Role In Mucosal Healing Research Articles

HucMSC-Exo Promote Mucosal Healing in Experimental Colitis by Accelerating Intestinal Stem Cells and Epithelium Regeneration via Wnt Signaling Pathway.

Mucosal healing has emerged as a crucial therapeutic goal for inflammatory bowel diseases (IBD). Exosomes (Exo) as a potential acellular candidate for stem cell therapy might be competent to promote mucosal healing, while its mechanism remains unexplored. Exosomes derived from human umbilical cord mesenchymal stem cells (hucMSCs) were subjected to experimental colitis mice intraperitoneally to estimate the role in mucosal healing and the regeneration of intestinal stem cells (ISCs) and epithelium. The intestinal organoid model of IBD was constructed utilizing tumor necrosis factor (TNF)-α for subsequent function analysis in vitro. Transcriptome sequencing was performed to decipher the underlying mechanism and Wnt-C59, an oral Wnt inhibitor, was used to confirm that further. Finally, the potential specific components of hucMSC‑exo were investigated based on several existing miRNA expression datasets. HucMSC-exo showed striking potential for mucosal healing in colitis mice, characterized by decreased histopathological injuries and neutrophil infiltration as well as improved epithelial integrity. HucMSC-exo up-regulated the expression of leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), a specific marker for ISCs and accelerated the proliferation of intestinal epithelium. HucMSC-exo endowed intestinal organoids with more excellent capacity to grow and bud under TNF-α stimulation. More than that, the fact that hucMSC-exo activated the canonical Wnt signaling pathway to promote mucosal healing was uncovered by not only RNA-sequencing but also relevant experimental data. Finally, bioinformatics analysis of the existing miRNA expression datasets indicated that several miRNAs abundant in hucMSC-exo involved widely in regeneration or repair related biological processes and Wnt signaling pathway might be one of the most important signal transduction pathways. Our results suggested that hucMSC-exo could facilitate mucosal healing in experimental colitis by accelerating ISCs and intestinal epithelium regeneration via transferring key miRNAs, which was dependent on the activation of Wnt/β-catenin signaling pathway.

P067 The effect of a probiotic mix on mucosal healing and fibrotic responses in healthy colonic subepithelial myofibroblasts

Abstract Background Various probiotic strains play a positive role in Inflammatory Bowel Disease and might support mucosal healing. Colonic Subepithelial Myofibroblasts (SEMFs) have a pivotal role in mucosal healing and fibrosis, by migrating to the trauma region and secreting collagen. Our study aimed to investigate whether different strains of probiotics can affect the migration capacity and the fibrotic phenotype of SEMFs isolated from healthy individuals. Methods The probiotic mix of Lactobacillus acidophilus, Lactobacillus plantarum, Bifidobacterium lactis and Saccharomyces boulardii was reconstituted in SEMFs culture medium, they were identified by Gram staining and their viability was assessed by Trypan Blue staining. Primary SEMFs were isolated from colonic biopsies from healthy individuals, and stimulated with 102, 104 or 108 cfu/ml of the mix for 6h or 48h; in 6h total RNA was collected and mRNA expression of collagen type I, III, fibronectin, tissue factor (TF) and α-SMA was measured by quantitative PCR, and in 48h their effect on migration rate through the Wound Healing Assay and collagen secretion via Sircol was assessed. Results Trypan Blue confirmed that the majority of the probiotic mix was alive, and all three bacterial strains and the yeast were stained Gram positive. Stimulation of SEMFs with the probiotic mix resulted in different effects depending on its concentration; 102 cfu/ml downregulated protein collagen secretion (3.4μg/ml, IQR: 2.7–5.0, p<0.01 vs control 6.3μg/ml, IQR: 5.2–6.7) and α-SMA mRNA production (0.7-fold, IQR: 0.7–0.8, p<0.01), 104 cfu/ml upregulated the Fibronectin mRNA expression (1.6-fold, IQR: 1.2–1.8, p<0.0001) and 108 cfu/ml downregulated collagen type I (0.2-fold, IQR: 0.1–0.8, p<0.01) and III mRNAs (0.3-fold, IQR: 0.1–0.8, p<0.01). In addition, all three concentrations resulted in the overall upregulation of TF mRNA expression. Regarding the effect of the probiotic mix on SEMFs migration capacity, 104 cfu/ml of the probiotic mix resulted in increased migration rate by 133.8% (IQR: 102.8–150.2, p<0.01) after 24h, while the use of 102 cfu/ml and 108 cfu/ml decreased it by 58.2% (IQR: 34.8–79.7, p<0.01) and by 46.8% (IQR: 34.3–72.1, p<0.01) respectively. Conclusion This study provides evidence that the probiotic strains L. plantarum, L. acidophillus, B. lactis and S. boulardii remain viable in SEMFs’ culture medium and have the ability to interact with and alter the behavior of SEMFs. Moreover, the effect of the probiotic mix on SEMFs fibrotic phenotype is dependent of the concentration of the probiotics used. Further preclinical research is needed in order to identify the effect of each strain, as well as the suitable dose and combinations in various pathological conditions.

