Disruption Of Mucosal Barrier Research Articles

P-183 Kindlin 1and Kindlin 2 Regulate Adhesion and Migration of Colonic Epithelial Cells

The Intestinal epithelial barrier plays an important role in the pathophysiology of inflammatory bowel disease (IBD). Integrity and barrier properties of the intestinal epithelium are determined by specialized adhesive structures such as intercellular junctions and focal adhesions, which respectively mediate cell-cell and cell-matrix interactions. Disassembly of epithelial junctions and matrix adhesion mediates disruption of the gut barrier during acute inflammation, whereas restoration of these adhesion structures is critical for epithelial restitution. Kindlins are unique cytosolic adaptor proteins that are enriched in both epithelial junctions and matrix adhesions. They have multiple binding partners including major classes of integrins and different cytoskeletal regulators. Importantly, mutations in the kindlin-1 gene result in Kindler syndrome, a genetic disorder associated with severe colitis, and deletion of kindlin-2 gene in mice is embryonically lethal. Despite these dramatic phenotypes caused by kindlin dysfunctions, little is known regarding the role of these adaptor proteins in regulation of the intestinal mucosal barrier disruption and restitution. This study was performed using a well-differentiated clone of HT29 human colonic epithelial cell line (HT29cF8). Transient downregulation of kindlin isoforms was achieved using RNA interference. Stable overexpression of kindlins 1 and 2 was achieved using a lentiviral expression system. Cell lines were cultured either on collagen-coated, permeable polycarbonate filters (0.4 mm pore size), or on 6-well plastic plates, for permeability, adhesion and motility assays. Barrier function of epithelial cell monolayers was determined via transepithelial electrical resistance (TEER) measurements Focal adhesions and cytoskeleton were visualized by immunofluorescence labeling and confocal microscopy. Overexpression of either kindlin 1 and/or kindlin 2 resulted in a significant increase in TEER, while siRNA-mediated knockdown of either isoform caused a substantial increase in paracellular permeability. Interestingly, both overexpression and depletion of kindlin 1 attenuated collective cell migration as determined by wound closure assay. By contrast, downregulation of kindlin 2 expression did not affect cell motility. Analysis of cell adhesion and spreading on a collagen matrix revealed significant attenuation of matrix adhesion and spreading of kindlin 1 and kindlin 2 overexpressing cells. These effects correlate well with a marked reduction of the phosphorylated form of focal adhesion protein, paxillin. Additionally, kindlin 1 overexpression regulated an increased level of non-muscle myosin IIB, which is indicative of increased contractile forces. Our data highlights kindlins as important regulators of barrier properties and restitution of human intestinal epithelium.

Association of Collagenous Disorders of the Gut and Common Variable Immunodeficiency

Introduction: Common variable immunodeficiency (CVID) can lead to disruption of the gut mucosal immune barrier. Our aim was to determine the association between immunoglobulin deficiency state-like CVID and collagenous infiltrative disorders of the gut and study their treatment outcomes. A review of literature was performed followed by a retrospective search for cases with immunoglobulin deficiency with collagneous infiltration of the gut in a pathologic database from 2007 to 2013. There were 3 such patients reported in the literature (Table 1). They had a good short-term outcome on budesonide. There were 4 patients in our pathological database having collagenous infiltrative disorder and CVID (Table 2). Only 1 patient out of 4 had decreased plasma cells in the submucosa, as expected in low immunoglobulin states. All patients had improvement in their symptoms on immunoglobulin therapy, with considerable remission on budesonide. To our knowledge, the association between collagenous infiltrative disoreders of the gut and CVID, its prompt response to immunoglobulins with good maintainence with budesonide, and increased plasma cells in mucosa, are all novel findings. In patients with antibody deficiency and chronic diarrhea, collagneous colitis should be considered as effective treatment is available.Table 1: Reported Cases in the LiteratureTable 2: Cases from Retrospective Search

Alcoholic disease: liver and beyond.

