ABSTRACT
BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) has been recommended for achalasia treatment. To prevent the potential of infective risk, antibiotic prophylaxis is usually administered, whereas the additional need of antibiotic therapy after POEM is uncertain. The primary endpoint was to determine whether prophylaxis versus prophylaxis plus short therapy was needed after POEM. METHODS: Consecutive patients scheduled for POEM were randomly assigned (1:1) to group A (prophylactic cefazolin 2 g IV) or group B (prophylaxis + cefazolin 2 g IV × 3 followed by oral amoxicillin/clavulanate 3 g/day). Infective risk was assessed by means of host response, namely body temperature and serum levels of white blood cells and C-reactive protein; immune response (the cytokines interleukin [IL]-6, IL-1ß, and tumor necrosis factor-α and microbial translocation mediators lipopolysaccharide binding protein and soluble CD14); and blood cultures at time points before (t0) and after (t1, t2) POEM. RESULTS: After POEM, none of the 124 enrolled patients (54.6 ± 12.6 years old; 64 men) developed any fever (body temperature: t0, 36.56± .49°C; t1, 36.53± .52°C; t2, 36.48± .41°C), without any differences between groups at any time point. Regarding systemic inflammation, no difference was reported between groups in serum levels of C-reactive protein and white blood cells. Considering microbial translocation mediated response, lipopolysaccharide binding protein (group A: t0, 1539 ± 168.6 pg/mL; t1, 1321 ± 149.1 pg/mL; t2, 2492 ± 283.2 pg/mL; group B: t0, 1318 ± 115.9 pg/mL; t1, 1492 ± 163.8 pg/mL; t2, 2600 ± 328.2 pg/mL) and soluble CD14 (group A: t0, 2.16 ± .15 µg/mL; t1, 1.89 ± .15 µg/mL; t2, 2.2 ± .15 µg/mL; group B: t0, 2.1 ± .13 µg/mL; t1, 2 ± .13 µg/mL; t2, 2.5 ± .2 µg/mL) were similar between the 2 groups; the immune response cytokines IL-6, IL-1ß, and tumor necrosis factor-α also were similar in the 2 groups. In relation to blood cultures, at t1 the group B bacteremia rate was 3.2% (2/62) and group A was 1.6% (1/62) with no difference (P = .6). All subsequent blood cultures were negative at t2. CONCLUSIONS: According to our study, postprophylactic short-term antimicrobial therapy after POEM is not required because of a very low residual infective risk. (Clinical trial registration number: NCT03587337.).
Subject(s)
Digestive System Surgical Procedures , Esophageal Achalasia , Myotomy , Natural Orifice Endoscopic Surgery , Adult , Aged , Anti-Bacterial Agents/therapeutic use , Esophageal Sphincter, Lower , Esophagoscopy , Female , Humans , Male , Middle Aged , Treatment OutcomeABSTRACT
INTRODUCTION: Several studies have shown that inflammatory bowel diseases (IBD) patients treated with thiopurines have an increased risk of developing skin cancer. SOURCES OF DATA: This review is based on recent published literature regarding the use of thiopurines in IBD and skin malignancies. AREAS OF AGREEMENT: Exposure to thiopurines is significantly associated with nonmelanoma skin cancer, but not with melanoma. Primary and secondary prevention including sun-protective measures and regular dermatologic screening are recommended in IBD patients, particularly in those exposed to thiopurines. AREAS OF CONTROVERSY: Both when and how immunosuppressive therapy should be resumed in patients with a prior history of skin cancer still remain debatable topics. GROWING POINTS: The benefit-risk balance between thiopurine therapy and risk of skin cancer should be evaluated in the drug decision process. AREAS TIMELY FOR DEVELOPING RESEARCH: The approval of new effective strategies requires the re-evaluation of the positioning of thiopurines within the therapeutic algorithm based on an increasingly individualized approach.
Subject(s)
Inflammatory Bowel Diseases , Melanoma , Skin Neoplasms , Crime , Humans , Immunosuppressive Agents/adverse effects , Inflammatory Bowel Diseases/drug therapy , Melanoma/prevention & control , Skin Neoplasms/chemically induced , Skin Neoplasms/prevention & controlABSTRACT
Colorectal cancer (CRC) is one of the most malignant tumors worldwide. Stromal cells residing in the tumor microenvironment strongly contribute to cancer progression through their crosstalk with cancer cells and extracellular matrix. Here we provide the first evidence that CRC-associated lymphatic endothelium displays a distinct matrisome-associated transcriptomic signature, which distinguishes them from healthy intestinal lymphatics. We also demonstrate that CRC-associated human intestinal lymphatic endothelial cells regulate tumor cell growth via growth differentiation factor 11, a soluble matrisome component which in CRC patients was found to be associated with tumor progression. Our data provide new insights into lymphatic contribution to CRC growth, aside from their conventional role as conduits of metastasis.