Correlation of Intestinal Mucosal Healing and Tight Junction Protein Expression in Ulcerative Colitis Patients

BackgroundThe aim of this study was to investigate the relationship between intestinal mucosal healing and tight junction (TJ) protein expression in patients with ulcerative colitis (UC). Materials and MethodsA total of 40 patients with UC were included as an experimental group and UC disease activity was evaluated using the Mayo clinic score (MCS) and 8 patients with normal distal colon served as the control group. The expression of TJ proteins including occludin, ZO-1 and claudin-2 were determined by immunohistochemistry and their correlation with clinical characteristics were also analyzed. ResultsStatistically significant differences regarding the MCS and Mayo endoscopic subscore (MES) were observed in both groups (P < 0.01). The Geboes index was significantly increased in patients with active UC compared to patients with quiescent UC and normal controls (P < 0.01). Patients with active and quiescent UC had upregulated expression of claudin-2 and reduced expression of occludin and ZO-1 compared to those of normal controls. The expression of ZO-1 was significantly higher in patients with quiescent UC with mucosa healing (P < 0.05) compared with those without mucosal healing. The expression of ZO-1 and occludin was negatively correlated with MCS, MES, Geboes, C-reaction protein and erythrocyte sedimentation rate. The expression of claudin-2 was positively correlated with MCS, MES, Geboes, C-reaction protein and erythrocyte sedimentation rate. ConclusionsThese findings suggest that TJ proteins play a crucial role in mucosal healing, and may be a potential marker of response when evaluating therapeutic interventions.

Analysis of endogenous lipids during intestinal wound healing.

Intestinal wound healing is a new therapeutic goal for inflammatory bowel disease (IBD) as complete healing of the mucosa is the key element of clinical remission in IBD. Previous studies showed that termination of inflammation can be achieved by adding pro-resolving lipids like DHA and EPA exogenously. However, the roles of these lipids in mucosal healing have not been investigated. To recapitulate intestinal healing process, mice were received dextran sodium sulfate (DSS) for 7 days in the drinking water followed by regular tap water for 5 additional days. DSS-induced intestinal inflammation featuring body weight loss, histological tissue damage, increased cytokine production and infiltration of inflammatory cells was gradually reduced upon switching to water. To investigate whether endogenous lipids play a role in mucosal healing, the lipidomics analysis of mouse serum was performed. Reduced levels of arachidonic acid, the biosynthetic precursor of prostaglandin F (PGF)2α, 19H-PGF1α, the metabolite of prostacyclin, and 20H-PGF2α, the metabolite of PGF2α, suggest subsiding inflammation. In contrast, increased levels of an active metabolite of resolvin D1 along with decreased levels of its precursor DHA as well as decreased levels of the precursor of resolvin E, 18-hydroxy-eicosapentaenoic acid, suggest inauguration of mucosal healing by endogenous lipids. Furthermore, exogenously supplied fish oil enhanced the process even further. These results suggest the presence of mucosal healing regulated by endogenous pro-healing lipids and also indicate that the remission state of IBD could be prolonged by enhancing the levels of these lipids.

MP36-04 LOW TESTOSTERONE IS COMMON IN PATIENTS WITH ANTERIOR URETHRAL STRICTURE: RISK-FACTOR OR COINCIDENCE?

