate (DSS) in their drinking water. Colitis symptoms were assessed 10 days later, the parameters determined included body weight, rectal bleeding, colon length, colonic MPO and MDA levels, and colon histologic damage. RESULTS: Treatment with FP15 significantly reduced the inflammation and oxidative stress in arthritis and colitis. FP15 reduced both the incidence and severity of arthritis in mice and this was associated with reduced paw MPO and MDA levels. Similarly, in colitis, FP15 reduced colon damage, and this was associated with reduced colon neutrophil infiltration and oxidative stress. CONCLUSIONS: The protective effect of FP15 suggests that peroxynitrite plays a significant pathogenetic role in arthritis and colitis in the currently employed rodent models. Further work is needed to determine whether neutralization of peroxynitrite also represents a promising strategy to treat human inflammatory diseases such as arthritis and colitis.

Administration, Oral↗
PubMed2002

Effects of chronic inflammatory bowel diseases on left ventricular structure and function: a study protocol.

BACKGROUND: Experimental evidences suggest an increased collagen deposition in inflammatory bowel diseases (IBD). In particular, large amounts of collagen type I, III and V have been described and correlated to the development of intestinal fibrotic lesions. No information has been available until now about the possible increased collagen deposition far from the main target organ. In the hypothesis that chronic inflammation and increased collagen metabolism are reflected also in the systemic circulation, we aimed this study to evaluate the effects on left ventricular wall structure by assessing splancnic and systemic collagen metabolism (procollagen III assay), deposition (ultrasonic tissue characterization), and cardiac function (echocardiography) in patients with different long standing history of IBD, before and after surgery. METHODS: Thirty patients affected by active IBD, 15 with Crohn and 15 with Ulcerative Colitis, submitted to surgery will be enrolled in the study in a double blind fashion. They will be studied before the surgical operation and 6, 12 months after surgery. A control group of 15 healthy age and gender-matched subjects will also be studied. At each interval blood samples will be collected in order to assess the collagen metabolism; a transthoracic echocardiogram will be recorded for the subsequent determination of cardiac function and collagen deposition. DISCUSSION: From this study protocol we expect additional information about the association between IBD and cardiovascular disorders; in particular to address the question if chronic inflammation, through the altered collagen metabolism, could affect left ventricular structure and function in a manner directly related to the estimated duration of the disease.

Adolescent↗
PubMed1988

Shiga-like toxin production and connective tissue protein binding of Escherichia coli isolated from a patient with ulcerative colitis.

A 15-year-old girl with her first relapse of ulcerative colitis was treated with salicylazosulfapyridine, steroids, metronidazole and parenteral nutrition for 4 weeks without significant improvement. Her faecal specimens were negative for established intestinal pathogens, but strains of Escherichia coli producing Shiga-like toxin and expressing binding of fibronectin and collagen were repeatedly isolated. Neutralizing antibodies to Shiga-like toxin were detected in serum samples. Improvement was achieved during treatment with mecillinam to which the E. coli strains were sensitive.

Adolescent↗
PubMed2003

Comparison of E-selectin expression at mRNA and protein levels in murine models of inflammation.

BACKGROUND: Drug targeting to activated endothelial cells via E-selectin is currently being explored as a new approach to treat chronic inflammatory disorders. This approach uses E-selectin directed antibodies as carrier molecules to selectively deliver anti-inflammatory drugs into activated endothelial cells, thereby theoretically decreasing drug-associated side-effects. Therapeutic effects of developed drug targeting constructs will have to be tested in animal models of inflammation, in which E-selectin is expressed during the course of the disease. In this study several murine models of inflammation were investigated regarding expression of E-selectin. METHODS: E-selectin expression was determined both at the mRNA level using RT-PCR and at the protein level by immunohistochemistry using two monoclonal antibodies (10E9.6 and MES-1). The models studied included delayed type hypersensitivity induced skin inflammation, dextran sodium sulphate induced colitis, kidney ischemia/reperfusion injury, atherosclerosis in ApoE knockout mice, and collagen induced arthritis. RESULTS: In all animal models E-selectin mRNA expression was detected, although to a different extent. In contrast, only the delayed type hypersensitivity model and, to a minor extent, the collagen induced arthritis model showed E-selectin protein expression. CONCLUSION: These results stress the need to determine E-selectin protein expression and not only mRNA expression, when choosing an animal model for testing E-selectin directed drug targeting preparations. In addition, in the arthritis model, E-selectin protein detection was dependent on the particular anti-E-selectin antibody used. This finding may not only have implications for the development and/or choice of homing devices to be used in E-selectin directed drug targeting preparations, but also for inflammation research in general.

Animals↗
PubMed2004

Prevention of fibrosis in experimental colitis by captopril: the role of tgf-beta1.

