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Cell adhesion and migration. IV. Lymphocyte trafficking in the intestine and liver.

Naive lymphocytes patrol continuously between the blood and different lymphatic tissues to sample the whole body for foreign antigens. During inflammation, leukocyte recruitment into tissue is enhanced to promote the recruitment of a range of effector cells into the affected area. The complex recirculatory pathways that underlie this process are governed by adhesion receptors on blood-borne leukocytes and by their specific ligands expressed on the luminal aspect of endothelial cells lining the vessels. Gut-associated lymphatic tissues are positioned strategically at the major port of entry for foreign antigens. They form a functionally unified entity that utilizes both the afferent and efferent arms of the immune response to respond to the large array of antigens entering via the gut under normal conditions as well as during inflammation. Once antigens have been absorbed from the gut, they may enter the portal vein and the liver where the immune response can be further regulated by the resident immune cells of the liver. Thus the gut and liver form an important barrier to enteral antigens, and leukocyte recruitment to these sites will need to be carefully regulated to ensure effective immune surveillance. In this article, we describe the current concepts of lymphocyte adhesion in these two organs as revealed by animal models. Subsequently, we discuss how well these principles apply to the lymphocyte-endothelial cell interactions in humans and what additional insights can be obtained from human studies.

Cell Adhesion↗

Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution.

BACKGROUND & AIMS: Ulcerative colitis (UC) is characterized by a Th2 immune response with inflammation and epithelial barrier dysfunction. So far, Th2 cytokines have not been shown to directly influence epithelial barrier function. METHODS: Lamina propria mononuclear cells (LPMCs) were stimulated and interleukin (IL)-13 was measured by enzyme-linked immunosorbent assay. Functional IL-13 and IL-4 effects were studied on HT-29/B6 colonic epithelial cells in Ussing chambers and by conductance scanning. Apoptosis was detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling assays. IL-13/IL-4 receptors were analyzed by reverse-transcription polymerase chain reaction and immunofluorescence. Western blotting combined with immunofluorescence was used to detect tight junction proteins. Furthermore, restitution velocity was measured. Finally, mucosal biopsy specimens from patients with UC were compared with cultured cells for these features. RESULTS: LPMCs from patients with UC produced large amounts of IL-13 (985 +/- 73 pg/mL), much more than from controls or patients with Crohn's disease. IL-13Ralpha1 and IL-4Ralpha receptors were present in HT-29/B6 cells and colonic epithelial cells of control patients and patients with UC. IL-13 had a dose-dependent effect on transepithelial resistance of HT-29/B6 monolayers (reduction to 60% +/- 4%), whereas IL-4 had no effect. This was due to an increased number of apoptotic cells (5.6-fold +/- 0.9-fold) and an increased expression of the pore-forming tight junction protein claudin-2 to 295% +/- 37%, both of which contributed equally. Finally, epithelial restitution velocity decreased from 15.1 +/- 0.6 to 10.6 +/- 0.5 microm/h after treatment with IL-13. Parallel changes were observed in human samples, with an increase in claudin-2 expression to 956% +/- 252%. CONCLUSIONS: IL-13 was identified as an important effector cytokine in UC that impairs epithelial barrier function by affecting epithelial apoptosis, tight junctions, and restitution velocity.

Adult↗

Probiotic therapy in the prevention of pouchitis onset: decreased interleukin-1beta, interleukin-8, and interferon-gamma gene expression.

BACKGROUND: Probiotic therapy has been shown to prevent the onset of pouchitis and to improve the quality of life in ulcerative colitis patients who required ileal pouch anal anastomosis. Pouchitis has been associated with elevated levels of proinflammatory cytokines and chemokines. METHODS: In this retrospective analysis of archived endoscopic samples from responding patients enrolled in the above-mentioned trial, we were interested in studying mucosal gene expression of the pleiotropic proinflammatory cytokines (interleukin-1beta, interleukin-6), TH1 cytokines (interferon-gamma, tumor necrosis factor-alpha, interleukin-12), regulatory cytokines (interleukin-10, transforming growth factor-beta), and the chemokine interleukin-8. In addition to assessment of cytokine gene expression, the presence of polymorphonuclear cells in the mucosal tissue was evaluated. RESULTS: Data show that patients who were treated with probiotics had significant lower mucosal mRNA expression levels of interleukin-1beta, interleukin-8, and interferon-gamma compared with placebo-treated patients. In addition, a lower number of polymorphonuclear cells was present in the tissue of patients within the probiotic group compared with the number of polymorphonuclear cells in the tissue of patients receiving placebo and patients having an episode of pouchitis. CONCLUSIONS: These data suggest that probiotic treatment regulates the mucosal immune response by reducing mucosal levels of neutrophil-chemoattractant IL-8 and tissue influx of polymorphonuclear cells, and may further act by inhibition of T-cell activation, by reinforcement of barrier function and by a tight control of the potent pro-inflammatory cytokine IL-1beta.