You have accessJournal of UrologyTrauma/Reconstruction/Diversion: Urethral Reconstruction (including Stricture, Diverticulum) I1 Apr 2017MP36-04 LOW TESTOSTERONE IS COMMON IN PATIENTS WITH ANTERIOR URETHRAL STRICTURE: RISK-FACTOR OR COINCIDENCE? Jeffrey Spencer, Michael Daughtery, Stephen Blakely, Dmitriy Nikolavsky, and Timothy Byler Jeffrey SpencerJeffrey Spencer More articles by this author , Michael DaughteryMichael Daughtery More articles by this author , Stephen BlakelyStephen Blakely More articles by this author , Dmitriy NikolavskyDmitriy Nikolavsky More articles by this author , and Timothy BylerTimothy Byler More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1115AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Testosterone is known to have key involvement in urethral development with devastating consequences in its absence. It has also been shown to have an important role in mucosal healing. We hypothesized that urethral stricture formation may form in the background of low testosterone. We aimed to evaluate a hypothesis by McCullough and colleagues regarding an increased prevalence of low testosterone found in men with anterior urethral strictures. METHODS Using a prospectively maintained male urethral stricture database from February 2014 to September 2016, we identified all men treated for anterior urethral stricture with a serum total testosterone level and stratified them by age. Prior to reconstruction, men with anterior urethral strictures had been advised to have testosterone levels drawn. Patients with radiation-induced stricture or pelvic fracture urethral distraction injuries were excluded. Prevalence of low-testosterone, defined as serum testosterone less than 300ng/dL, was calculated. Age-matched data from a national database (NHANES), were used as a reference. RESULTS We identified 68/103 (66%) men with anterior urethral strictures who had pre-operative testosterone levels measured. Of these, an additional 5 were excluded for a study group of 63 patients. Figure 1 describes the prevalence of low testosterone in our cohort and the NHANES database stratified by age group. Overall, low testosterone was found in 47.6% of men in the anterior urethral strictures group and 27.5% of patients in the national database. CONCLUSIONS Low testosterone is more common in this group of patients with urethral strictures than can be expected in the general population based on a national database. Further investigation is warranted into the relationship between serum testosterone and idiopathic anterior stricture formation. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e467 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Jeffrey Spencer More articles by this author Michael Daughtery More articles by this author Stephen Blakely More articles by this author Dmitriy Nikolavsky More articles by this author Timothy Byler More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Mo1650 - Dipotassium Glycyrrhizate Modulates Genes with a Key Role in Mucosal Healing in Mice with a DSS-Induced Colitis and Improves in vitro Epithelial Barrier Functions

Mo1650 - Dipotassium Glycyrrhizate Modulates Genes with a Key Role in Mucosal Healing in Mice with a DSS-Induced Colitis and Improves in vitro Epithelial Barrier Functions

Bradykinin stimulates protein kinase D–mediated colonic myofibroblast migration via cyclooxygenase-2 and heat shock protein 27

BackgroundInflammatory bowel disease is characterized by episodic intestinal injury and repair. Myofibroblasts are gastrointestinal tract stromal cells that regulate the reparative process and are known targets of inflammatory mediators including bradykinin (BK). However, the mechanisms through which inflammation regulates myofibroblast-induced wound healing remain incompletely understood. Here, we demonstrate, for the first time, that BK stimulates myofibroblast migration through protein kinase D (PKD)–mediated activation of the cyclooxygenase-2 (COX-2) and heat shock protein 27 (Hsp27) pathways. Materials and methodsCCD-18Co is a human colonic myofibroblast cell line used from passages 8 to 14. An in vitro scratch assay assessed the effect of BK (100 nM) on myofibroblast migration over 24 h in the presence or absence of several inhibitors (CID755673 [10 μM] and NS398 [10 μM]). Hsp27 small interfering RNA evaluated the effect of Hsp27 on colonic myofibroblast migration. Antibodies to pPKD, pHsp27, and COX-2 evaluated expression levels by Western blot. ResultsBK stimulated myofibroblast migration over 24 h. BK also led to rapid and sustained phosphorylation of PKD at Ser-916, rapid phosphorylation of Hsp27 at Ser-82, and increased COX-2 expression over 4 h. BK-mediated COX-2 expression and Hsp27 phosphorylation were both inhibited by the PKD inhibitor CID755673. Similarly, BK-induced myofibroblast migration was significantly inhibited by CID755673 (P < 0.05), by the direct COX-2 inhibitor NS398 (P < 0.05), and by Hsp27 small interfering RNA (P < 0.05). ConclusionsBK stimulates myofibroblast migration through PKD-mediated activation of COX-2 and Hsp27. PKD, COX-2, and Hsp27 all appear to regulate myofibroblast cell migration, a stromal population that may play an important role in mucosal healing in the setting of inflammation.