Subject(s)
Bone Morphogenetic Proteins/genetics , Colorectal Neoplasms/genetics , Endothelium, Lymphatic/cytology , Extracellular Matrix/genetics , Growth Differentiation Factors/genetics , Animals , Caco-2 Cells , Cell Culture Techniques/methods , Cell Proliferation , Cells, Cultured , Disease Progression , Endothelial Cells/chemistry , Endothelial Cells/cytology , Endothelium, Lymphatic/chemistry , Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Humans , Mice , Neoplasm Transplantation , Tumor MicroenvironmentABSTRACT
BACKGROUND & AIMS: Alterations in signaling pathways that regulate resolution of inflammation (resolving pathways) contribute to pathogenesis of ulcerative colitis (UC). The resolution process is regulated by lipid mediators, such as those derived from the ω-3 docosahexaenoic acid (DHA), whose esterified form is transported by the major facilitator superfamily domain containing 2A (MFSD2A) through the endothelium of brain, retina, and placenta. We investigated if and how MFSD2A regulates lipid metabolism of gut endothelial cells to promote resolution of intestinal inflammation. METHODS: We performed lipidomic and functional analyses of MFSD2A in mucosal biopsies and primary human intestinal microvascular endothelial cells (HIMECs) isolated from surgical specimens from patients with active, resolving UC and healthy individuals without UC (controls). MFSD2A was knocked down in HIMECs with small hairpin RNAs or overexpressed from a lentiviral vector. Human circulating endothelial progenitor cells that overexpress MFSD2A were transferred to CD1 nude mice with dextran sodium sulfate-induced colitis, with or without oral administration of DHA. RESULTS: Colonic biopsies from patients with UC had reduced levels of inflammation-resolving DHA-derived epoxy metabolites compared to healthy colon tissues or tissues with resolution of inflammation. Production of these metabolites by HIMECs required MFSD2A, which is required for DHA retention and metabolism in the gut vasculature. In mice with colitis, transplanted endothelial progenitor cells that overexpressed MFSD2A not only localized to the inflamed mucosa but also restored the ability of the endothelium to resolve intestinal inflammation, compared with mice with colitis that did not receive MFSD2A-overexpressing endothelial progenitors. CONCLUSIONS: Levels of DHA-derived epoxides are lower in colon tissues from patients with UC than healthy and resolving mucosa. Production of these metabolites by gut endothelium requires MFSD2A; endothelial progenitor cells that overexpress MFSD2A reduce colitis in mice. This pathway might be induced to resolve intestinal inflammation in patients with colitis.
Subject(s)
Colitis/prevention & control , Colon/metabolism , Docosahexaenoic Acids/metabolism , Endothelial Progenitor Cells/metabolism , Membrane Transport Proteins/metabolism , Tumor Suppressor Proteins/metabolism , Animals , Cells, Cultured , Colitis/chemically induced , Colitis/genetics , Colitis/metabolism , Colon/drug effects , Colon/pathology , Cytochrome P-450 Enzyme System/metabolism , Dextran Sulfate , Disease Models, Animal , Docosahexaenoic Acids/pharmacology , Endothelial Progenitor Cells/drug effects , Endothelial Progenitor Cells/pathology , Endothelial Progenitor Cells/transplantation , Epoxy Compounds/metabolism , Humans , Membrane Transport Proteins/genetics , Mice, Nude , Oxylipins/metabolism , RNA Interference , Signal Transduction , Symporters , Transfection , Tumor Necrosis Factor-alpha/pharmacology , Tumor Suppressor Proteins/geneticsABSTRACT