Adolescent↗

Altered gut barrier function to Candida during parenteral nutrition.

We hypothesize that catheter-related sepsis with Candida during total parenteral nutrition (TPN) is caused by Candida translocation from the gut. Fifty male Sabra rats weighing 330 +/- 40 g were randomized into four groups and put into metabolic cages: group 1 (n = 16), nonoperated free-feeding controls; group 2 (n = 10), infused with normal saline and free feeding; group 3 (n = 14), infused with TPN solution for a total of 36 kcal and 1.5 g g protein.100 g-1 body wt.day-1;group 4 (n = 10), same TPN regimen as group 3 but also receiving oral and intravenous antibiotics. On day 7, all animals received 1.5 x 10(10) viable Candida albicans CBS 562 cells by gavage, and 24 h later, the number of Candida colony-forming units in blood, mesenteric lymph nodes, and kidneys was determined. No growth of Candida was detected in group 1 or group 2. Positive Candida cultures were found in the blood, mesenteric lymph nodes, and kidneys of groups 3 and 4, although levels reached statistical significance only for mesenteric lymph nodes in group 3. Because Candida growth occurred exclusively in groups receiving TPN and bowel rest, we conclude that altered gut-barrier function to Candida occurs during TPN and speculate that Candida sepsis during TPN might be the result of Candida translocation from the gut due to the combination of high-density Candida colonization and favorable local conditions in the gut induced by TPN and bowel rest.

Animals↗

Multidrug resistance protein 4 protects bone marrow, thymus, spleen, and intestine from nucleotide analogue-induced damage.

Nucleoside-based analogues are mainstays in the treatment of cancer, viral infections, and inflammatory diseases. Recent studies showing that the ATP-binding cassette transporter, multidrug resistance protein 4, is able to efflux nucleoside and nucleotide analogues from transfected cells suggests that the pump may affect the efficacy of this class of agents. However, the in vivo pharmacologic functions of the pump are largely unexplored. Here, using Mrp4(-/-) mice as a model system, and the nucleotide analogue, 9'-(2'-phosphonylmethoxyethyl)-adenine (PMEA) as a probe, we investigate the ability of Mrp4 to function in vivo as an endogenous resistance factor. In the absence of alterations in plasma PMEA levels, Mrp4-null mice treated with PMEA exhibit increased lethality associated with marked toxicity in several tissues. Affected tissues include the bone marrow, spleen, thymus, and gastrointestinal tract. In addition, PMEA penetration into the brain is increased in Mrp4(-/-) mice. These findings indicate that Mrp4 is an endogenous resistance factor, and that the pump may be a component of the blood-brain barrier for nucleoside-based analogues. This is the first demonstration that an ATP-binding cassette transporter can affect in vivo tissue sensitivity towards this class of agents.

Adenine↗

Identification of BCRP as transporter of benzo[a]pyrene conjugates metabolically formed in Caco-2 cells and its induction by Ah-receptor agonists.

