title: Enteric Neuronal Damage, Intramuscular Denervation and Smooth Muscle Phenotype Changes as Mechanisms of Chagasic Megacolon: Evidence from a Long-Term Murine Model of Trypanosoma cruzi Infection.
abstract: We developed a novel murine model of long-term infection with Trypanosoma cruzi with the aim to elucidate the pathogenesis of megacolon and the associated adaptive and neuromuscular intestinal disorders. Our intent was to produce a chronic stage of the disease since the early treatment should avoid 100% mortality of untreated animals at acute phase. Treatment allowed animals to be kept infected and alive in order to develop the chronic phase of infection with low parasitism as in human disease. A group of Swiss mice was infected with the Y strain of T. cruzi. At the 11th day after infection, a sub-group was euthanized (acute-phase group) and another sub-group was treated with benznidazole and euthanized 15 months after infection (chronic-phase group). Whole colon samples were harvested and used for studying the histopathology of the intestinal smooth muscle and the plasticity of the enteric nerves. In the acute phase, all animals presented inflammatory lesions associated with intense and diffuse parasitism of the muscular and submucosa layers, which were enlarged when compared with the controls. The occurrence of intense degenerative inflammatory changes and increased reticular fibers suggests inflammatory-induced necrosis of muscle cells. In the chronic phase, parasitism was insignificant; however, the architecture of Aüerbach plexuses was focally affected in the inflamed areas, and a significant decrease in the number of neurons and in the density of intramuscular nerve bundles was detected. Other changes observed included increased thickness of the colon wall, diffuse muscle cell hypertrophy, and increased collagen deposition, indicating early fibrosis in the damaged areas. Mast cell count significantly increased in the muscular layers. We propose a model for studying the long-term (15 months) pathogenesis of Chagasic megacolon in mice that mimics the human disease, which persists for several years and has not been fully elucidated. We hypothesize that the long-term inflammatory process mediates neuronal damage and intramuscular and intramural denervation, leading to phenotypic changes in smooth muscle cells associated with fibrosis. These long-term structural changes may represent the basic mechanism for the formation of the Chagasic megacolon.
authors.affiliation: Departamento de Patologia Geral Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Camila França
authors.initials: CF
authors.lastname: Campos
authors.affiliation: Departamento de Ciências Biológicas/LAFEX, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Silvia Dantas
authors.initials: SD
authors.lastname: Cangussú
authors.affiliation: Departamento de Patologia Geral Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Ana Luiza Cassin
authors.initials: AL
authors.lastname: Duz
authors.affiliation: Departamento de Patologia Geral Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Christiane Teixeira
authors.initials: CT
authors.lastname: Cartelle
authors.affiliation: Departamento de Patologia Geral Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Maria de Lourdes
authors.initials: Mde L
authors.lastname: Noviello
authors.affiliation: Departamento de Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Vanja Maria
authors.initials: VM
authors.lastname: Veloso
authors.affiliation: Departamento de Ciências Biológicas/NUPEB, Universidade Federal de Ouro Preto, Ouro Preto, Minas Gerais, Brazil.
authors.forename: Maria Terezinha
authors.initials: MT
authors.lastname: Bahia
authors.affiliation: Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Camila Megale
authors.initials: CM
authors.lastname: Almeida-Leite
authors.affiliation: Departamento de Patologia Geral Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
authors.forename: Rosa Maria Esteves
authors.initials: RM
authors.lastname: Arantes
mesh_terms: D000818:Animals; D014355:Chagas Disease / Q000150:complications / Q000473:pathology*; D003714:Denervation; D004195:Disease Models, Animal; D017615:Enteric Nervous System / Q000473:pathology*; D005260:Female; D008531:Megacolon / Q000150:complications / Q000473:pathology*; D051379:Mice; D009130:Muscle, Smooth / Q000294:innervation; D009474:Neurons / Q000473:pathology*