The harmful use of alcohol is a worldwide problem. It has been estimated that alcohol abuse represents the world's third largest risk factor for disease and disability; it is a causal factor of 60 types of diseases and injuries and a concurrent cause of at least 200 others. Liver is the main organ responsible for metabolizing ethanol, thus it has been considered for long time the major victim of the harmful use of alcohol. Ethanol and its bioactive products, acetaldehyde-acetate, fatty acid ethanol esters, ethanol-protein adducts, have been regarded as hepatotoxins that directly and indirectly exert their toxic effect on the liver. A similar mechanism has been postulated for the alcohol-related pancreatic damage. Alcohol and its metabolites directly injure acinar cells and elicit stellate cells to produce and deposit extracellular matrix thus triggering the "necrosis-fibrosis" sequence that finally leads to atrophy and fibrosis, morphological hallmarks of alcoholic chronic pancreatitis. Even if less attention has been paid to the upper and lower gastrointestinal tract, ethanol produces harmful effects by inducing: (1) direct damaging of the mucosa of the esophagus and stomach; (2) modification of the sphincterial pressure and impairment of motility; and (3) alteration of gastric acid output. In the intestine, ethanol can damage the intestinal mucosa directly or indirectly by altering the resident microflora and impairing the mucosal immune system. Notably, disruption of the intestinal mucosal barrier of the small and large intestine contribute to liver damage. This review summarizes the most clinically relevant alcohol-related diseases of the digestive tract focusing on the pathogenic mechanisms by which ethanol damages liver, pancreas and gastrointestinal tract.

IL-10 modulates DSS-induced colitis through a macrophage-ROS-NO axis.

Breakdown of the epithelial barrier due to toxins or other insults leads to severe colitis. IL-10 is a critical regulator of this, yet its cellular targets and mechanisms of action are not resolved. We address this here. Mice with a macrophage-selective deletion of IL-10Rα (IL-10RαMdel) developed markedly enhanced DSS-induced colitis that did not significantly differ from disease in IL-10−/− or IL-10Rα−/− mice; no impact of IL-10Rα-deficiency in other lineages was observed. IL-10RαMdel colitis was associated with increased mucosal barrier disruption in the setting of intact epithelial regeneration. Lamina propria macrophages did not show numerical or phenotypic differences from controls, or a competitive advantage over wild type cells. Pro-inflammatory cytokine production, and particularly TNF-α, was increased, though TNF-α neutralization failed to reveal a defining role for this cytokine in the aggravated disease. Rather, IL-10RαMdel lamina propria macrophages produced substantially greater levels of NO and ROS than controls. Inhibition of these had modest effects in wild type mice, though dramatically reduced colitis severity in IL-10RαMdel mice, and largely eliminated the differential effect of DSS in them. Therefore, IL-10’s palliative actions in DSS-induced colitis pre-dominantly results from its macrophage specific effects. Downregulation of NO and ROS production are central to IL-10’s protective actions.

HIV-1 gp120 Induces TLR2- and TLR4-Mediated Innate Immune Activation in Human Female Genital Epithelium

Although women constitute half of all HIV-1-infected people worldwide (UNAIDS World AIDS Day Report, 2011), the earliest events in the female reproductive tract (FRT) during heterosexual HIV-1 transmission are poorly understood. Recently, we demonstrated that HIV-1 could directly impair the mucosal epithelial barrier in the FRT. This suggested that the HIV-1 envelope glycoprotein gp120 was being recognized by a membrane receptor on genital epithelial cells, leading to innate immune activation. In this study, we report that pattern-recognition receptors TLR2 and -4 bind to HIV-1 gp120 and trigger proinflammatory cytokine production via activation of NF-κB. The gp120-TLR interaction also required the presence of heparan sulfate (HS). Bead-binding assays showed that gp120 can bind to HS, TLR2, and TLR4, and studies in transfected HEK293 cells demonstrated that HS and TLR2 and -4 were necessary to mediate downstream signaling. Exposure to seminal plasma from HIV-1-infected and uninfected men with gp120 added to it induced a significant proinflammatory cytokine response from genital epithelial cells and disruption of tight junctions, indicating a role for gp120 in mucosal barrier disruption during HIV-1 heterosexual transmission. These studies provide, for the first time to our knowledge, a possible mechanism by which HIV-1 gp120 could directly initiate innate immune activation in the FRT during heterosexual transmission.

