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Identifier 000402053
Title Ο ρόλος του λιπώδους ιστού στις ΙΦΕΝ και οι σηματοδοτικοί μηχανισμοί της ουσίας Π
Alternative Title The role of fat tissue in inflammatory bowel disease (IBD) and the signalling pathways of substance P
Author Σιδερή, Αριστέα
Reviewer Τσατσάνης, Χρήστος
Ποθουλάκης, Χαράλαμπος
Παπαδάκης, Κωνσταντίνος
Καρδάσης, Δημήτριος
Καραγιαννίδης, Ιορδάνης
Μπέρτιας, Γεώργιος
Σιδηρόπουλος, Πρόδρομος
Abstract Ulcerative colitis (UC) and Crohn’s disease (CD), collectively referred to as inflammatory bowel diseases (IBD), are distinct chronic gastrointestinal diseases with 20 new cases per 10,000 people at risk. IBD are multifactorial diseases that dramatically affect quality of life and have increased morbidity. Genetic factors, microbial and immunological factors interact to orchestrate the course and severity of IBD symptoms. IBD incidence is much higher in Western societies, leading to multiple hypotheses concerning the potential contribution of lifestyle and environmental influences in their pathophysiology. The vast majority of the available pharmacological therapies for IBD have important, and sometimes detrimental side effects (since they unselectively inhibit immune signaling pathways), whereas surgical approaches often do not offer final resolution of disease or have debilitating side effects. Evidently, the need for novel approaches aiming to discover different ways of treating IBD is pressing. One of the main changes of lifestyle in Western societies, where IBD are increased, is the prevalence of obesity—the epidemic of modern times. Obesity is a multifactorial and complicated disease that contributes to the development and progress of multiple cardiovascular and metabolic diseases and syndromes, including inflammation and cancer. Until recently, adipose tissue was considered to represent an energy storage compartment. Broad research in the field of obesity in recent years has shown that adipose tissue is a metabolically and endocrinologically active organ able to produce numerous hormones and cytokines (both pro-inflammatory and anti-inflammatory), named adipokines. It is now considered that obesity represents a constant sate of low-grade inflammation due to the increased production of adipokines from the hypertrophic, malfunctioning adipocytes and their precursors. Epidemiological studies link obesity with worse overall prognosis and shorter period between diagnosis and need of surgical intervention in CD patients. Other studies, however, failed to reproduce this association probably due to differences in the selection of patient groups. . Additionally, studies suggest that fat can affect function of other tissues via newly discovered processes. For example, preadipocytes are able to influence cancer cell differentiation by releasing various vesicle types carrying genetic material. The ability of adipose tissue to interact and influence neighboring tissues and distant organ physiology represents a new and unexplored field. Along these lines, IBD can serve as an ideal disease model for research of adipose tissue–organ interactions. Mesenteric, omental and peri-renal fat are some of the possible sources of signaling molecules on affected intestine during IBD. Of particular interest is the macroscopically increased mesenteric fat surrounding the affected intestine (“creeping” fat), which has been a hallmark of CD, as well as the mesenteric fat that hosts the majority of lymph nodes draining the intestine. Despite the anatomic proximity of the intestine with the surrounding adipose tissue and the commonly acknowledged presence of “creeping” fat in CD, the potential communication between adipose tissue and the intestine in IBD has not been examined. In this study, we assessed the role of substance P (SP) in modulating adipose tissue functions during IBD. SP is a neuropeptide expressed mainly in the central andperipheral nervous system, the enteric nervous system and the immune system (SP is involved in immune system regulation since both the peptide and its receptors are expressed by diverse immune cell populations). The involvement of SP in the pathophysiology of numerous diseases such as depression and inflammatory pain signaling, multiple inflammatory conditions, malignancies, cardiovascular diseases, skin disorders, irritable bowel syndrome, obesity and IBD has been well documented. Focusing on IBD, multiple studies with animal models, human tissues and cells show that SP can influence the disease course both at early and late stages. This influence involves modified expression of SP or the neurokinin receptor 1 (NK-1R) its high affinity receptor) in enteric tissues. More specifically, NK-1R is up-regulated in the intestine of patients with IBD, and even though NK-1R knockout mice have no apparent change in phenotype, they present with differential responses to colitis (either the TNBS or DSS model). SP and NK-1R