Inflammatory bowel disease （IBD） arises from disruption of immune tolerance to the gut commensal microbiota, leading to chronic intestinal inflammation and mucosal damage in genetically predisposed hosts. In healthy...Inflammatory bowel disease （IBD） arises from disruption of immune tolerance to the gut commensal microbiota, leading to chronic intestinal inflammation and mucosal damage in genetically predisposed hosts. In healthy individuals the intestinal microbiota have a symbiotic relationship with the host organism and possess important and unique functions, including a metabolic function （i.e. digestion of dietary compounds and xenobiotics, fermentation of undigestible carbohydrates with production of short chain fatty acids）, a mucosal barrier function （i.e. by inhibiting pathogen invasion and strengthening epithelial barrier integrity）, and an immune modula- tory function （i.e. mucosal immune system priming and maintenance of intestinal epithelium homeostasis）. A fine balance regulates the mechanism that allows co- existence of mammals with their commensal bacteria. In IBD this mechanism of immune tolerance is impaired because of several potential causative factors. The gut microbiota composition and activity of IBD patients are abnormal, with a decreased prevalence of dominant members of the human commensal microbiota （i.e. Clostridium IXa and IV groups, Bacteroides, bifldobacteria） and a concomitant increase in detrimental bacteria （i.e. sulphate-reducing bacteria, Escherichia coll. The observed dysbiosis is concomitant with defectiveinnate immunity and bacterial killing （i.e. reduced mucosal defensins and IgA, malfunctioning phagocytosis） and overaggressive adaptive immune response （due to ineffective regulatory T cells and antigen presenting cells）, which are considered the basis of IBD pathogen- esis. However, we still do not know how the interplay between these parameters causes the disease. Studies looking at gut microbial composition, epithelial integrity and mucosal immune markers in genotyped IBD populations are therefore warranted to shed light on this obscure pathogenesis.展开更多
Inflammation and coagulation constantly influence each other and are constantly in balance.Emerging evidence supports this statement in acute inflammatory diseases,such as sepsis,but it also seems to be very important...Inflammation and coagulation constantly influence each other and are constantly in balance.Emerging evidence supports this statement in acute inflammatory diseases,such as sepsis,but it also seems to be very important in chronic inflammatory settings,such as inflammatory bowel disease(IBD).Patients with Crohn's disease and ulcerative colitis have an increased risk of thromboembolic events,and several abnormalities concerning coagulation components occur in the endothelial cells of intestinal vessels,where most severe inflammatory abnormalities occur.The aims of this review are to update and classify the type of coagulation system abnormalities in IBD,and analyze the strict and delicate balance between coagulation and inflammation at the mucosal level.Recent studies on possible therapeutic applications arising from investigations on coagulation abnormalities associated with IBD pathogenesis will also be briefly presented and critically reviewed.展开更多
NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily.It was originally considered to be essential in the generation and maintenance of dopaminergic neurons,and associated with n...NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily.It was originally considered to be essential in the generation and maintenance of dopaminergic neurons,and associated with neurological disorders such as Parkinson's disease.Recently,NR4A2 has been found to play a critical role in some inflammatory diseases and cancer.NR4A2 can be efficiently trans-activated by some proinflammatory cytokines,such as tumor necrosis factor-α,interleukin-1β,and vascular endothelial growth factor(VEGF).The nuclear factor-κB signaling pathway serves as a principal regulator of inducible NR4A expression in immune cells.NR4A2 can trans-activate Foxp3,a hallmark specifically expressed in regulatory T(Treg) cells,and plays a critical role in the differentiation,maintenance,and function of Treg cells.NR4A2 in T lymphocytes is pivotal for Treg cell induction and suppression of aberrant induction of Th1 under physiological and pathological conditions.High density of Foxp3 + Treg cells is significantly associated with gastrointestinal inflammation,tumor immune escape,and disease progression.NR4A2 is produced at high levels in