Infliximab Restores the Dysfunctional Matrix Remodeling Protein and Growth Factor Gene Expression in Patients with Inflammatory Bowel Disease

Bruyn, Magali de; Machiels, Kathleen; Vandooren, Jennifer; Lemmens, Bart; Lommel, Leentje Van; Breynaert, Christine; Goten, Jan Van der; Staelens, Dominiek; Billiet, Thomas; Hertogh, Gert De; Ferrante, Marc; Assche, Gert Van; Vermeire, Séverine; Opdenakker, Ghislain; Schuit, Frans; Rutgeerts, Paul; Arijs, Ingrid

doi:10.1097/01.mib.0000438430.15553.90

Cited by 38 publications

(38 citation statements)

References 40 publications

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“…Arjis et al showed restoration of abberant mucosal function by infliximab. 33 The ability to potentially quantitate mucosal disturbance would allow for evaluation of all patients with quantitative measurements, and as mucosal healing is now an established important endpoint, using a “treat-to-target” paradigm, biopsy procurement is very feasible. 34 …”

Section: Discussionmentioning

confidence: 99%

Molecular Patterns in Human Ulcerative Colitis and Correlation with Response to Infliximab

Halloran

Chang

Shih

et al. 2014

Inflammatory Bowel Diseases

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Objective As a T cell-mediated disease of the colonic epithelium, ulcerative colitis (UC) is likely to share pathogenic elements with other T cell-mediated inflammatory diseases. Recently microarray analysis revealed large scale molecular changes in T cell-mediated rejection (TCMR) of kidney and heart transplants. We hypothesized that similar disturbances might be operating in UC and could provide insights into responsiveness to therapy. Methods We studied 56 colon biopsies from patients with colitis characterizing the clinical and histological features and using microarrays to defined the mRNA phenotype. We expressed the microarray results using previously defined pathogenesis-based transcript sets (PBTs). We also studied 48 published microarray files from human colon biopsies downloaded from the Gene Expression Omnibus (GEO) database, classified by response to infliximab therapy, to examine if the molecular measurements derived from our studies correlated with non-responsiveness to treatment. Results UC biopsies manifested coordinate transcript changes resembling rejecting transplants, with effector T cell, IFNG-induced, macrophage, and injury transcripts increasing while parenchymal transcripts decreased. The disturbance in gene expression, summarized as principal component 1 (PC1), correlated with conventional clinical and histologic assessments. When assessed in microarray results from published studies, the disturbance (PC1) predicted response to infliximab: patients with intense disturbance did not achieve clinical response, although quantitative improvement was seen even in many clinical non-responders. Similar changes were seen in Crohn's colitis. Conclusions The molecular phenotype of UC manifests a large scale coordinate disturbance reflecting changes in inflammatory cells and parenchymal elements that correlates with conventional features and predicts response to infliximab.

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Section: Discussionmentioning

confidence: 99%

Molecular Patterns in Human Ulcerative Colitis and Correlation with Response to Infliximab

Halloran

Chang

Shih

et al. 2014

Inflammatory Bowel Diseases

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“…2 ADAMDEC1, first identified in 1997, is the sole member of a subsidiary class of the ADAM family. 1 It has been linked to a number of inflammatory diseases including atherosclerosis, 3 pulmonary sarcoidosis, 4 osteoarthritis, 5,6 Crohn’s disease, 7,8 and to gastrointestinal [GI] malignancies–gastric adenocarcinoma 9, 10 and colorectal cancer. 11, 12 The physiological role of ADAMDEC1 remains to be determined.…”