Prolyl hydroxylase domain-containing proteins (PHDs) regulate the adaptation of cells to hypoxia. Pan-hydroxylase inhibition is protective in experimental colitis, in which PHD1 plays a prominent role. However, it is currently unknown how PHD1 targeting regulates this protection and which cell type(s) are involved. Here, we demonstrated that Phd1 deletion in endothelial and haematopoietic cells (Phd1f/f Tie2:cre) protected mice from dextran sulphate sodium (DSS)-induced colitis, with reduced epithelial erosions, immune cell infiltration, and colonic microvascular dysfunction, whereas the response of Phd2f/+ Tie2:cre and Phd3f/f Tie2:cre mice to DSS was similar to that of their littermate controls. Using bone marrow chimeras and cell-specific cre mice, we demonstrated that ablation of Phd1 in haematopoietic cells but not in endothelial cells was both necessary and sufficient to inhibit experimental colitis. This effect relied, at least in part, on skewing of Phd1-deficient bone marrow-derived macrophages towards an anti-inflammatory M2 phenotype. These cells showed an attenuated nuclear factor-κB-dependent response to lipopolysaccharide (LPS), which in turn diminished endothelial chemokine expression. In addition, Phd1 deficiency in dendritic cells significantly reduced interleukin-1ß production in response to LPS. Taken together, our results further support the development of selective PHD1 inhibitors for ulcerative colitis, and identify haematopoietic cells as their primary target. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Subject(s)
Colitis, Ulcerative/drug therapy , Macrophages/metabolism , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Animals , Bone Marrow/drug effects , Bone Marrow/immunology , Colitis, Ulcerative/immunology , Colitis, Ulcerative/pathology , Colon/drug effects , Colon/pathology , Dendritic Cells/drug effects , Dendritic Cells/pathology , Endothelial Cells/drug effects , Endothelial Cells/pathology , Female , Gene Deletion , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/genetics , Interleukin-1beta/genetics , Interleukin-1beta/metabolism , Lipopolysaccharides , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , NF-kappa B/genetics , NF-kappa B/metabolism , Procollagen-Proline Dioxygenase/deficiency , Procollagen-Proline Dioxygenase/geneticsABSTRACT
BACKGROUND & AIMS: Colorectal cancer (CRC) is highly metastatic. Metastases spread directly into local tissue or invade distant organs via blood and lymphatic vessels, but the role of lymphangiogenesis in CRC progression has not been determined. Lymphangiogenesis is induced via vascular endothelial growth factor C (VEGFC) activation of its receptor, VEGFR3; high levels of VEGFC have been measured in colorectal tumors undergoing lymphangiogenesis and correlated with metastasis. We investigated VEGFC signaling and lymphatic barriers in human tumor tissues and mice with orthotopic colorectal tumors. METHODS: We performed immunohistochemical, immunoblot, and real-time polymerase chain reaction analyses of colorectal tumor specimens collected from patients; healthy intestinal tissues collected during operations of patients without CRC were used as controls. CT26 CRC cells were injected into the distal posterior rectum of BALB/c-nude mice. Mice were given injections of an antibody against VEGFR3 or an adenovirus encoding human VEGFC before orthotopic tumors and metastases formed. Lymph node, lung, and liver tissues were collected and evaluated by flow cytometry. We measured expression of vascular endothelial cadherin (CDH5) on lymphatic vessels in mice and in human intestinal lymphatic endothelial cells. RESULTS: Levels of podoplanin (a marker of lymphatic vessels), VEGFC, and VEGFR3 were increased in colorectal tumor tissues, compared with controls. Mice that expressed VEGFC from the adenoviral vector had increased lymphatic vessel density and more metastases in lymph nodes, lungs, and livers, compared with control mice. Anti-VEGFR3 antibody reduced numbers of lymphatic vessels in colons and prevented metastasis. Expression of VEGFC compromised the lymphatic endothelial barrier in mice and endothelial cells, reducing expression of CDH5, increasing permeability, and increasing trans-endothelial migration by CRC cells. Opposite effects were observed in mice and cells when VEGFR3 was blocked. CONCLUSIONS: VEGFC signaling via VEGFR3 promotes lymphangiogenesis and metastasis by orthotopic colorectal tumors in mice and reduces lymphatic endothelial barrier integrity. Levels of VEGFC and markers of lymphatic vessels are increased in CRC tissues from patients, compared with healthy intestine. Strategies to block VEGFR3 might be developed to prevent CRC metastasis in patients.