Dysregulation of Anti-Inflammatory Annexin A1 Expression in Progressive Crohns Disease

BackgroundDevelopment of inflammatory bowel disease (IBD) involves the interplay of environmental and genetic factors with the host immune system. Mechanisms contributing to immune dysregulation in IBD are not fully defined. Development of novel therapeutic strategies is focused on controlling aberrant immune response in IBD. Current IBD therapy utilizes a combination of immunomodulators and biologics to suppress pro-inflammatory effectors of IBD. However, the role of immunomodulatory factors such as annexin A1 (ANXA1) is not well understood. The goal of this study was to examine the association between ANXA1 and IBD, and the effects of anti-TNF-α, Infliximab (IFX), therapy on ANXA1 expression.MethodsANXA1 and TNF-α transcript levels in PBMC were measured by RT PCR. Clinical follow up included the administration of serial ibdQs. ANXA1 expression in the gut mucosa was measured by IHC. Plasma ANXA1 levels were measured by ELISA.ResultsWe found that the reduction in ANXA1 protein levels in plasma coincided with a decrease in the ANXA1 mRNA expression in peripheral blood of IBD patients. ANXA1 expression is upregulated during IFX therapy in patients with a successful intervention but not in clinical non-responders. The IFX therapy also modified the cellular immune activation in the peripheral blood of IBD patients. Decreased expression of ANXA1 was detected in the colonic mucosa of IBD patients with incomplete resolution of inflammation during continuous therapy, which correlated with increased levels of TNF-α transcripts. Gut mucosal epithelial barrier disruption was evident by increased plasma bacterial 16S levels.ConclusionLoss of ANXA1 expression may support inflammation during IBD and can serve as a biomarker of disease progression. Changes in ANXA1 levels may be predictive of therapeutic efficacy.

The changes induced by cyclophosphamide in intestinal barrier and microflora in mice

Infection is one of the most commonly encountered complication during chemotherapy treatment, and recent studies showed that such infections are aroused primarily from the intestinal microflora through bacterial translocation. We aimed to investigate the alterations of mucosal barrier and colonization resistance in mouse treated with cyclophosphamide (CTX) to further understand the translocation mechanism. Male Balb/c mice were administered intraperitoneally with CTX at 25mg/kg, 50mg/kg and 100mg/kg for 5 days. We found that pretreatment with CTX, especially at high dose, increased the potentially pathogenic bacteria counts (Escherichia coli, enterobacteraceae, Pseudomonas and enterococci) and the intestinal permeability, which was associated with the reduction of tight junctions and adherens junctions. Our results suggested that disruption of mucosal barrier and colonization resistance may be partly responsible for the bacterial translocation during chemotherapy. Thus, modulation of mechanical mucosal barrier and colonization resistance might represent a new opportunity for applications in cancer patients to reduce infectious complications.

IL-10 modulates DSS-induced colitis through a macrophage -ROS-NO axis (P3254)

Abstract IL-10 is a critical regulator of colitis development. Yet, its cellular targets and mechanisms of action are not fully resolved. To identify lineages and mechanisms responsible for IL-10's protective effects in colitis, we generated mice with cell type-restricted deficiencies in IL-10 responsiveness by using DSS colitis model with mice bearing deletions of the IL-10Rα in T cells, B cells, DCs, or macrophages. Mice with a macrophage-selective deletion of IL-10Rα (IL-10RαMdel) developed markedly enhanced colitis that did not significantly differ from disease in IL- 10-/- or IL-10Rα-/- mice; no impact of IL-10Rα-deficiency in other lineages was observed. IL-10RαMdel colitis was associated with increased mucosal barrier disruption in the setting of intact epithelial regeneration. Quantitation and phenotypic assessment of lamina propria macrophages did not identify differences from controls. IL-10Rα-deficient macrophages also did not display a competitive advantage over wild type cells in mixed chimeras. Pro-inflammatory cytokine production, and particularly TNF-α, was increased, though TNF-α neutralization failed to reveal a defining role for the cytokine in the aggravated disease. IL-10RαMdel lamina propria macrophages produced substantially greater levels of NO and ROS than control macrophages. Inhibition of these more dramatically reduced colitis severity in IL-10RαMdel mice, and largely eliminated the differential effect of DSS in IL-10RαMdel and control mice.