Clinical outcome after discontinuation of infliximab in patients with ulcerative colitis in deep remission

Abstract Introduction Infliximab (IFX) is effective in treating ulcerative colitis (UC) and in achieving mucosal healing (MH). Little is known about the role of mucosal healing (MH) in the subsequent evolution of the disease and the consequences of discontinuing treatment. Aims To evaluate the characteristics and evolution of patients with UC treated with IFX who discontinued treatment after disease remission. Methods Observational, prospective study of patients with moderate to severe UC, corticosteroid-resistant/corticosteroid-dependent, naive to anti-TNF. IFX administration regimen: 5 mg/kg at 0-2-6 weeks and every 8 weeks thereafter until week 54. In patients achieving MH, IFX was discontinued and the patients were followed-up for at least 20 months. Clinical remission (CR): Mayo score Results Of the 21 patients enrolled, 19 completed the study (colectomy, n = 1; non-responder, n = 1). Mean age: 47.8 years. UC: severe (n = 13) and moderate (n = 6); most patients (n = 11) were steroid-resistant; 57.8% received combined treatment with immunosuppressants, and 31.5% intensified treatment. Week 54: 16 patients (84.2%) showed clinical response, 13 (68.4%) showed CR, and 12 (63.2%) deep remission. Of these, 6 (25%) presented a new episode of UC, and in 3 (25%) IFX was restarted within 12 weeks of discontinuation, with all patients responding. Of the total sample, 91.7% remained IFX-free at week 8, and 75% at week 12, with no remission during follow-up. None of the patients required hospitalisation or surgery. Conclusions Half of patients with deep remission of UC with IFX therapy presented a new episode after treatment discontinuation, and in 25% IFX therapy was restarted.

Evolución clínica tras la suspensión de infliximab en pacientes con colitis ulcerosa en remisión profunda

IntroductionInfliximab (IFX) is effective in treating ulcerative colitis (UC) and in achieving mucosal healing (MH). Little is known about the role of mucosal healing (MH) in the subsequent evolution of the disease and the consequences of discontinuing treatment. AimsTo evaluate the characteristics and evolution of patients with UC treated with IFX who discontinued treatment after disease remission. MethodsObservational, prospective study of patients with moderate to severe UC, corticosteroid-resistant/corticosteroid-dependent, naïve to anti-TNF. IFX administration regimen: 5 mg/kg at 0-2-6 weeks and every 8 weeks thereafter until week 54. In patients achieving MH, IFX was discontinued and the patients were followed-up for at least 20 months. Clinical remission (CR): mayo score <2; Clinical response: decrease in mayo score of 3 points; MH: mayo score 0-1; Deep remission: patient with CR and MH. ResultsOf the 21 patients enrolled, 19 completed the study (colectomy, n = 1; non-responder, n = 1). Mean age: 47.8 years. UC: severe (n = 13) and moderate (n = 6); most patients (n = 11) were steroid-resistant; 57.8% received combined treatment with immunosuppressants, and 31.5% intensified treatment. Week 54: 16 patients (84.2%) showed clinical response, 13 (68.4%) showed CR, and 12 (63.2%) deep remission. Of these, 6 (25%) presented a new episode of UC, and in 3 (25%) IFX was restarted within 12 weeks of discontinuation, with all patients responding. Of the total sample, 91.7% remained IFX-free at week 8, and 75% at week 12, with no remission during follow-up. None of the patients required hospitalization or surgery. ConclusionsHalf of patients with deep remission of UC with IFX therapy presented a new episode after treatment discontinuation, and in 25% IFX therapy was restarted.