Subject(s)
Colorectal Neoplasms/metabolism , Endothelial Cells/metabolism , Endothelium, Lymphatic/metabolism , Liver Neoplasms/metabolism , Lung Neoplasms/metabolism , Transendothelial and Transepithelial Migration , Vascular Endothelial Growth Factor C/metabolism , Animals , Antigens, CD/metabolism , Cadherins/metabolism , Case-Control Studies , Cell Line, Tumor , Cell Proliferation , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Endothelial Cells/pathology , Endothelium, Lymphatic/pathology , Endothelium, Vascular/metabolism , Endothelium, Vascular/pathology , Humans , Liver Neoplasms/genetics , Liver Neoplasms/secondary , Lung Neoplasms/genetics , Lung Neoplasms/secondary , Lymphangiogenesis , Lymphatic Metastasis , Mice, Inbred BALB C , Mice, Nude , Neoplasm Invasiveness , Signal Transduction , Time Factors , Transfection , Vascular Endothelial Growth Factor C/genetics , Vascular Endothelial Growth Factor Receptor-3/metabolismABSTRACT
OBJECTIVE: Inflammation plays crucial roles in the pathogenesis of several chronic inflammatory disorders, including Crohn's disease (CD) and UC, the two major forms of IBD. The urokinase plasminogen activator receptor (uPAR) exerts pleiotropic functions over the course of both physiological and pathological processes. uPAR not only has a key role in fibrinolysis but also modulates the development of protective immunity. Additionally, uPAR supports extracellular matrix degradation and regulates cell migration, adhesion and proliferation, thus influencing the development of inflammatory and immune responses. This study aimed to evaluate the role of uPAR in the pathogenesis of IBD. DESIGN: The functional role of uPAR was assessed in established experimental models of colitis. uPAR deficiency effects on cytokine release, polarisation and bacterial phagocytosis were analysed in colonic macrophages. uPAR expression was analysed in surgical specimens collected from normal subjects and patients with IBD. RESULTS: In mice, uPAR expression is positively regulated as colitis progresses. uPAR-KO mice displayed severe inflammation compared with wild-type littermates, as indicated by clinical assessment, endoscopy and colon histology. The absence of uPAR led to an increased production of inflammatory cytokines by macrophages that showed an M1 polarisation and impaired phagocytosis. In human IBD, CD68(+) macrophages derived from the inflamed mucosa expressed low levels of uPAR. CONCLUSIONS: These findings point to uPAR as an essential component of intestinal macrophage functions and unravel a new potential target to control mucosal inflammation in IBD.
Subject(s)
Inflammatory Bowel Diseases/immunology , Macrophages/physiology , Phagocytosis/physiology , Receptors, Urokinase Plasminogen Activator/physiology , Animals , Humans , Mice , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
BACKGROUND AND AIMS: Triggering receptor expressed on myeloid cells (TREM)-2 is a surface receptor detected on macrophages, dendritic cells, and microglia that binds repeated anionic motifs on yeast and Gram-positive and Gram-negative bacteria. Little is known about TREM-2 expression and function in the intestine or its role in inflammatory bowel disease (IBD). We investigated the expression of TREM-2 in the intestinal lamina propria and its role in the development of colonic inflammation. METHODS: We measured levels of TREM-2 in lamina propria mononuclear cells from surgical specimens collected from patients with IBD or cancer (controls). We analyzed the development of colitis in TREM-2 knockout and wild-type mice. Colon samples were isolated from mice and analyzed for cytokine expression, phagocytosis of bacteria, proliferation in colonic crypts, lamina propria mononuclear cell function, and T-cell activation by ovalbumin. RESULTS: TREM-2 was virtually absent from colon samples of control patients, but levels were significantly higher in within the inflamed mucosa of patients with IBD; it was mainly expressed by CD11c(+) cells. Levels of TREM-2 increased as acute or chronic colitis was induced in mice. TREM-2 knockout mice developed less severe colitis than wild-type mice; the knockout mice lost less body weight, had a lower disease activity index, and had smaller mucosal lesions in endoscopic analysis. Colon dendritic cells from TREM-2 knockout mice produced lower levels of inflammatory cytokines and had reduced levels of bacterial killing and T-cell activation than cells from wild-type mice. CONCLUSIONS: TREM-2 contributes to mucosal inflammation during development of colitis in mice. Levels of TREM-2 are increased within the inflamed mucosa of patients with IBD, indicating its potential as a therapeutic target.
Subject(s)
Colon/metabolism , Inflammatory Bowel Diseases/immunology , Intestinal Mucosa/metabolism , Lymphocyte Activation/immunology , Membrane Glycoproteins/biosynthesis , Receptors, Immunologic/biosynthesis , Animals , Colon/immunology , Colon/pathology , Disease Models, Animal , Female , Flow Cytometry , Humans , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Cells/immunology , Myeloid Cells/metabolism , Myeloid Cells/pathologyABSTRACT
The Triggering Receptors Expressed on Myeloid cells (TREM) are a family of cell-surface molecules that control inflammation, bone homeostasis, neurological development and blood coagulation. TREM-1 and TREM-2, the best-characterized receptors so far, play divergent roles in several infectious diseases. In the intestine, TREM-1 is highly expressed by macrophages, contributing to inflammatory bowel disease (IBD) pathogenesis. Contrary to current understanding, TREM-2 also promotes inflammation in IBD by fueling dendritic cell functions. This review will focus specifically on recent insights into the role of TREM proteins in IBD development, and discuss opportunities for novel treatment approaches.