Piroxicam-β-Cyclodextrin: A GI Safer Piroxicam

Although NSAIDs are very effective drugs, their use is associated with a broad spectrum of adverse reactions in the liver, kidney, cardiovascular (CV) system, skin and gut. Gastrointestinal (GI) side effects are the most common and constitute a wide clinical spectrum ranging from dyspepsia, heartburn and abdominal discomfort to more serious events such as peptic ulcer with life-threatening complications of bleeding and perforation. The appreciation that CV risk is also increased further complicates the choices of physicians prescribing anti-inflammatory therapy. Despite prevention strategies should be implemented in patients at risk, gastroprotection is often underused and adherence to treatment is generally poor. A more appealing approach would be therefore to develop drugs that are devoid of or have reduced GI toxicity. Gastro-duodenal mucosa possesses many defensive mechanisms and NSAIDs have a deleterious effect on most of them. This results in a mucosa less able to cope with even a reduced acid load. NSAIDs cause gastro-duodenal damage, by two main mechanisms: a physiochemical disruption of the gastric mucosal barrier and systemic inhibition of gastric mucosal protection, through inhibition of cyclooxygenase (COX, PG endoperoxide G/H synthase) activity of the GI mucosa. However, against a background of COX inhibition by anti-inflammatory doses of NSAIDs, their physicochemical properties, in particular their acidity, underlie the topical effect leading to short-term damage. It has been shown that esterification of acidic NSAIDs suppresses their gastrotoxicity without adversely affecting anti-inflammatory activity. Another way to develop NSAIDs with better GI tolerability is to complex these molecules with cyclodextrins (CDs), giving rise to so-called “inclusion complexes” that can have physical, chemical and biological properties very different from either those of the drug or the cyclodextrin. Complexation of NSAIDs with β-cyclodextrin potentially leads to a more rapid onset of action after oral administration and improved GI tolerability because of minimization of the drug gastric effects. One such drug, piroxicam-β-cyclodextrin (PBC), has been used in Europe for 25 years. Preclinical and clinical pharmacology of PBC do show that the β-cyclodextrin inclusion complex of piroxicam is better tolerated from the upper GI tract than free piroxicam, while retaining all the analgesic and anti-inflammatory properties of the parent compound. In addition, the drug is endowed with a quick absorption rate, which translates into a faster onset of analgesic activity, an effect confirmed in several clinical studies. An analysis of the available trials show that PBC has a GI safety profile, which is better than that displayed by uncomplexed piroxicam. Being an inclusion complex of piroxicam, whose CV safety has been pointed out by several observational studies, PBC should be viewed as a CV safe anti-inflmmatory compound and a GI safer alternative to piroxicam. As a consequence, it should be considered as a useful addition to our therapeutic armamentarium.

STAT6 Deficiency Ameliorates Severity of Oxazolone Colitis by Decreasing Expression of Claudin-2 and Th2-Inducing Cytokines

Patients suffering from ulcerative colitis (UC) exhibit chronic colonic inflammation caused by a dysregulated mucosal immune response and epithelial barrier disruption. Th2 cytokines, including IL-13, have been implicated in the pathogenesis of UC. IL-13 induces phosphorylation of STAT6, and we previously demonstrated increased epithelial p-STAT6 in children with UC. In this study, we investigated the role of STAT6 in oxazolone colitis, a murine model of UC, by inducing colitis in STAT6-deficient (STAT6(-/-)) and wild type (WT) mice. We observed increased epithelial cell, T cell, macrophage, and NKT cell STAT6 phosphorylation, as well as increased p-STAT6(+) IL-13-producing NKT cells, in colitic WT mice. Colitis was attenuated in STAT6(-/-) mice, with improvements in weight, colon length, and histopathology. There was decreased induction of the pore-forming tight junction protein claudin-2 in STAT6(-/-) mice. Similarly, short hairpin RNA STAT6 knockdown reduced claudin-2 induction and transepithelial resistance decrease in IL-13-treated human T84 cells. Tissue expression of IL-13, IFN-γ, IL-17, and IL-10 mRNA was similarly induced in WT and STAT6(-/-) colitic mice; however, we observed increased mRNA expression for the Th2-inducing cytokines IL-33 and thymic stromal lymphopoietin in WT mice with colitis, which was abrogated in STAT6(-/-) mice. Mesenteric lymph node cells from STAT6(-/-) mice with colitis exhibited reduced secretion of IL-4, IL-5, IL-13, and IFN-γ. IL-33 augmented mesenteric lymph node cell secretion of IL-5, IL-13, IL-6, and IFN-γ. These data implicate STAT6 in the pathogenesis of colitis in vivo with important roles in altering epithelial barrier function and regulating Th2-inducing cytokine production.