P008. Targeting of TSLP by miR-31 may play an important role in mucosal healing, in ulcerative colitis.

P008. Targeting of TSLP by miR-31 may play an important role in mucosal healing, in ulcerative colitis.

Differential expression of mucosal trefoil factors and mucins in pediatric inflammatory bowel diseases.

In the intestinal mucosa trefoil factors (TFF) and mucins (Muc) - primarily produced by goblet cells - are thought to play a major role in providing barrier function during infection and inflammation. To investigate their role in pediatric Crohn's disease (CD) and ulcerative colitis (UC) we obtained mucosal biopsies of children with CD, UC and healthy controls and analyzed genetic expression. Levels of TFF2 mRNA were lower in inflamed mucosal samples (terminal ileum (TI) and duodenum) of children with CD, but higher in non-inflamed mucosal samples when compared to healthy controls (p < 0.05). Similarly, TFF2 levels in the TI were significantly lower in inflamed UC tissue. Adjustment for goblet cell density revealed slightly less marked, yet significantly different gene expression in IBD and controls. Furthermore, TI expression of TFF2 and Muc2 was inversely correlated with interleukin-8 expression in CD (p = 0.027). In Summary, our data demonstrate significant changes in Muc and TFF mRNA expression in pediatric patients with IBD suggesting a role in mucosal healing. Further studies are needed to elucidate a potential use as biomarkers for disease progression.

Chronic rhinosinusitis without nasal polyps is associated with increased expression of trefoil factor family peptides

Trefoil factor family (TFF) peptides are mucin-associated secretory products that are produced in the airways and gastrointestinal tract. These peptides appear to play an important role in mucosal healing and epithelial protection and are overexpressed in chronically inflamed gastrointestinal tissues. We hypothesize that TFF peptides may also be differentially expressed in the sinonasal tissue of patients with and without chronic rhinosinusitis (CRS). Ethmoid sinus tissue was obtained from patients with CRS without nasal polyps (CRSsNP) (n = 12), CRS with nasal polyps (CRSwNP) (n = 12), and nondiseased controls (n = 7). Messenger RNA (mRNA) and protein were extracted from samples and expression of TFF1, TFF2, and TFF3 were assessed using quantitative real-time polymerase chain reaction qRT-PCR and Western blots, respectively. Tissue localization of TFF expression was confirmed using immunohistochemistry. TFF1 and TFF3 were both highly expressed in sinonasal tissue, while TFF2 was expressed at near-undetectable levels. CRSsNP tissue had a statistically significant increase in the expression of both TFF1 and TFF3. No difference in TFF expression was found between control and CRSwNP patients. TFF1 and TFF3 are overexpressed in CRSsNP. The role of TFF peptides in mucosal protection and repair suggests a possible important physiologic role in maintaining the sinonasal epithelial barrier and modulating innate immunity in the sinonasal tract.

The Role of Mucosal Healing in the Treatment of Patients With Inflammatory Bowel Disease

Mucosal healing is a promising therapeutic endpoint in the treatment of inflammatory bowel disease. Currently, the treatment of IBD focuses predominantly on clinical remission, without requiring a demonstration of mucosal healing. However, recent studies suggest that achieving mucosal healing engenders better outcomes. In this review, we will examine the concept of mucosal healing, including its definitions and assessment techniques, and will evaluate the data regarding the potential benefits of achieving mucosal healing in the treatment of IBD. Furthermore, we will discuss how often mucosal healing can be expected with each of the therapies for IBD. While achieving mucosal healing is an ideal outcome, it may not be practical or feasible in any given patient. Although we suggest that mucosal healing be discussed with all patients, the practicing physician should realize that this goal may not be possible and should manage the patient accordingly.