BACKGROUND & AIMS: There is a body of evidence to suggest that the local activation of angiotensin II (ANG II) plays a pivotal role in fibrogenic response involving the kidney, heart, lung, pancreas and liver. In such conditions, fibrosis is mediated, at least partially, through ANG II induction of the cytokine transforming growth factor-beta1 (TGF-beta1). Both ANG II and TGF-beta1 also seem to be involved in intestinal fibrosis and stenosis, particularly in Crohn's disease. The aim of the present study was, firstly, to determine the effects of the angiotensin-converting enzyme inhibitor, captopril, on colonic fibrosis in experimental colitis in rats and, secondly, to check the role of TGF-beta1 on these effects. METHODS: Colitis was induced in rats by intracolonic administration of TNBS. Colonic fibrosis was assessed 21 days later by macroscopic and microscopic evaluation. Levels of collagen alpha1 gene expression, hydroxyproline, angiotensin II and TGF-beta1 proteins, and TGF-beta1 mRNA were measured on the colonic tissue. RESULTS: In chronic colitis, captopril significantly reduced the score of macroscopic and histologic lesions, as well as the colonic tissue levels of collagen alpha1, hydroxyproline, ANG II and TGF-beta1 proteins, and TGF-beta1 mRNA. CONCLUSIONS: These data demonstrate for the first time that the prophylactic administration of captopril is effective in preventing colonic fibrosis in TNBS-induced colitis. The antifibrotic action of captopril could be due to the blockade of TGFbeta-1 overexpression, and/or to a direct down-regulation of TGFbeta-1 transcript.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Femoral neck osteopenia in patients with inflammatory bowel disease.

OBJECTIVE: The mechanism of bone loss in patients with inflammatory bowel disease (IBD) is not completely understood. The aim of this study was to assess indices of bone turnover and bone mineral density (BMD) in the lumbar spine and femoral neck in IBD patients. METHODS: Sixty-three patients with Crohn's disease and 41 with ulcerative colitis were studied. Serum bone-specific alkaline phosphatase (B-ALP), osteocalcin, parathyroid hormone (PTH), 25 hydroxyvitamin D, interleukin-6 (IL-6), and urinary N-telopeptide cross linked type 1 collagen (NTX) were determined. BMD of the lumbar spine and femoral neck was determined by dual x-ray absorptiometry in 59 patients. RESULTS: In the femoral neck 42% of the patients had osteopenia (-2.5 SD < BMD T score < -1 SD) and another 41% had osteoporosis (BMD T score < -2.5). In the spine 34% of the patients had osteopenia and additional 42% had osteoporosis. BMD T scores were lower in the femoral neck compared to the spine. Reduced BMD was unrelated to gender, disease type, lifetime corticosteroid dose, but inversely correlated with disease duration (r = -0.36, p < 0.05). Serum IL-6 was higher in IBD patients compared to controls. A reduced level of osteocalcin, a marker of bone formation, was present in 7% of patients and an increase in NTX, a marker of bone resorption, in 25% of them. Osteoporotic IBD patients (spine or hip BMD T score < -2.5) had increased serum IL-6, osteocalcin and PTH level compared to nonosteoporotic patients. CONCLUSIONS: There is a high prevalence of reduced BMD at the spine and femoral neck in IBD patients, which is more severe in the hip. Bone turnover in osteoporotic IBD patients is associated with an increase in osteocalcin, PTH and IL-6. IL-6 may play a role in the pathogenesis of bone loss in IBD.

Adult↗
PubMed2000

Dose-dependent effects of recombinant human interleukin-11 on contractile properties in rabbit 2,4,6-trinitrobenzene sulfonic acid colitis.

We studied the effect of recombinant human interleukin-11 (rhIL-11), a cytokine with protective effects against injury to the intestinal mucosa, on inflammatory changes in the muscle layers of the gut, in rabbits with colitis. A single dose of rhIL-11 (4, 40, or 720 microg/kg) was given 1 h before colitis was induced with 135 mg/kg 2, 4,6-trinitrobenzene sulfonic acid (TNBS), followed by a continuous s. c. administration of 4, 40, or 720 microg/kg. day rhIL-11 or saline for 5 days. Colitis affected mucosal architecture, general mechanical properties (passive tension increased with 12.3 g/mm(2), optimal stretch decreased with 26%), and collagen content (decreased from 366 +/- 25 to 237 +/- 13 microg/mg of protein). Changes in passive tension and collagen content were normalized by the highest and lowest dose of rhIL-11, respectively, but neither dose could normalize the optimal stretch. Colitis also decreased maximal contractile tension in response to acetylcholine (ACh), motilin, substance P (SP), K(+), and prostaglandin E(2) but this was normalized with 40 microg/kg. day (motilin, SP) and 720 microg/kg. day (ACh, K(+)) rhIL-11 but not for prostaglandin E(2). For motilin and SP, receptor density was decreased in colitis and normalized in treated rabbits. Colitis also increased the contractile potency toward ACh, an effect already reversed by rhIL-11, 4 microg/kg. day. In conclusion, rhIL-11 partially normalizes disturbed tension generation in experimental colitis. The use of this cytokine in the treatment of irritable bowel disease may contribute to the restoration of motor dysfunction.