Breast cancer resistance protein (BCRP/ABCG2) is known to actively transport various anticancer drugs and to restrict the uptake of the food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine from the gut lumen. The present study reveals that BCRP is involved in the transport of phase-2 metabolites of the carcinogen benzo[a]pyrene (BP) in the human intestinal cell line Caco-2. Treatment with the selective BCRP inhibitor Ko 143 (5 microM) inhibited the apical transport of BP-3-sulfate (BP3S) to 83% of control levels in TC7 cells and to 64% of control levels in Caco-2 cells. The apical transport of BP-3-glucuronide was inhibited by Ko 143 to 76% of control levels in TC7 cells. Furthermore, the expression of BCRP is most likely aryl hydrocarbon receptor (AhR) dependent, as treatment of Caco-2 cells with known AhR agonists including 2,3,7,8-tetrachlorodibenzo-p-dioxin, BP, indolo[3,2-b]carbazole and benzo[k]fluoranthene increased both mRNA and protein levels of BCRP. Induced BCRP protein was found to be functionally active, since pre-treatment of TC7 cells with oltipraz, indolo[3,2-b]carbazole or benzo[k]fluoranthene increased the amount of apically transported BP3S to as much as 180% of that in the controls. The induction of BCRP (mRNA and protein expression) by indolo[3,2-b]carbazole was inhibited in Caco-2 cells by co-incubation with the AhR antagonist PD98059 (2'-amino-3'-methoxyflavone). In summary, this study provides strong evidence that BCRP is an important part of the intestinal barrier protecting the body from food-associated contaminants such as the carcinogen BP.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

(51)CrEDTA colonic permeability and therapy response in patients with ulcerative colitis.

Orally administered (51)Cr-labelled ethylenediaminetetraacetic acid ((51)CrEDTA) has been used to evaluate intestinal permeability in inflammatory bowel disease, especially Crohn's disease. However, information about colonic permeability in ulcerative colitis (UC) is relatively scarce. The aim of this study was to investigate the urinary excretion of orally administered (51)CrEDTA, its relation to disease activity and its response to medical therapy in patients with UC. Forty-three patients with UC and 19 controls were examined. Disease activity was evaluated by endoscopy. In 19 patients with active UC, the (51)CrEDTA permeability test was repeated after medical therapy. (51)CrEDTA (95 microCi; 26 MBq) was given orally after an overnight fast and urine was collected over a 24 h period. The first urine samples were taken 5 h and the second 24 h after the oral administration of (51)CrEDTA. Urine samples were counted in a gamma counter. In controls, the median 5 h and 24 h excretions were 0.10% and 0.93%, respectively. Patients with UC showed significantly increased urine (51)CrEDTA excretion at both time intervals (5 h: 2.41%, P<0.0002; 24 h: 6.72%, P<0.0001). There was also a significant correlation between intestinal permeability and disease activity (5 h: r=0.45, P=0.0025; 24 h: r=0.51 P=0.0006). After medical therapy, (51)CrEDTA urinary excretion was significantly decreased (pre-treatment UC: 7.87%; post-treatment UC: 2.50%; P<0.0002). Briefly, the (51)CrEDTA test reflected colonic permeability in UC and might be useful as an indicator of disease severity. Moreover, this study suggested that, in patients with UC, medical therapy not only leads to the recovery of acute inflammation but also restores mucosal barrier integrity and function.

Adult↗

Resistance to acid of canine kidney (MDCK) and human colonic (T84) and ileo-caecal (HCT-8) adenocarcinoma epithelial cell monolayers in vitro.

Monolayers of canine kidney (MDCK) and human lower intestinal (T84 and HCT-8) cell lines generated significant transepithelial electrical resistance (700-5000 omega cm2). Electrical integrity was maintained upon acidification of the apical and/or basolateral surfaces to pH 3.0, and this was associated with increased transepithelial electrical resistance, and generation of a potential difference at pH less than 4.5. These results indicate that resistance to acid is a general phenomenon of epithelial layers, and that monolayers of epithelial cells, including those of human origin, are a homogeneous and simple model for studying epithelial barrier function in vitro.

Adenocarcinoma↗

Epithelial hypoxia-inducible factor-1 is protective in murine experimental colitis.

Mucosal epithelial cells are uniquely equipped to maintain barrier function even under adverse conditions. Previous studies have implicated hypoxia in mucosal tissue damage resulting from both acute and chronic inflammation. Given the importance of the transcriptional regulator hypoxia-inducible factor-1 (HIF-1) for adaptive hypoxia responses, we hypothesized that HIF-1 may serve as a barrier-protective element during mucosal inflammation. Initial studies of hapten-based murine colitis revealed extensive mucosal hypoxia and concomitant HIF-1 activation during colitis. To study this in more detail, we generated 2 mouse lines with intestinal epithelium-targeted expression of either mutant Hif1a (inability to form HIF-1) or mutant von Hippel-Lindau gene (Vhlh; constitutively active HIF-1). Studies of colitis in these mice revealed that decreased HIF-1 expression correlated with more severe clinical symptoms (mortality, weight loss, colon length), while increased HIF levels were protective in these parameters. Furthermore, colons with constitutive activation of HIF displayed increased expression levels of HIF-1-regulated barrier-protective genes (multidrug resistance gene-1, intestinal trefoil factor, CD73), resulting in attenuated loss of barrier during colitis in vivo. Taken together, these studies provide insight into tissue microenvironmental changes during model inflammatory bowel disease and identify HIF-1 as a critical factor for barrier protection during mucosal insult.