Intestinal growth factors: Potential use in the treatment of inflammatory bowel disease and their role in mucosal healing

A key feature of inflammatory bowel disease (IBD) is impaired epithelial repair. Human growth factors comprise an array of signaling molecules that lead to ligand-specific signal transduction. Their downstream effects are associated with several cellular functions including epithelial healing in response to injury. Several studies have described specific growth factor deficiencies in patients with IBD, implicating their role in disease pathophysiology. The aim of this review was to describe currently known enterocyte-targeted growth factors, their mechanisms of action, and their potential therapeutic utility. The National Library of Medicine (http://www.pubmed.gov) and meeting abstracts were searched using the following terms: growth factor, intestine, colon, inflammatory bowel disease, Crohn's disease, ulcerative colitis, colitis, animal model, transforming growth factor, bone morphogenetic protein, activins, growth hormone, fibroblast growth factor, epidermal growth factor (EGF), keratinocyte growth factor (KGF), glucagon-like peptide II, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), vascular endothelial growth factor (VEGF) inhibitors, and trefoil factors. Several growth factors are therapeutic candidates in IBD. Growth hormone, KGF, EGF, teduglutide, GM-CSF/G-CSF have entered early clinical trials, whereas others are currently in preclinical evaluation. There are several growth factors responsible for epithelial repair. Preliminary studies using recombinant growth factors seem promising in IBD preclinical and clinical trials.

Complications intestinales liées aux AINS

Chronic use of non-salicylate NSAIDs causes in most individuals an asymptomatic enteropathy involving the small bowel, particularly its distal part. This enteropathy is characterised by an increase in intestinal permeability and a mild mucosal inflammation. Hypoalbuminemia and iron deficiency may occur. In addition, non-salicylate NSAIDs may cause focal lesions of the small intestine. Ulcerations and ulcers, that can be accidentally discovered during an ileoscopy, may cause acute or chronic bleeding. Deep ulcers may provoke sudden peritonitis. Small bowel diaphragms are rare fibrotic lesions, specifically associated with the use of non-salicylate NSAIDs or salicylates (duodenal diaphragms only). NSAID use is not associated with a constant toxicity on colonic mucosa. NSAID-induced colonic ulcers and diaphragms are rare. In patients with colonic diverticulosis, NSAID intake is a risk factor for severe attacks of diverticulitis. Acute or chronic use of non-salicylate NSAIDs increases the risk for ischemic colitis and flare-ups of inflammatory bowel disease. De novo colitis caused by non-salicylate NSAIDs are rare. The definite diagnosis of this entity relies on the absence of recurrence of colitis in the 2-3 following years. Such a recurrence would lead to the post-hoc diagnosis of first attack of inflammatory bowel disease triggered by NSAID use. Experimental data suggest that selective COX-2 inhibitors do not alter constantly mucosa of the small intestine. Pilot epidemiological works suggest that severe intestinal lesions are less frequent in association with COX-2 inhibitor use than in association with conventional NSAIDs. However, COX-2 appears as playing a beneficial role in mucosal healing, and it seems that COX-2 inhibitors, like conventional NSAIDs, may trigger flare-ups of inflammatory bowel disease.

Growth factors and the gastrointestinal tract.

This paper reviews areas of interest in gut mucosal growth factor physiology. Several epidermal growth factor (EGF)-like peptides (EGF, transforming growth factor [TGF]-alpha, heparin-binding EGF-like peptide, amphiregulin, and betacellulin) have been identified in the gut, EGF is produced by the salivary glands and is present in milk. It may act on the mucosa from the lumen as a surveillance peptide promoting mucosal repair. A stem-cell-derived "ulcer-associated cell lineage" develops adjacent to ulcers and produces EGF, which may play a role in ulcer healing. TGF-alpha is expressed by villus enterocytes and may have an important role in mucosal healing. The Trefoil peptides (pS2, spasmolytic polypeptide, intestinal trefoil factor) are protease resistant molecules secreted by mucin cells throughout the gut, with a role in mucosal healing. The TGF-beta family inhibit cell proliferation, and promote cell differentiation. TGF-beta has a gradient of expression along the crypt villus axis, with maximum production at the villus tip. It is suspected that it may prevent cell proliferation and support differentiation of villus enterocytes. Hepatocyte growth factor is a multifunctional growth factor expressed in many tissues, including the gastrointestinal tract. It has a role in organogenesis. Intestinal adaptation is highly dependent on enteral nutrition, and it is likely that growth factors are involved in adaptation. Little is known, however, about interactions between nutrients and growth factors. Milk contains a range of potentially important growth factors. Their biological significance is uncertain, and this is an area of active research.