Subject(s)
Inflammatory Bowel Diseases/etiology , Inflammatory Bowel Diseases/metabolism , Myeloid Cells/metabolism , Receptors, Immunologic/metabolism , Animals , Humans , Inflammation/metabolism , Inflammation/pathology , Models, Biological , Receptors, Immunologic/chemistry , Receptors, Immunologic/genetics , Signal TransductionABSTRACT
The protein C (PC) pathway is a well-characterized coagulation system. Endothelial PC receptors and thrombomodulin mediate the conversion of PC to its activated form, a potent anticoagulant and anti-inflammatory molecule. Here we show that the PC pathway is expressed on intestinal epithelial cells. The epithelial expression of PC and endothelial PC receptor is down-regulated In patients with inflammatory bowel disease. PC(-/-)/PC(Tg) mice, expressing only 3% of WT PC, developed spontaneous intestinal inflammation and were prone to severe experimental colitis. These mice also demonstrated spontaneous elevated production of inflammatory cytokines and increased intestinal permeability. Structural analysis of epithelial tight junction molecules revealed that lack of PC leads to decreased JAM-A and claudin-3 expression and an altered pattern of ZO-1 expression. In vitro, treatment of epithelial cells with activated PC led to protection of tight junction disruption induced by TNF-α, and in vivo, topical treatment with activated PC led to mucosal healing and amelioration of colitis. Taken together, these findings demonstrate that the PC pathway is a unique system involved in controlling intestinal homeostasis and inflammation by regulating epithelial barrier function.
Subject(s)
Colitis/genetics , Epithelial Cells/metabolism , Inflammatory Bowel Diseases/genetics , Protein C/genetics , Animals , Anticoagulants/pharmacology , Antigens, CD/genetics , Antigens, CD/metabolism , Caco-2 Cells , Cells, Cultured , Colitis/metabolism , Endothelial Protein C Receptor , Epithelial Cells/drug effects , Epithelial Cells/pathology , Gene Expression , Humans , Immunohistochemistry , Inflammatory Bowel Diseases/metabolism , Interleukin-6/metabolism , Interleukin-8/metabolism , Intestinal Mucosa/drug effects , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Intestines/pathology , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Phosphoproteins/genetics , Phosphoproteins/metabolism , Protein C/pharmacology , Protein C/physiology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/genetics , Signal Transduction/physiology , Tight Junctions/drug effects , Tight Junctions/metabolism , Zonula Occludens-1 ProteinABSTRACT
BACKGROUND: Patients on immunosuppressive drugs have been excluded from COVID-19 vaccines trials, creating concerns regarding their efficacy. AIMS: To explore the humoral response to COVID-19 vaccines in patients with inflammatory bowel disease (IBD) METHODS: Effectiveness and Safety of COVID-19 Vaccine in Patients with Inflammatory Bowel Disease (IBD) Treated with Immunomodulatory or Biological Drugs (ESCAPE-IBD) is a prospective, multicentre study promoted by the Italian Group for the study of Inflammatory Bowel Disease. We present data on serological response eight weeks after the second dose of COVID-19 vaccination in IBD patients and healthy controls (HCs). RESULTS: 1076 patients with IBD and 1126 HCs were analyzed. Seropositivity for anti-SARS-CoV-2 IgG was reported for most IBD patients, even if with a lesser rate compared with HCs (92.1% vs. 97.9%; p<0.001). HCs had higher antibody concentrations (median OD 8.72 [IQR 5.2-14-2]) compared to the whole cohort of IBD patients (median OD 1.54 [IQR 0.8-3.6]; p<0.001) and the subgroup of IBD patients (n=280) without any treatment or on aminosalicylates only (median OD 1.72 [IQR 1.0-4.1]; p<0.001). CONCLUSIONS: Although most IBD patients showed seropositivity after COVID-19 vaccines, the magnitude of the humoral response was significantly lower than in HCs. Differently from other studies, these findings seem to be mostly unrelated to the use of immune-modifying treatments (ClinicalTrials.govID:NCT04769258).
Subject(s)
Aminosalicylic Acid , COVID-19 , Inflammatory Bowel Diseases , Humans , COVID-19 Vaccines , Prospective Studies , COVID-19/prevention & control , Antibodies, Viral , Inflammatory Bowel Diseases/drug therapyABSTRACT
BACKGROUND AND AIMS: The purpose of this study was to present data on the safety of anti- severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in a cohort of inflammatory bowel disease (IBD) patients of an ongoing multicenter study (ESCAPE-IBD) sponsored by the Italian Group for the study of Inflammatory Bowel Disease (ClinicalTrials.gov Identifier: NCT04769258). METHODS: Anti-SARS-CoV-2 vaccination was administrated to 809 IBD patients. Interviews were conducted to report adverse events related to vaccination. Of these 809, 346 patients were surveyed on the pandemic burden and the main reason for hesitancy in coronavirus disease 2019 vaccination. The chi-square test was used to compare categorical variables. Logistic regression was used to assess the relationship between disease-related characteristics and the onset of adverse events. RESULTS: About 45% of patients had at least one side effect, following the first dose (10%), the second (15%), and both doses (19%). All the adverse events were mild and lasted only a few days. Logistic regression analysis revealed that female sex ( P â <â 0.001), younger age ( P â =â 0.001), seroconversion ( P â =â 0.002), and comorbidity ( P â <â 0.001) were significantly associated with adverse events. The survey showed that the main concerns were the possibility of adverse event (33%). Almost all patients (99%) felt safer having been vaccinated at their IBD reference center. CONCLUSION: The vaccine reactions experienced in IBD patients were mostly self-limited. We found high acceptance and good safety of SARS-CoV-2 vaccination in our cohort.