Animals↗

Mucosal immunity and inflammation. V. Innate mechanisms of mucosal defense and repair: the best offense is a good defense.

Well-coordinated mechanisms have evolved that provide both innate protection against gastrointestinal mucosal injury and facilitation of rapid mucosal repair following mucosal damage. Generic protection from injury is provided by intrinsic structural features of the epithelium that form a highly competent barrier and a complex formed at the apical surface by trefoil peptides that comprise the interface between mucosa and lumen. When the epithelial barrier has been broken, regardless of the nature of the injury, epithelial surface continuity is rapidly reestablished through restitution as cells migrate and elongate. This process is promoted by trefoil peptides at the apical surface and a large array of cytokines and growth factors acting at the basolateral pole. Many of these regulatory peptides are products of the immune and other lamina propria cell populations, which are activated following disruption of the mucosal barrier. Thus efforts to repair the epithelium follow inherently from inflammatory effects after initial damage; the repair process in turn may allow abrogation of further inflammation. Ultimate repair of injury requires both proliferative replacement of damaged epithelial cells and remodeling of extracellular matrix and deeper cell populations to restore normal architecture and a fully functional mucosa.

Animals↗

Muscarinic acetylcholine receptor activation increases transcellular transport of macromolecules across mouse and human intestinal epithelium in vitro.

The intestinal epithelium acts as a barrier restricting uptake of luminal macromolecules such as dietary antigens and microbes. Here, we examined the role of cholinergic signalling in the regulation of permeability to macromolecules. Mouse jejunum was mounted in Ussing chambers and permeability was determined by measuring the flux of the antigen-sized protein, horseradish peroxidase (HRP), across the tissue. Baseline HRP permeability was significantly reduced by neural blockade with tetrodotoxin or cholinergic muscarinic antagonism with atropine, suggesting that ongoing release of endogenous acetylcholine from enteric nerves regulates barrier function. Exogenous addition of the muscarinic agonist bethanechol caused significant increases in both HRP flux and the area of HRP-containing endosomes in enterocytes. Bethanechol-enhanced HRP flux was abrogated by the M3 receptor antagonist, 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP), the phospholipase A(2) inhibitor quinacrine, and the cyclooxygenase inhibitor indomethacin. Complementary in vitro studies showed direct effects of bethanechol on T84 epithelial cells, where increased HRP uptake was associated with increased F-actin, and increased cytosolic phospholipase A(2) (cPLA(2)) phosphorylation. Taken together, these results provide evidence for cholinergic regulation of transepithelial transport of macromolecules, mainly mediated by activation of M3 receptors with subsequent involvement of phospholipase A(2) and cyclooxygenase products.

Actins↗

Qualitative and quantitative comparison of gut bacterial colonization in enterally and parenterally fed neonatal pigs.

Total parenteral nutrition (TPN) has been associated with mucosal atrophy, impaired gut barrier function, and translocation of luminal bacteria with resultant sepsis in preterm human infants. Currently, we examined the effects of enteral (ENT) or TPN treatments on translocation events in neonatal pigs and on colonization and composition of microbiota in the neonatal gut. Newborn, colostrum-deprived pigs (<24 hours old) were fitted with intravenous catheters and were fed either ENT (n = 13) or TPN (n = 13) for 7 days. After 7 days of treatment, pigs were euthanized and samples were collected for bacterial culture from the blood, intestinal tract and organs. ENT pigs had increased numbers of bacterial genera isolated, higher concentrations of bacteria (CFU/g), and increased colonization of all segments of the intestinal tract compared to the TPN pigs. Translocation of bacteria from the intestinal tract to tissues or blood was similar (8 of 13) for both groups. The ENT group had 1/13 positive for Clostridium difficile toxin A whereas the TPN group had 5/13. We concluded that ENT favored increased bacterial concentrations comprised of more speciation in the gastrointestinal tract compared to TPN, and that TPN-treated piglets were at higher risk of colonization by toxin-expressing strains of C. difficile.