Immunology of inflmmatory bowel disease

Examination of T-cell function in both animal models and patients with inflammatory bowel disease (IBD) has consistently demonstrated the importance of interleukin-12-driven T-helper 1 CD4 + T-cell responses, with resultant secretion of interferon-γ, interleukin- 1 β, and tumor necrosis factor. Demonstration of this central regulatory pathway in the immunopathogenesis of IBD will allow novel, selective therapeutic approaches to be developed and appropriately evaluated in both animal models and patients with IBD. Studies of autoantibodies in IBD continue to demonstrate the possible importance of antineutrophil cytoplasmic antibodies in delineating subsets of patients with chronic IBD. Delineation of histones as well as nonhistone nuclear antigens as possible targets for perinuclear antineutrophil cytoplasmic antibodies provides an exciting new area for future research. The examination of specific adhesion molecules on endothelial cells has revealed that they may play important roles in both extraintestinal manifestations of IBD as well as the initiation and perpetuation of mucosal inflammatory processes. Nitric oxide and reactive oxygen metabolites are important mediators as well as markers of mucosal inflammation and injury in IBD. Inducible nitric oxide synthease may play an important role in mucosal healing and recovery from intestinal injury.

Keratinocyte growth factor ameliorates mucosal injury in an experimental model of colitis in rats

BACKGROUND & AIMS: Keratinocyte growth factor (KGF) is known to enhance tissue repair in the skin; however, its role in the gastrointestinal tract is largely unknown. The aim of this study was to evaluate the effects of exogenous KGF in an experimental model of colitis in rats. METHODS: KGF was administered before or after induction of colitis with 2,4,6-trinitrobenzenesulfonic acid/ethanol. In the first two study groups, KGF (5 mg/kg) was administered intraperitoneally 24 hours and 1 hour before induction of colitis; animals were killed 8 hours (n=10) and 1 week (n=10) after injury. In subsequent study groups, KGF or vehicle treatment was begun 24 hours after the induction of colitis at doses of 5 (n=20), 1 (n=10), and 0.1 (n=10) mg/kg intraperitoneally and continued once daily for 1 week. Colonic tissue samples were evaluated macroscopically and microscopically for mucosal injury and assayed for myeloperoxidase activity. RESULTS: Administration of KGF after but not before induction of colitis significantly ameliorated tissue damage. Macroscopic necrosis and microscopic ulcerations were reduced by 40%- 50% at KGF doses of 1 and 5 mg/kg. CONCLUSIONS: Exogenous KGF has a key role in mucosal healing in an experimental model of colitis in rats. (Gastroenterology 1996 Apr;110(4):1077-83)

Trefoil peptides: a newly recognized family of epithelial mucin-associated molecules

Members of the trefoil family of peptides are generally small stable secreted molecules, structurally related by the presence of one, or up to six, compact 6-cysteine motifs. Several trefoil peptides are expressed in mammalian gut and Xenopus gut and skin, often in association with mucins. Chronic ulcerative conditions of the gut, such as Crohn's disease, result in the growth of glandular structures of the ulcer-associated cell lineage (UACL) that secrete epidermal growth factor/urogastrone, transforming growth factor-alpha, and at least three trefoil peptides [pS2, human spasmolytic polypeptide (hSP), and intestinal trefoil factor (hITF/hP1.B)]. Neuroendocrine and goblet cells near the UACL are "recruited" into expressing pS2 and hSP, but the purpose of this concerted expression is unclear. A role in mucosal healing has been proposed. Biological functions of trefoil peptides have been difficult to establish. Pancreatic spasmolytic polypeptide of porcine origin inhibits gastric acid secretion and smooth muscle contraction and is a growth factor for some cultured cells, but pS2, once thought to be breast cancer specific, is not a mitogen. Recombinant trefoil peptides have allowed localization of binding sites and will allow structure-activity relationships to be studied, once the functions are clear.