Subject(s)
COVID-19 , Drug-Related Side Effects and Adverse Reactions , Inflammatory Bowel Diseases , Humans , Female , COVID-19/epidemiology , COVID-19/prevention & control , SARS-CoV-2 , Pandemics , Inflammatory Bowel Diseases/drug therapy , Inflammatory Bowel Diseases/epidemiology , Vaccination/adverse effectsABSTRACT
Inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are life-long disorders characterized by the chronic relapsing inflammation of the gastrointestinal tract with the intermittent need for escalation treatment and, eventually, even surgery. The total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is the surgical intervention of choice in subjects affected by ulcerative colitis (UC). Although IPAA provides satisfactory functional outcomes, it can be susceptible to some complications, including pouchitis as the most common. Furthermore, 10-20% of the pouchitis may develop into chronic pouchitis. The etiology of pouchitis is mostly unclear. However, the efficacy of antibiotics in pouchitis suggests that the dysbiosis of the IPAA microbiota plays an important role in its pathogenesis. We aimed to review the role of the microbiota in the pathogenesis and as a target therapy in subjects who develop pouchitis after undergoing the surgical intervention of total proctocolectomy with IPAA reconstruction.
Subject(s)
Colitis, Ulcerative , Microbiota , Pouchitis , Proctocolectomy, Restorative , Anastomosis, Surgical/adverse effects , Colitis, Ulcerative/complications , Colitis, Ulcerative/surgery , Humans , Pouchitis/etiology , Pouchitis/therapy , Proctocolectomy, Restorative/adverse effectsABSTRACT
Although angiogenesis is viewed as a fundamental component of inflammatory bowel disease (IBD) pathogenesis, we presently lack a thorough knowledge of the cell type(s) involved in its induction and maintenance in the inflamed intestinal mucosa. This study aimed to determine whether platelet (PLT) adhesion to inflamed intestinal endothelial cells of human origin may favour angiogenesis. Unstimulated or thrombin-activated human PLT were overlaid on resting or tumour necrosis factor (TNF)-α-treated human intestinal microvascular endothelial cells (HIMEC), in the presence or absence of blocking antibodies to either vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, integrin α(v)ß(3) , tissue factor (TF) or fractalkine (FKN). PLT adhesion to HIMEC was evaluated by fluorescence microscopy, and release of angiogenic factors (VEGF and soluble CD40L) was measured by ELISA. A matrigel tubule formation assay was used to estimate PLT capacity to induce angiogenesis after co-culturing with HIMEC. TNF-α up-regulated ICAM-1, α(v)ß(3) and FKN expression on HIMEC. When thrombin-activated PLT were co-cultured with unstimulated HIMEC, PLT adhesion increased significantly, and this response was further enhanced by HIMEC activation with TNF-α. PLT adhesion to HIMEC was VCAM-1 and TF independent but ICAM-1, FKN and integrin α(v)ß(3) dependent. VEGF and sCD40L were undetectable in HIMEC cultures either before or after TNF-α stimulation. By contrast, VEGF and sCD40L release significantly increased when resting or activated PLT were co-cultured with TNF-α-pre-treated HIMEC. These effects were much more pronounced when PLT were derived from IBD patients. Importantly, thrombin-activated PLT promoted tubule formation in HIMEC, a functional estimate of their angiogenic potential. In conclusion, PLT adhesion to TNF-α-pre-treated HIMEC is mediated by ICAM-1, FKN and α(v)ß(3) , and is associated with VEGF and sCD40L release. These findings suggest that inflamed HIMEC may recruit PLT which, upon release of pro-angiogenic factors, actively contribute to inflammation-induced angiogenesis.