Mucosal Plasma Cell Barrier Disruption During Intestine Transplant Rejection

Intestinal allograft mucosa undergoes repopulation with host immunocytes. However, critical changes within key immunocyte subsets are not known. To explain acute cellular rejection after intestine transplantation (ITx) on the basis of altered mucosal immunocytes, rejecting and rejection-free ITx allografts (n=17) were compared with genome-wide expression arrays. Cells identified by cell/lineage-specific genes were evaluated by immunohistochemistry. The corresponding phenotype and donor-specific alloreactivity were characterized in peripheral blood. Time-dependent changes in candidate cell(s) were evaluated in biopsies from an independent cohort of 12 children with ITx. Among 107 differentially expressed genes, three B-cell lineage-specific genes, CCR10, STAP1, and IGLL1, were down-regulated during ITx rejection and were selected for and achieved technical quantitative reverse transcription polymerase chain reaction replication. Down-regulation of the immunoglobulin (Ig)A+ plasma cell-specific CCR10 gene correlated with decreased mature mucosal CD138+ plasma cell numbers in corresponding biopsy specimens (r=0.761, P=0.006) and inversely correlated with enhanced alloreactivity of CD154+ T-cytotoxic memory cells (r=-0.56, P=0.031), which predict acute cellular rejection with high sensitivity. An independent cohort of serial biopsy specimens from 12 ITx recipients (1) confirmed relative CD138+ plasma cell depletion during rejection (P=0.042) and (2) showed increased IgG+-to-IgA+ cell ratios within 4 hr of reperfusion in rejection-prone allografts (P=0.037) and during ITx rejection (P=0.025), compared with rejection-free allografts. No differences existed late after ITx. Increased peripheral IgG+ CD27+ CD19+ memory B cells (P=0.004) were seen during ITx rejection in archived peripheral blood lymphocyte from test and replication cohorts. Protracted depletion of the mucosal CD138+ plasma cell barrier and early mucosal infiltration with memory IgG+ cells characterize the rejection-prone intestine allograft. Mucosal IgA+ plasma cell barrier reconstitution may augur resolution of ITx rejection.

MicroRNA‐146a‐mediated downregulation of IRAK1 protects mouse and human small intestine against ischemia/reperfusion injury

Intestinal ischemia/reperfusion (I/R) injury causes inflammation and tissue damage and is associated with high morbidity and mortality. Uncontrolled activation of the innate immune system through toll-like receptors (Tlr) plays a key role in I/R-mediated tissue damage but the underlying mechanisms have not been fully resolved. Here, we identify post-transcriptional upregulation of the essential Tlr signalling molecule interleukin 1 receptor-associated kinase (Irak) 1 as the causative mechanism for post-ischemic immune hyper-responsiveness of intestinal epithelial cells. Increased Irak1 protein levels enhanced epithelial ligand responsiveness, chemokine secretion, apoptosis and mucosal barrier disruption in an experimental intestinal I/R model using wild-type, Irak1−/− and Tlr4−/− mice and ischemic human intestinal tissue. Irak1 accumulation under hypoxic conditions was associated with reduced K48 ubiquitination and enhanced Senp1-mediated deSUMOylation of Irak1. Importantly, administration of microRNA (miR)-146a or induction of miR-146a by the phytochemical diindolylmethane controlled Irak1 upregulation and prevented immune hyper-responsiveness in mouse and human tissue. These findings indicate that Irak1 accumulation triggers I/R-induced epithelial immune hyper-responsiveness and suggest that the induction of miR-146a offers a promising strategy to prevent I/R tissue injury.