Animals↗

Dietary modification of atopic disease: Use of probiotics in the prevention of atopic dermatitis.

The increased prevalence of atopic diseases, atopic dermatitis, allergic rhinitis, and asthma has been described as an epidemic. New approaches in the fight against allergic diseases are called for, the target being the persistence of the atopic T helper 2-skewed immune responder pattern beyond infancy. Atopic dermatitis, the earliest of these conditions, might act as a portal for the development of IgE-mediated atopic manifestations. Abundant evidence implies that specific strains selected from the healthy gut microbiota exhibit powerful antipathogenic and anti-inflammatory capabilities, and several targets for the probiotic approach have emerged in atopic dermatitis: degradation/structural modification of enteral antigens, normalization of the properties of aberrant indigenous microbiota and of gut barrier functions, regulation of the secretion of inflammatory mediators, and promotion of the development of the immune system. Better understanding of the effects of different probiotic strains and deeper insight into the mechanisms of the heterogeneous manifestations of atopic disease are needed for the validation of specific strains carrying anti-allergic potential.

Dermatitis, Atopic↗

Identification of hepoxilin A3 in inflammatory events: a required role in neutrophil migration across intestinal epithelia.

The mechanism by which neutrophils [polymorphonuclear leukocyte (PMNs)] are stimulated to move across epithelial barriers at mucosal surfaces has been basically unknown in biology. IL-8 has been shown to stimulate PMNs to leave the bloodstream at a local site of mucosal inflammation, but the chemical gradient used by PMNs to move between adjacent epithelial cells and traverse the tight junction at the apical neck of these mucosal barriers has eluded identification. Our studies not only identify this factor, previously termed pathogen-elicited epithelial chemoattractant, as the eicosanoid hepoxilin A(3) (hepA(3)) but also demonstrate that it is a key factor promoting the final step in PMN recruitment to sites of mucosal inflammation. We show that hepA(3) is synthesized by epithelial cells and secreted from their apical surface in response to conditions that stimulate inflammatory events. Our data further establish that hepA(3) acts to draw PMNs, via the establishment of a gradient across the epithelial tight junction complex. The functional significance of hepA(3) to target PMNs to the lumen of the gut at sites of inflammation was demonstrated by the finding that disruption of the 12-lipoxygenase pathway (required for hepA(3) production) could dramatically reduce PMN-mediated tissue trauma, demonstrating that hepA(3) is a key regulator of mucosal inflammation.

8,11,14-Eicosatrienoic Acid↗

Congenital agastria.

Congenital agastria has never before been reported. Congenital microgastria is rare but is well documented. We have cared for a Melanesian child in whom there was no radiological, anatomical, or physiological evidence of either a rudimentary stomach or a pylorus. The esophagus joined the first part of the duodenum directly. At this esophago-duodenal junction there was microscopic evidence of fundic-type gastric mucosa. The intestine was normally rotated and there was a functioning spleen. The child also had a severe micrognathia and a cleft soft palate and required a tracheostomy to relieve upper airway obstruction. The combination of micrognathia and agastria presented a difficult nutritional delivery problem. A jejunal pouch was constructed and placed between the esophagus and duodenum to provide some storage capacity. The child grew and developed well for almost 3 years. He suffered three episodes of severe acute enteritis, probably related to lack of the protective acid-pepsin barrier against ingested microorganisms. Unfortunately, the third episode of acute enteritis caused his death 3 months after returning home to his own country.

Child, Preschool↗

Abdominal cluster transplantation and management of perioperative hemodynamic changes.