Subject(s)
Blood Platelets/metabolism , Endothelial Cells/metabolism , Microvessels/metabolism , Platelet Adhesiveness/physiology , Blood Platelets/cytology , CD40 Ligand/metabolism , Cells, Cultured , Chemokine CX3CL1/metabolism , Coculture Techniques , Endothelial Cells/drug effects , Endothelial Cells/pathology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Inflammation/metabolism , Inflammation/pathology , Inflammation/physiopathology , Inflammatory Bowel Diseases/metabolism , Inflammatory Bowel Diseases/pathology , Inflammatory Bowel Diseases/physiopathology , Integrin alphaVbeta3/metabolism , Intercellular Adhesion Molecule-1/metabolism , Intestines/blood supply , Intestines/pathology , Male , Microscopy, Fluorescence , Microvessels/pathology , Neovascularization, Pathologic/physiopathology , Thromboplastin/metabolism , Tumor Necrosis Factor-alpha/pharmacology , Vascular Cell Adhesion Molecule-1/metabolism , Vascular Endothelial Growth Factor A/metabolismABSTRACT
OBJECTIVES: Inflammation-driven angiogenesis contributes to the pathogenesis of inflammatory bowel disease (IBD). In line with this, the efficacy of inhibitors of angiogenesis has been demonstrated in experimental models of colitis. Currently, the ability of infliximab, an anti-tumor necrosis factor-α (TNF-α) agent that is highly beneficial in patients with IBD, to affect mucosal angiogenesis in patients with Crohn's disease (CD) and ulcerative colitis (UC) is unknown. METHODS: Patients with active CD (n=14) were treated with infliximab for 1 year, and peripheral blood and intestinal mucosa samples were collected before and after treatment. Mucosal angiogenesis was evaluated by CD31 and Ki-67 staining in endoscopic biopsies at baseline (week 0) and at week 54. The release of vascular endothelial growth factor-A (VEGF-A) by cultured mucosal extracts was measured by enzyme-linked immunosorbent assay (ELISA), before and after administration of infliximab, as well as in cultures of human intestinal fibroblasts (HIFs) stimulated with TNF-α in the presence or absence of infliximab. Migration of human intestinal microvascular endothelial cells (HIMECs) was investigated by migration assays. RESULTS: Microvessel density was significantly higher in the mucosa from patients with CD compared with tissue from healthy control individuals. Of the 14 patients, 8 (57%) showed a clinical remission in response to infliximab, which was associated with a significant reduction of microvascular density. Morphometric vessel analysis further confirmed the significant reduction of the area of vascular section after administration of infliximab. Furthermore, the expression levels of the proliferation marker Ki-67 in endothelial cells were significantly reduced after treatment. The mucosal concentration of VEGF-A was also significantly decreased, whereas in vitro exposure of HIF to infliximab virtually abolished TNF-α-induced VEGF-A production. These phenomena did not occur in patients who showed no clinical response to infliximab. CONCLUSIONS: Administration of infliximab downregulates mucosal angiogenesis in patients with CD and restrains production of VEGF-A by mucosal fibroblasts. It is proposed that this ameliorates inflammation-driven angiogenesis in the gut mucosa and contributes to the therapeutic efficacy of blockade of TNF-α.
Subject(s)
Angiogenesis Inhibitors/therapeutic use , Antibodies, Monoclonal/therapeutic use , Crohn Disease/drug therapy , Intestinal Mucosa/drug effects , Neovascularization, Pathologic/prevention & control , Adult , Blood Vessels/pathology , Cell Movement/drug effects , Crohn Disease/complications , Crohn Disease/pathology , Crohn Disease/physiopathology , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Female , Fibroblasts/metabolism , Humans , Infliximab , Intestinal Mucosa/blood supply , Ki-67 Antigen/drug effects , Male , Microcirculation/drug effects , Middle Aged , Neovascularization, Pathologic/etiology , Tumor Necrosis Factor-alpha/metabolism , Vascular Endothelial Growth Factor A/antagonists & inhibitors , Vascular Endothelial Growth Factor A/biosynthesis , Young AdultABSTRACT
BACKGROUND AND AIMS: Inflammatory CC chemokines have long been associated with cancer, but unequivocal evidence of a role in clinically relevant models of carcinogenesis is lacking. D6, a promiscuous decoy receptor that scavenges inflammatory CC chemokines, plays a non-redundant role in reducing the inflammatory response in various organs. As inflammation is a key player in the development of inflammatory bowel disease (IBD) and IBD-associated colorectal cancer, we investigated D6 expression in human colitis and colon cancer, and its role in experimental colitis and inflammation-associated colon cancer. RESULTS: In humans, D6 was mainly expressed by lymphatic vessels and leukocytes in the mucosa of individuals with IBD and colon cancer, as well as the mucosa of control individuals. Mice lacking expression of D6 were significantly more susceptible to experimental colitis than wild-type mice and failed to resolve colitis, with significantly higher levels of several pro-inflammatory chemokines. In bone marrow chimeric mice, the ability of D6 to regulate colitis was tracked to the stromal/lymphatic compartment, with no contribution of haemopoietic cells. Finally, after administration of the carcinogen azoxymethane, D6(-/-) mice showed increased susceptibility to colitis-associated cancer in the distal segment of the colon compared with wild-type mice. CONCLUSIONS: D6 expressed on lymphatic vessels plays a key role in the control of intestinal inflammation and the development of inflammation-associated colon cancer. Our results reveal a new unexpected role for the lymphatic system in the pathogenesis of IBD and intestinal cancer, and candidate chemokines as novel players in tumour promotion and progression.