CD133 + colorectal carcinoma(CRC) cells and significantly upregulated by cyclooxygenase-2-derived prostaglandin E 2 in a cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA)-dependent manner in CRC cells.The cAMP/PKA signaling pathway is the common pathway of NR4A2-related inflammation and cancer.NR4A2 trans-activates osteopontin,a direct target of the Wnt/β-catenin pathway associated with CRC invasion,metastasis,and poor prognosis.Knockdown of endogenous NR4A2 expression attenuates VEGF-induced endothelial cell proliferation,migration and in vivo angiogenesis.Taken together,NR4A2 emerges as an important nuclear factor linking gastrointestinal inflammation and cancer,especially CRC,and should serve as a candidate therapeutic target for inflammation-related gastrointestinal cancer.展开更多
Disturbance of the inflammatory response in the gut is important in several clinical diseases ranging from inflmmatory bowel disease to postoperative ileus. Several feedback mechanisms exist that control the inflammat...Disturbance of the inflammatory response in the gut is important in several clinical diseases ranging from inflmmatory bowel disease to postoperative ileus. Several feedback mechanisms exist that control the inflammatory cascade and avoid collateral damage. In the gast rointestinal tract, it is of particular importance tocontrol the immune response to maintain the balance that allows dietary up take and utilization of nutrientson one hand, while preventing invasion of bacteria and toxins on the other hand. The process of digestion and absorption of nutrients requires a relative hyporesponsiveness of the immune cells in the gut to luminacontents which is not yet fully understood. Recentlythe autonomic nervous system has been identifi ed asan important pathway to control local and systemic inflammation and gut barrier integrity. Activation of thepathway is possible via electrical or via pharm acological interventions, but is also achieved in a physiologicamanner by ingestion of dietary lipids. Administration of dietary lipids has been shown to be very effectivein reducing the inflammatory cascade and maintaining intestinal barrier integrity in several experimental studies. This beneficial effect of nutrition on the inflammatory response and intestinal barrier integrity opens new therapeutic opportunities for treatment of certain gastrointestinal disorders. Furthermore, this neural feedback mechanism provides more insight in the relative hyporesponsiveness of the immune cells in the gut. Here, we will discuss the regulatory function of the autonomic nervous system on the inflammatory response and gut barrier function and the potential benefit in a clinical setting.展开更多
文摘Inflammatory bowel disease （IBD） arises from disruption of immune tolerance to the gut commensal microbiota, leading to chronic intestinal inflammation and mucosal damage in genetically predisposed hosts. In healthy individuals the intestinal microbiota have a symbiotic relationship with the host organism and possess important and unique functions, including a metabolic function （i.e. digestion of dietary compounds and xenobiotics, fermentation of undigestible carbohydrates with production of short chain fatty acids）, a mucosal barrier function （i.e. by inhibiting pathogen invasion and strengthening epithelial barrier integrity）, and an immune modula- tory function （i.e. mucosal immune system priming and maintenance of intestinal epithelium homeostasis）. A fine balance regulates the mechanism that allows co- existence of mammals with their commensal bacteria. In IBD this mechanism of immune tolerance is impaired because of several potential causative factors. The gut microbiota composition and activity of IBD patients are abnormal, with a decreased prevalence of dominant members of the human commensal microbiota （i.e. Clostridium IXa and IV groups, Bacteroides, bifldobacteria） and a concomitant increase in detrimental bacteria （i.e. sulphate-reducing bacteria, Escherichia coll. The observed dysbiosis is concomitant with defectiveinnate immunity and bacterial killing （i.e. reduced mucosal defensins and IgA, malfunctioning phagocytosis） and overaggressive adaptive immune response （due to ineffective regulatory T cells and antigen presenting cells）, which are considered the basis of IBD pathogen- esis. However, we still do not know how the interplay between these parameters causes the disease. Studies looking at gut microbial composition, epithelial integrity and mucosal immune markers in genotyped IBD populations are therefore warranted to shed light on this obscure pathogenesis.