Activation of NF-κB pathway in oral buccal mucosa during small intestinal ischemia-reperfusion injury

BackgroundIntestinal ischemia-reperfusion injury induces intestinal mucosal barrier disruption, systemic inflammatory response syndrome, multiorgan failure, and death. The major pathway for the systemic inflammatory responses depends on nuclear factor kappa B (NF-κB). However, direct measuring of NF-κB in injured tissues is not routinely available. Our aim was to determine whether NF-кB pathway in buccal mucosa is activated during intestinal ischemia-reperfusion injury. Materials and methodsMale Sprague-Dawley rats were prepared for the animal experiment. Superior mesenteric artery (SMA) was exposed and clamped for 30 min in the intestinal ischemia-reperfusion (IR) group. SMA was exposed only in control group. Serum, buccal mucosa, and small intestinal mucosa were harvested in 90 min after reperfusion in IR or 120 min after SMA exposure in control group. Serum cytokine levels and tissue NF-κB pathway activities were measured. ResultsSerum TNF-α (5.49 ± 2.72 versus 1.77 ± 1.20 pg/mL, P = 0.002) and interleukin-6 (232.32 ± 29.98 versus 115.92 ± 17.81 pg/mL, P = 0.002) levels were significantly higher in IR than control group. Intestinal mucosal cytoplasmic phosphorylated inhibitor kappa B (IκB)/IκB ratio, nuclear NF-κB expression, and NF-κB DNA-binding activity were significantly higher in IR than control group. Buccal mucosal cytoplasmic phosphorylated IκB/IκB ratio, nuclear NF-κB expression, and NF-κB DNA-binding activity were also higher in IR than control group. ConclusionBuccal mucosal NF-κB pathway was activated by intestinal ischemia-reperfusion injury. The present study suggests that buccal mucosal may be considered as an indicator for the assessment of intestinal ischemia-reperfusion injury.

Protective role of 1,25(OH)2vitamin D3 in the mucosal injury and epithelial barrier disruption in DSS-induced acute colitis in mice

BackgroundIntestinal hyper-permeability plays a critical role in the etiopathogenesis of inflammatory bowel disease (IBD) by affecting the penetration of pathogens, toxic compounds and macromolecules. 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active form of vitamin D, has been shown to be an important regulator of IBD and recent epidemiology suggests that patients with IBD have an impaired vitamin D status. The purpose of this study is to investigate the possible protective effects of 1,25(OH)2D3 on mucosal injury and epithelial barrier disruption on dextran sulfate sodium (DSS)-induced acute colitis model.MethodsWe used DSS-induced acute colitis model to investigate the protective effects of 1,25(OH)2D3 on mucosal injury and epithelial barrier integrity. Severity of colitis was evaluated by disease activity index (DAI), body weight (BW) change, colon length, histology, myeloperoxidase (MPO) activity, and proinflammatory cytokine production including tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). In vitro the protective role of 1,25(OH)2D3 was assessed by incubating Caco-2 cells with or without DSS and measuring transepithelial electrical resistance (TEER) and fluorescein isothiocyanate dextran (FITC-D). The intestinal permeability was analyzed by FITC-D, bacterial translocation and measurement of lipopolysaccharide (LPS). Ultrastructural features of the colon tissue and Caco-2 cell monolayer were observed by electron microscopy. Expressions of tight junction (TJ) proteins in the colon mucosa and Caco-2 cells were detected by immunohistochemistry, immunofluorescence, Western blot and real-time fluorescent quantitative PCR, respectively.ResultsDSS-induced acute colitis model was characterized by a reduced BW, AUC of BW, serum calcium, higher DAI, AUC of DAI, shortened colon length, elevated MPO activity, worsened histologic inflammation, increased mononuclear cell numbers in mesenteric lymph nodes (MLNs) and colonic lamina propria (LP), and enhanced proteins and mRNA levels of TNF-α and IFN-γ. 1,25(OH)2D3 markedly increased expressions of TJ proteins and mRNA and decreased the FITC-D permeability and the level of LPS. Furthermore, 1,25(OH)2D3 abrogated bacterial translocation to MLNs and ameliorated ultrastructural features of the colon epithelium by scanning electron microscopy (SEM). In vitro, 1,25(OH)2D3 increased TEER, TJ proteins and mRNA expressions, decreased the FITC-D permeability, and preserved structural integrity of the TJ in Caco-2 cells.Conclusions1,25(OH)2D3 may play a protective role in mucosal barrier homeostasis by maintaining the integrity of junction complexes and in healing capacity of the colon epithelium. 1,25(OH)2D3 may represent an attractive and novel therapeutic agent for the adjuvant therapy of IBD.

