Functional gastrointestinal disorders are highly prevalent conditions affecting at least 30-40% of the western population. These disorders are characterized by occurrence of digestive symptoms in the absence of any identifiable organic cause. Mostly, functional abnormalities involve gastrointestinal motility and/or sensitivity, with a broad spectrum of symptoms severity. Several factors should be then considered to address the impact of the different gastrointestinal disorders: chronic idiopathic intestinal pseudo-obstruction for the severe prognosis, esophageal achalasia for the marked impact of patients'quality life, functional dyspepsia and irritable bowel syndrome for the high prevalence and the involvement of economic resources. Functional and/or structural damage of the enteric nervous system with its glial component seems likely to be a common trademark in each of these syndromes. Although the pathophysiological mechanisms underlying the damage of the enteric neuronal network are still not well defined, it has been recently proposed that functional gastrointestinal disorders may be secondary to transient infection of the digestive system. In keeping with this, different infectious agents may either directly, or through the activation of the immune system, alter the enteric nervous system and or gastrointestinal muscle with impaired motility, sensitivity or secretion and symptoms onset. Moreover, it should be noted that host response to infection is genetically determined, and thus it is possible that individual genetic determinants can be also involved. The general aim of the present research proposal is to study the pathophysiological mechanisms, the biomolecular aspects and the genetic determinants underlying post-infectious functional gastrointestinal disorders. Specifically, individual research units will collaborate in order to address: A) in an animal model of Herpes Simplex 1 virus (HSV-1) infection of the enteric neurons: i) the effect of neurotoxic agents, stress or high dose steroids on HSV-1 reactivation; ii) the correlation between HSV-1 reactivation in the enteric nervous system and the impairment of gastrointestinal motility; B) in an in vitro model of primary culture of human smooth muscle cells: i) the effect of bacterial products on cells contractility; ii) the mechanisms involved in bacterial products cells recognition's trough the analysis of Toll-Like Receptors (TLRs); iii) the intracellular effect of TLRs activation and its correlation with cell contractility; C) in patients with esophageal achalasia: i) the characterization of lymphocytes infiltrating the lower esophageal sphincter; ii) the specific viral epitopes involved in lymphocytes activation; D) in patients with post-infectious dyspepsia: i) mucosal inducible Nitric Oxide Synthase (iNOS) expression, the relative nitric oxide (NO) production and its association with impaired gastric sensitivity and motility and dyspeptic symptoms; ii) the role of enteric glia in NO production; E) the impact of HSV-1 infection and other neurotropic viruses in the enteric nervous system of patients with severe dysmotility related to an underlying neuropathy, such as intestinal pseudoobstruction; F) the role of intestinal inflammation in the pathophysiology of visceral hypersensitivity in patients with post-infectious irritable bowel syndrome; G) the association between the iNOS gene promoter polymorphisms and esophageal achalasia and post-infectious dyspepsia.

La dispepsia post-infettiva: evoluzione sintomatologica- funzionale, predisposizione genetica, ruolo dell'Ossido Nitrico Sintetasi inducibile e coinvolgimento della glia entererica.

CUOMO, ROSARIO;SARNELLI, GIOVANNI;DE GIORGI, FRANCESCO;SAVARESE, MARIA FLAVIA
2007

Abstract

Functional gastrointestinal disorders are highly prevalent conditions affecting at least 30-40% of the western population. These disorders are characterized by occurrence of digestive symptoms in the absence of any identifiable organic cause. Mostly, functional abnormalities involve gastrointestinal motility and/or sensitivity, with a broad spectrum of symptoms severity. Several factors should be then considered to address the impact of the different gastrointestinal disorders: chronic idiopathic intestinal pseudo-obstruction for the severe prognosis, esophageal achalasia for the marked impact of patients'quality life, functional dyspepsia and irritable bowel syndrome for the high prevalence and the involvement of economic resources. Functional and/or structural damage of the enteric nervous system with its glial component seems likely to be a common trademark in each of these syndromes. Although the pathophysiological mechanisms underlying the damage of the enteric neuronal network are still not well defined, it has been recently proposed that functional gastrointestinal disorders may be secondary to transient infection of the digestive system. In keeping with this, different infectious agents may either directly, or through the activation of the immune system, alter the enteric nervous system and or gastrointestinal muscle with impaired motility, sensitivity or secretion and symptoms onset. Moreover, it should be noted that host response to infection is genetically determined, and thus it is possible that individual genetic determinants can be also involved. The general aim of the present research proposal is to study the pathophysiological mechanisms, the biomolecular aspects and the genetic determinants underlying post-infectious functional gastrointestinal disorders. Specifically, individual research units will collaborate in order to address: A) in an animal model of Herpes Simplex 1 virus (HSV-1) infection of the enteric neurons: i) the effect of neurotoxic agents, stress or high dose steroids on HSV-1 reactivation; ii) the correlation between HSV-1 reactivation in the enteric nervous system and the impairment of gastrointestinal motility; B) in an in vitro model of primary culture of human smooth muscle cells: i) the effect of bacterial products on cells contractility; ii) the mechanisms involved in bacterial products cells recognition's trough the analysis of Toll-Like Receptors (TLRs); iii) the intracellular effect of TLRs activation and its correlation with cell contractility; C) in patients with esophageal achalasia: i) the characterization of lymphocytes infiltrating the lower esophageal sphincter; ii) the specific viral epitopes involved in lymphocytes activation; D) in patients with post-infectious dyspepsia: i) mucosal inducible Nitric Oxide Synthase (iNOS) expression, the relative nitric oxide (NO) production and its association with impaired gastric sensitivity and motility and dyspeptic symptoms; ii) the role of enteric glia in NO production; E) the impact of HSV-1 infection and other neurotropic viruses in the enteric nervous system of patients with severe dysmotility related to an underlying neuropathy, such as intestinal pseudoobstruction; F) the role of intestinal inflammation in the pathophysiology of visceral hypersensitivity in patients with post-infectious irritable bowel syndrome; G) the association between the iNOS gene promoter polymorphisms and esophageal achalasia and post-infectious dyspepsia.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/304432
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