knockout animals demonstrate improved colitis in the acute phase, but severe colitis deterioration during chronic colitis. Additionally, SP antagonists inhibit acute colitis induction. These studies clearly demonstrate the different roles of SP-NK-1R interactions in different stages of colitis. Regarding the role of SP in adipose tissue, recent publications indicate the presence of NK-1R in preadipocytes and the ability of SP to promote preadipocyte proliferation following NK-1R coupling. However, the role of SP on adipose tissue cells under chronic inflammation during IBD has not been examined. This study aims to elucidate new, adipose tissue-associated mechanisms and pathways that are important in determining IBD outcome. Utilizing multiple approaches, this study attempts to identify inflammatory molecules produced by the mesenteric adipose tissue and clarify the potential functions of these molecules on the enteric epithelium during inflammation. For this purpose, animal models of colitis and obesity, human tissue and cells isolated from patients with or without IBD, as well as colonic epithelial cell lines were utilized. This approach aims to identify novel molecules–mechanisms–pathways–systems–interactions, increase our understanding in IBD pathophysiology, and contribute to future targeted therapies against IBD, or against a broader spectrum of diseases where adipose tissue participates in their pathophysiology. We found that obese animals exhibit dramatically increased colitis phenotypes than lean animals. Weight loss, mortality, “creeping” fat accumulation were also associated with histological abnormalities observed in the colon of mice with colitis. At the molecular level, alterations of the cytokine expression in the colon as well as in the “creeping” fat of animals with colitis were observed, while some responses were most pronounced in obese animals. Colon and “creeping” fat also had differential inflammatory cell infiltrates in obese animals with colitis and the adiponectin (an important adipokine found to be up-regulated in the serum of IBD patients); the adiponectin receptor axis may play a major role in the generation of the different phenotypes. When mesenteric adipose tissue biopsies or isolated preadipocytes (from patients with or without IBD) were used, the results were in agreement with the observations made in the animal models. Interestingly, biopsies and isolated cells from non-IBD, UC and CD patients demonstrated differential adipokine secretion patterns, suggesting the potentialdisease-dependent effects of mesenteric adipose tissue in the pathophysiology of these diseases. Additionally, mesenteric adipose tissue supernatans were able to elicit disease-specific responses when transferred to colonic epithelial cells. Overall, our results provide the first evidence in the literature supporting the involvement of mesenteric adipose tissue in the pathophysiology of UC and the first to describe interactions of human adipose tissue-derived molecules on human colonic epithelial cells. The adiponectin–adiponectin receptor axis that was recognized to participate in colonic inflammation in animal experiments seems to be affected in IBD patients as well, as indicated in our experiments using adipose tissue and colonic biopsies. Furthermore, differential regulation of the SP-NK-1R system in human preadipocytes of IBD patients is also demonstrated in this study. As previously suggested, this regulation is disease-specific and seems to lead to the differential production of pro- and anti-inflammatory cytokines in preadipocytes in response to SP. Analysis of common and differential responses of UC and CD preadipocytes to SP also revealed that interleukin 17A (IL-17A) is the most notable common molecule to increase, and further analysis of human colonic biopsies shows that the receptor for IL-17Ais up-regulated in IBD patients compared to control biopsies. IL-17A has been investigated extensively in CD, and its production from adipose tissue is described for the first time in IBD. SP regulation of IL-17A expression has also been demonstrated in macrophages in a different study. In conclusion, novel potential systems and pathways involved in IBD are discovered. These pathways may lead to future potential pharmacological therapies for diseases like UC and CD, where there is only a very limited number of therapeutic approaches. The differences in mesenteric adipose tissue observed in IBD, regardless of whether they consist triggering factors or are secondary to nearby inflammation, suggest that adipose tissue may be an active participant in the pathophysiology of IBD.
Language English
Subject Adipose
Intestinal inflammation
Obesity
Preadipocytes
Εντερική φλεγμονή
Λιποκύτταρα
Παχυσαρκία
Issue date 2016-07-19
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/6/e/e/metadata-dlib-1470045890-231693-18656.tkl Bookmark and Share
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