Role of IL-22 in protecting mucosal barrier disruption by HIV-1

Role of IL-22 in protecting mucosal barrier disruption by HIV-1

What’s New in Shock, March 2012?

What’s New in Shock, March 2012?

TLR9 Agonist Protects Mice from Radiation-Induced Gastrointestinal Syndrome

PurposeRadiation-induced gastrointestinal syndrome (RIGS) is due to the clonogenic loss of crypt cells and villi depopulation, resulting in disruption of mucosal barrier, bacterial invasion, inflammation and sepsis. Intestinal macrophages could recognize invading bacterial DNA via TLR9 receptors and transmit regenerative signals to the neighboring crypt. We therefore investigated whether systemic administration of designer TLR9 agonist could ameliorate RIGS by activating TLR9.Methods and MaterialsMale C57Bl6 mice were distributed in four experimental cohorts, whole body irradiation (WBI) (8.4–10.4 Gy), TLR9 agonist (1 mg/kg s.c.), 1 h pre- or post-WBI and TLR9 agonist+WBI+iMyd88 (pretreatment with inhibitory peptide against Myd88). Animals were observed for survival and intestine was harvested for histological analysis. BALB/c mice with CT26 colon tumors in abdominal wall were irradiated with 14 Gy single dose of whole abdominal irradiation (AIR) for tumor growth study.ResultsMice receiving pre-WBI TLR9 agonist demonstrated improvement of survival after 10.4 Gy (p<0.03), 9.4 Gy (p<0.008) and 8.4 Gy (p<0.002) of WBI, compared to untreated or iMyd88-treated controls. Post-WBI TLR9 agonist mitigates up to 8.4 Gy WBI (p<0.01). Histological analysis and xylose absorption test demonstrated significant structural and functional restitution of the intestine in WBI+TLR9 agonist cohorts. Although, AIR reduced tumor growth, all animals died within 12 days from RIGS. TLR9 agonist improved the survival of mice beyond 28 days post-AIR (p<0.008) with significant reduction of tumor growth (p<0.0001).ConclusionsTLR9 agonist treatment could serve both as a prophylactic or mitigating agent against acute radiation syndrome and also as an adjuvant therapy to increase the therapeutic ratio of abdominal Radiation Therapy for Gastro Intestinal malignancies.

TRiPping down the oesophagus

TRiPping down the oesophagus

Oral Administration of 1,25(OH)2d3 Protects Against Mucosal Injury and Epithelial Barrier Disruption in Acute Dextran Sulfate Sodium(DSS)-Induced Colitis in Mice

Oral Administration of 1,25(OH)2d3 Protects Against Mucosal Injury and Epithelial Barrier Disruption in Acute Dextran Sulfate Sodium(DSS)-Induced Colitis in Mice

Vocal Cord Actinomycosis: A Case Report

Introduction: Actinomycosis is a systemic chronic bacterial infection caused by Actinomyces Israelii, an anaerobic organism normally resident in the human mouth. However, the actinomycosis of the larynx is very rare, and only about 15 cases have been reported in the literature so far. Most of the cases reported occurred in patients who had previously undergone radiotherapy for laryngeal cancer. Case Report: Here we report a case of actinomycosis of the larynx in a 14-year-old shepherd boy who was not immunocompromised but had a history of tooth extraction two months prior to admission to the hospital and severe laryngitis one year prior to admission. Conclusion: Laryngeal actinomycosis might be related to poor oral hygiene and mucosal barrier disruption, as well as to being immunocompromised.