Section: Introductionmentioning

confidence: 99%

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

O’Shea

Chew

Dunne

et al. 2016

ECCOJC

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Background and Aims:ADAM [A Disintegrin And Metalloproteinase] is a family of peptidase proteins which have diverse roles in tissue homeostasis and immunity. Here, we study ADAM-like DECysin-1 [ADAMDEC1] a unique member of the ADAM family. ADAMDEC1 expression is restricted to the macrophage/dendritic cell populations of the gastrointestinal tract and secondary lymphoid tissue. The biological function of ADAMDEC1 is unknown but it has been hypothesised to play a role in immunity. The identification of reduced ADAMDEC1 expression in Crohn’s disease patients has provided evidence of a potential role in bowel inflammation.Methods:Adamdec1-/- mice were exposed to dextran sodium sulphate or infected orally with Citrobacter rodentium or Salmonella typhimurium. The clinical response was monitored.Results:The loss of Adamdec1 rendered mice more susceptible to the induction of bacterial and chemical induced colitis, as evidenced by increased neutrophil infiltration, greater IL-6 and IL-1β secretion, more weight loss and increased mortality. In the absence of Adamdec1, greater numbers of Citrobacter rodentium were found in the spleen, suggestive of a breakdown in mucosal immunity which resulted in bacteraemia.Conclusion:In summary, ADAMDEC1 protects the bowel from chemical and bacterial insults, failure of which may predispose to Crohn’s disease.

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“…34 Of note, one of the mechanisms by which infliximab, an anti-TNF-a monoclonal antibody, may reduce inflammation in human inflammatory bowel disease is through reduction in MMP levels. 35 The same molecular mechanisms apply in the case of wound healing in ulcer disease. The action of sucralfate goes beyond simply supplementing the mucosal barrier of the gastric epithelium and includes stabilizing acid and base (a and b)-FGF and preventing their degradation.…”

Section: Other Small Moleculesmentioning

confidence: 95%

Nutritional Aspects of Gastrointestinal Wound Healing

Mukherjee

Kavalukas

Barbul

2016

Advances in Wound Care

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Significance: Although the wound healing cascade is similar in many tissues, in the gastrointestinal tract mucosal healing is critical for processes such as inflammatory bowel disease and ulcers and healing of the mucosa, submucosa, and serosal layers is needed for surgical anastomoses and for enterocutaneous fistula. Failure of wound healing can result in complications including infection, prolonged hospitalization, critical illness, organ failure, readmission, new or worsening enterocutaneous fistula, and even death. Recent Advances: Recent advances are relevant for the role of specific micronutrients, such as vitamin D, trace elements, and the interplay between molecules with pro-and antioxidant properties. Our understanding of the role of other small molecules, genes, proteins, and macronutrients is also rapidly changing. Recent work has elucidated relationships between oxidative stress, nutritional supplementation, and glucose metabolism. Thresholds have also been established to define adequate preoperative nutritional status. Critical Issues: Further work is needed to establish standards and definitions for measuring the extent of wound healing, particularly for inflammatory bowel disease and ulcers. In addition, a mounting body of evidence has determined the need for adequate preoperative nutritional supplementation for elective surgical procedures. Future Directions: A large portion of current work is restricted to model systems in rodents. Therefore, additional clinical and translational research is needed in this area to promote gastrointestinal wound healing in humans, particularly those suffering from critical illness, patients with enterocutaneous fistula, inflammatory bowel disease, and ulcers, and those undergoing surgical procedures.

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Infliximab Restores the Dysfunctional Matrix Remodeling Protein and Growth Factor Gene Expression in Patients with Inflammatory Bowel Disease

Abstract: Our data suggest that suppression of inflammation results in the arrest of epithelial damage and subsequent mucosal healing. Therefore, the therapeutic potential of agents targeting MMPs or growth factors as primary therapy seems rather complex.

Cited by 38 publications

References 40 publications

Molecular Patterns in Human Ulcerative Colitis and Correlation with Response to Infliximab

Molecular Patterns in Human Ulcerative Colitis and Correlation with Response to Infliximab

Critical Role of the Disintegrin Metalloprotease ADAM-like Decysin-1 [ADAMDEC1] for Intestinal Immunity and Inflammation

Nutritional Aspects of Gastrointestinal Wound Healing

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