BACKGROUND: Multivisceral transplantation (MTX, or cluster transplantation) is defined as the transplantation of three or more abdominal organs en bloc, namely the liver together with the pancreatoduodenal complex, the stomach as well as the small bowel with/without the right hemicolon. Up to May 1999, only 72 cases were reported to the Intestinal Transplant Registry. Organ cluster transplantation may carry with complex hemodynamic alterations. Based on our experience in two cases of abdominal cluster transplantation, we describe the technical details of multivisceral transplantation and the management of hemodynamic changes. METHODS: A Swan-Ganz catheter was placed to assist in monitoring the patients' hemodynamic status. After the transplantation, the 2 patients were closely observed in the intensive care unit in terms of vital signs;disseminated intravascular coagulation (DIC) including activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), fibrinogen (Fg) and D-dimer, and arterial blood gas; and quantity and characteristics of drainage. Additionally, intra-abdominal hemorrhage was supervised by bedside B-ultrasonography or enhanced computed tomography (CT) examination. Whole blood viscosity was monitored 2 weeks after transplantation. The blood flow of the hepatic artery and portal vein and arterial resistant index were assessed routinely by Doppler ultrasonography. RESULTS: Hemodynamic changes were observed during perioperation. Liver and renal function recovered within one week after transplantation. Enteral feedings and oral intake were gradually increased with a reciprocal decrease in parenteral nutrition. Despite systemic antibiotics were given according to the results of frequent cultures, patient 1 died from cytomegalovirus (CMV) infection 4 months after transplantation and patient 2 died of a systemic sepsis 2 months after the operation. CONCLUSIONS: Many factors contribute to the success of multivisceral transplantation. In order to maintain hemodynamics stable during perioperation, preoperative coagulatory function should be corrected, and stable circulation, serum electrocyte balance, and normal body temperature should be kept during the operation in addition to the treatment of intra-abdominal hemorrhage and making up for the loss of body fluid. However, complications, infection and rejection are barriers for the improvement of graft survival.

Adenomatous Polyps↗

Synthesis and evaluation of novel coumarin-based esterase-sensitive cyclic prodrugs of peptidomimetic RGD analogs with improved membrane permeability.

Earlier, we reported the development of a coumarin-based prodrug system that could be used for the preparation of cyclic prodrugs of opioid peptides. These cyclic prodrugs exhibited excellent membrane permeability characteristics. Therefore, it was of interest to determine the effects of this prodrug strategy on the membrane permeabilities of peptidomimetics which also have low membrane permeabilities. For this study, we have chosen two RGD (Arg-Gly-Asp) peptidomimetics, which have the potentials to be developed clinically as orally active antithrombotic agents. However, the clinical development of oral dosage forms of these RGD analogs has been hindered by their low intestinal mucosal permeability. Therefore, we have synthesized the corresponding coumarin-based cyclic prodrugs of these RGD peptidomimetics, which have the two most polar functional groups, a carboxyl and an amino group, masked as an ester and an amide, respectively. These cyclic prodrugs were shown to have higher membrane interaction potentials, as estimated by their partitioning between aqueous buffer and an immobilized artificial membrane, than the corresponding RGD analogs suggesting that they should exhibit good membrane permeation characteristics. Subsequently, in a separate study these cyclic prodrugs were shown to be 5 to 6-fold more able to permeate monolayers of Caco-2 cells, an in vitro cell culture model of the intestinal mucosa barrier, than the corresponding RGD peptidomimetics.

Caco-2 Cells↗

Apoptosis or necrosis--colonic epithelial cell survival.

The organization of the colonic epithelium is directed towards maintaining a continuous layer of cells with functional maturity at the surface, with a constant supply of epithelial cells of sufficient maturity from the crypts. Cells die by shedding at the surface or by undergoing apoptosis in situ, followed by shedding or phagocytosis. The nature of the predominant form of cell death in the normal colon remains uncertain but probably involves more than one route. Death of abnormal cells in the crypt is an important process to prevent clonal expansion and tumour formation. Apoptosis of normal cells is largely secondary to the effects of exposure to luminal factors, such as short-chain fatty adds and surfactants; loss of cell-substratum adhesion (anoikis) in the surface compartment; or cytokine-, oxidant stress- or lymphocyte-mediated death in association with inflammation. In inflammatory bowel disease (IBD) cell death can directly or indirectly compromise barrier function, impair effective epithelial restitution, lead to loss of stem cells and regenerative capacity, and has relevance to carcinogenesis. Therapeutic targeting of cell death in IBD is a double-edged sword--promotion of cell survival may favour more effective healing for active inflammation, while promotion of apoptosis may be protective from carcinogenesis.

Apoptosis↗