基金Supported by Italian Ministry of University,No. PRIN-2007Catholic University School of Medicine,No. Linea D1-2009
文摘Inflammation and coagulation constantly influence each other and are constantly in balance.Emerging evidence supports this statement in acute inflammatory diseases,such as sepsis,but it also seems to be very important in chronic inflammatory settings,such as inflammatory bowel disease(IBD).Patients with Crohn's disease and ulcerative colitis have an increased risk of thromboembolic events,and several abnormalities concerning coagulation components occur in the endothelial cells of intestinal vessels,where most severe inflammatory abnormalities occur.The aims of this review are to update and classify the type of coagulation system abnormalities in IBD,and analyze the strict and delicate balance between coagulation and inflammation at the mucosal level.Recent studies on possible therapeutic applications arising from investigations on coagulation abnormalities associated with IBD pathogenesis will also be briefly presented and critically reviewed.
基金Supported by National Natural Science Foundation of China, No.81025015,30921006,91129301
文摘NR4A2 is a transcription factor belonging to the steroid orphan nuclear receptor superfamily.It was originally considered to be essential in the generation and maintenance of dopaminergic neurons,and associated with neurological disorders such as Parkinson's disease.Recently,NR4A2 has been found to play a critical role in some inflammatory diseases and cancer.NR4A2 can be efficiently trans-activated by some proinflammatory cytokines,such as tumor necrosis factor-α,interleukin-1β,and vascular endothelial growth factor(VEGF).The nuclear factor-κB signaling pathway serves as a principal regulator of inducible NR4A expression in immune cells.NR4A2 can trans-activate Foxp3,a hallmark specifically expressed in regulatory T(Treg) cells,and plays a critical role in the differentiation,maintenance,and function of Treg cells.NR4A2 in T lymphocytes is pivotal for Treg cell induction and suppression of aberrant induction of Th1 under physiological and pathological conditions.High density of Foxp3 + Treg cells is significantly associated with gastrointestinal inflammation,tumor immune escape,and disease progression.NR4A2 is produced at high levels in CD133 + colorectal carcinoma(CRC) cells and significantly upregulated by cyclooxygenase-2-derived prostaglandin E 2 in a cyclic adenosine monophosphate(cAMP)/protein kinase A(PKA)-dependent manner in CRC cells.The cAMP/PKA signaling pathway is the common pathway of NR4A2-related inflammation and cancer.NR4A2 trans-activates osteopontin,a direct target of the Wnt/β-catenin pathway associated with CRC invasion,metastasis,and poor prognosis.Knockdown of endogenous NR4A2 expression attenuates VEGF-induced endothelial cell proliferation,migration and in vivo angiogenesis.Taken together,NR4A2 emerges as an important nuclear factor linking gastrointestinal inflammation and cancer,especially CRC,and should serve as a candidate therapeutic target for inflammation-related gastrointestinal cancer.
文摘Disturbance of the inflammatory response in the gut is important in several clinical diseases ranging from inflmmatory bowel disease to postoperative ileus. Several feedback mechanisms exist that control the inflammatory cascade and avoid collateral damage. In the gast rointestinal tract, it is of particular importance tocontrol the immune response to maintain the balance that allows dietary up take and utilization of nutrientson one hand, while preventing invasion of bacteria and toxins on the other hand. The process of digestion and absorption of nutrients requires a relative hyporesponsiveness of the immune cells in the gut to luminacontents which is not yet fully understood. Recentlythe autonomic nervous system has been identifi ed asan important pathway to control local and systemic inflammation and gut barrier integrity. Activation of thepathway is possible via electrical or via pharm acological interventions, but is also achieved in a physiologicamanner by ingestion of dietary lipids. Administration of dietary lipids has been shown to be very effectivein reducing the inflammatory cascade and maintaining intestinal barrier integrity in several experimental studies. This beneficial effect of nutrition on the inflammatory response and intestinal barrier integrity opens new therapeutic opportunities for treatment of certain gastrointestinal disorders. Furthermore, this neural feedback mechanism provides more insight in the relative hyporesponsiveness of the immune cells in the gut. Here, we will discuss the regulatory function of the autonomic nervous system on the inflammatory response and gut barrier function and the potential benefit in a clinical setting.