Acetylcholine↗
PubMed2005

Dietary n-3 polyunsaturated fatty acids reduce disease and colonic proinflammatory cytokines in a mouse model of colitis.

BACKGROUND: n-3 polyunsaturated fatty acids (PUFAs) reduce the severity of chronic inflammatory bowel disease, probably by means of reduction of immune cell activation or enhancement of the epithelial barrier. Using the severe combined immunodeficient (SCID) mouse model of colitis, this study examined the effect of dietary n-3 PUFAs on development of colitis and on immunologic, epithelial, and matrix parameters in the intestines of control and colitic animals. METHODS: SCID mice were fed n-3-enriched or control diet for 3 weeks before colitis induction by transplantation of CD45RB T cells and maintained on the same diet for 4 to 8 weeks. Phenotype of infiltrating cells, epithelial ZO-1 protein, and mucosal type I collagen were assessed by immunohistology and tissue cytokines by ELISA. RESULTS: Transplanted n-3-fed animals had significantly reduced pathology scores, colonic tumor necrosis factor-alpha, interleukin-12, and interleukin-1beta compared with animals fed standard diet. Proinflammatory cytokines were reduced despite a similar level of immune cell infiltration by T cells, CD11c cells, and CD11b cells. Neutrophil infiltration was significantly reduced in n-3-fed control and colitic mice, and other myeloid populations were reduced in mice on the n-3 diet. Epithelial ZO-1 expression was increased, and myofibroblast activation significantly decreased in transplanted n-3-fed animals compared with standard diet mice. Submucosal collagen synthesis was enhanced in n-3-fed mice. CONCLUSIONS: Dietary n-3 PUFAs reduced clinical colitis and colonic immunopathology in this model of colonic inflammation by decreasing proinflammatory cytokine synthesis, reducing myeloid cell recruitment and activation, and enhancing epithelial barrier function and mucosal wound healing mechanisms.

Animals↗
PubMed2004

Elevated serum procollagen type III peptide in splanchnic and peripheral circulation of patients with inflammatory bowel disease submitted to surgery.

BACKGROUND: In the hypothesis that the increased collagen metabolism in the intestinal wall of patients affected by inflammatory bowel disease (IBD) is reflected in the systemic circulation, we aimed the study to evaluate serum level of procollagen III peptide (PIIIP) in peripheral and splanchnic circulation by a commercial radioimmunoassay of patients with different histories of disease. METHODS: Twenty-seven patients, 17 with Crohn and 10 with ulcerative colitis submitted to surgery were studied. Blood samples were obtained before surgery from a peripheral vein and during surgery from the mesenteric vein draining the affected intestinal segment. Fifteen healthy age and sex matched subjects were studied to determine normal range for peripheral PIIIP. RESULTS: In IBD patients peripheral PIIIP level was significantly higher if compared with controls (5.0 +/- 1.9 vs 2.7 +/- 0.7 microg/l; p = 0.0001); splanchnic PIIIP level was 5.5 +/- 2.6 microg/l showing a positive gradient between splanchnic and peripheral concentrations of PIIIP. No significant differences between groups nor correlations with patients' age and duration of disease were found. CONCLUSIONS: We provide evidence that the increased local collagen metabolism in active IBD is reflected also in the systemic circulation irrespective of the history of the disease, suggesting that PIIIP should be considered more appropiately as a marker of the activity phases of IBD.

Adult↗
PubMed2005

Selective inhibition of phosphodiesterase-4 ameliorates chronic colitis and prevents intestinal fibrosis.

The phosphodiesterase-4 (PDE4) inhibitors may be an important target in the treatment of several inflammatory conditions. The anti-inflammatory effect of PDE4 inhibitors bears similarities with that of steroids, without interfering with the hypophysary-adrenal-axis. We compared the effect of rolipram, a selective PDE4 inhibitor, with steroids on the clinical course of experimental colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS). Three groups of rats (n = 20) received TNBS. One group received methylprednisolone from day 7, another group received rolipram from the same day, and control group received no further treatment. On days 14 and 21 after TNBS instillation, sets of 10 rats underwent colonic dialysis to measure eicosanoid release. Colonic lesions were blindly scored, and colons were homogenized for quantification of myeloperoxidase (MPO) activity and collagen content. Concentration of tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta1 (TGF-beta1) in colonic tissue was also measured. Both treatments reduced significantly the eicosanoid release and MPO activity. On day 14, both rolipram and methylprednisolone significantly reduced TNF-alpha content, but TGF-beta1 was only inhibited by rolipram. On day 21, lesion scores and collagen content were significantly reduced only in rolipram-treated group. In conclusion, PDE4 inhibition by rolipram markedly ameliorates the course of chronic colitis and it is superior to methylprednisolone in preventing late collagen deposition.

3',5'-Cyclic-AMP Phosphodiesterases↗