Subject(s)
Colonic Neoplasms/metabolism , Inflammatory Bowel Diseases/metabolism , Lymphatic Vessels/metabolism , Receptors, CCR10/physiology , Animals , Cell Transformation, Neoplastic/metabolism , Cell Transformation, Neoplastic/pathology , Chemokines/biosynthesis , Chemotaxis, Leukocyte , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/pathology , Colitis, Ulcerative/physiopathology , Colon/metabolism , Colonic Neoplasms/etiology , Colonic Neoplasms/pathology , Colonoscopy/methods , Disease Progression , Disease Susceptibility , Endothelial Cells/metabolism , Humans , Inflammation Mediators/metabolism , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/pathology , Intestinal Mucosa/metabolism , Leukocytes/pathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Organ Culture Techniques , Receptors, CCR10/deficiency , Receptors, CCR10/metabolism , Chemokine Receptor D6ABSTRACT
Microsatellite instability (MSI) is the landmark feature of DNA mismatch repair deficiency, which can be found in 15-20% of all colorectal cancers (CRC). This specific set of tumors has been initially perceived as a niche for geneticists or gastroenterologists focused on inherited predispositions. However, over the years, MSI has established itself as a key biomarker for the diagnosis, then extending to forecasting the disease behavior and prognostication, including the prediction of responsiveness to immunotherapy and eventually to kinase inhibitors, and possibly even to specific biological drugs. Thanks to the contribution of the characterization of MSI tumors, researchers have first acknowledged that a strong lymphocytic reaction is associated with a good prognosis. This understanding supported the prognostic implications in terms of the low metastatic potential of MSI-CRC and has led to modifications in the indications for adjuvant treatment. Furthermore, with the emergence of immunotherapy, this strong biomarker of responsiveness has exemplified the capability of re-activating an effective immune control by removing the brakes of immune evasion. Lately, a subset of MSI-CRC emerged as the ideal target for kinase inhibitors. This therapeutic scenario implies a paradox in which appropriate treatments for advanced disease are effective in a set of tumors that seldom evolve towards metastases.
ABSTRACT
The potential of endoscopic evaluation in the management of inflammatory bowel diseases (IBD) has undoubtedly grown over the last few years. When dealing with IBD patients, histological remission (HR) is now considered a desirable target along with symptomatic and endoscopic remission, due to its association with better long-term outcomes. Consequently, the ability of endoscopic techniques to reflect microscopic findings in vivo without having to collect biopsies has become of upmost importance. In this context, a more accurate evaluation of inflammatory disease activity and the detection of dysplasia represent two mainstay targets for IBD endoscopists. New diagnostic technologies have been developed, such as dye-less chromoendoscopy, endomicroscopy, and molecular imaging, but their real incorporation in daily practice is not yet well defined. Although dye-chromoendoscopy is still recommended as the gold standard approach in dysplasia surveillance, recent research questioned the superiority of this technique over new advanced dye-less modalities [narrow band imaging (NBI), Fuji intelligent color enhancement (FICE), i-scan, blue light imaging (BLI) and linked color imaging (LCI)]. The endoscopic armamentarium might also be enriched by new video capsule endoscopy for monitoring disease activity, and high expectations are placed on the application of artificial intelligence (AI) systems to reduce operator-subjectivity and inter-observer variability. The goal of this review is to provide an updated insight on contemporary knowledge regarding new endoscopic techniques and devices, with special focus on their role in the assessment of disease activity and colorectal cancer surveillance.
ABSTRACT
Inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are chronic inflammatory diseases of the gastrointestinal tract. In the last few years, the development of biological agents targeting cytokines and receptors involved in IBD pathogenesis has led to better outcomes and has improved the course of the disease. Despite their effectiveness, drugs such as tumor necrosis factor (TNF) inhibitors, anti-Interleukin-12/23 and anti-integrins, do not induce a response in about one-third of patients, and 40% of patients lose response over time. Therefore, more efficient therapies are required. Recent studies showed that TL1A (Tumor necrosis factor-like cytokine 1A) acts as a regulator of mucosal immunity and participates in immunological pathways involved in the IBD pathogenesis. In this review article, we analyze the role of TL1A as a new potential target therapy in IBD patients.