Dynamics of Capillaria-hepatica-induced hepatic septal fibrosis in rats / Dinâmica da fibrose septal hepática induzida por Capillaria hepatica em ratos

INTRODUCTION: The pathogenesis of septal hepatic fibrosis, induced in rats by Capillaria hepatica infection, was studied with the aid of a large collection of stored paraffin blocks, representative of the different evolutive phases of fibrosis which appeared in 100 percent of infected rats. METHODS: Studies were conducted involving histology, immunohistochemistry, immunofluorescence and morphometric methods, in order to observe the dynamic behavior of the cellular and matrix components of fibrosis, over a one year period of evolution. RESULTS: Observation verified that septal fibrosis originates from several portal spaces simultaneously. Its origin and progression involve blood vessel proliferation (angiogenesis), multiplication of actin-positive cells (pericytes and myofibroblasts) and progressive collagen deposition. By the end of 4-5 months, a progressive decrease in all these components was observed, when signs of regression of septal fibrosis became more evident over time. CONCLUSIONS: Besides indicating the fundamental role played by angiogenesis in the pathogenesis of fibrosis, these morphological data concerning the dynamics of this C. hepatica experimental model proved to be adequate for future investigations regarding the functional aspects of fibrosis induction, progression and regression.

INTRODUÇÃO: Um extenso material de patologia experimental arquivado em blocos de parafina, ilustrativo das diferentes fases da fibrose hepática septal, que 100 por cento dos ratos desenvolvem em seguida uma infecção com o nematódeo Capillaria hepatica. MÉTODOS: O material foi sistematicamente estudado com métodos morfológicos e morfométricos, no sentido de se verificar o comportamento dos elementos celulares e matriciais durante a evolução da fibrose hepática septal ao longo de um período de um ano. RESULTADOS: Foi constatado que a fibrose septal se origina de vários espaços porta ao mesmo tempo, com proliferação vascular (angiogênese), multiplicação de células actino-positivas (pericitos, miofibroblastas) e progressivo depósito de colágeno. Ao fim dos 4-5 meses há uma involução regressiva de todos estes indícios morfológicos, mas com alguns septos persistindo bem evidentes até o fim de um ano. CONCLUSÕES: Além de ilustrar o papel fundamental desempenhado pela angiogênese, o modelo se mostrou adequado para futuros estudos funcionais relacionados com a indução, progressão e regressão da fibrose hepática.

Capillaria hepatica-induced septal fibrosis in rats: a contribution to the study of liver fibrogenesis / Contribuição para o estudo da fibrogenesis hepática em ratos infectados com Capillaria hepatica

INTRODUCTION: Septal fibrosis of the liver regularly develops in rats infected with the nematode Capillaria hepatica. Curative treatment of the infection prevents the development of septal fibrosis when intervention occurs up to postinfection day (PID) 15, but not later. The present investigation aimed to demonstrate which parasitic factors are present when the process of septal fibrosis can no longer be prevented by curative treatment. METHODS: Wistar rats were infected with 600 embryonated eggs of C. hepatica administered by gavage and treated with ivermectin and mebendazole in separate groups at PIDs 10, 12, 15, 17 or 20. Rats from each group and their nontreated controls, were killed and examined 40 days after the end of treatment. RESULTS: Findings by PID 15 were compatible with the stage of complete maturation of infection, when worms and eggs were fully developed and a complex host-parasite multifocal necroinflammatory reaction showed greater intensity, but with no signs of septal fibrosis, which appeared from PID 17 onward. CONCLUSIONS: Since the worms spontaneously died by PID 15, not only septal fibrosis production, but also its maintenance and further development appeared dependent on the presence of eggs, which were the only parasitic factor remaining thereafter.

INTRODUÇÃO: A fibrose septal do fígado se desenvolve regularmente em ratos infectados pelo nematódeo Capillaria hepatica. O tratamento curativo da infecção, feito antes do 15º dia da infecção, mas não mais tarde, impediu o aparecimento da fibrose septal. O presente trabalho procura verificar qual o estado do parasitismo aos 15 dias da infecção, crucial para patogenia da fibrose septal. MÉTODOS: Ratos foram infectados por via digestiva com 600 ovos embrionados de C. hepatica e tratados com Ivermectina e mebendazol, em grupos separados, aos 10, 12, 15, 17 ou 20 dias após a infecção. O animal de cada grupo e seus respectivos controles foram mortos e examinados aos 40 dias após o fim do tratamento. RESULTADOS: Os achados aos 15 dias da infecção mostraram a maturação completa da parasitose, com presença de ovos e vermes, circundados por reação necro-inflamatória, mas ainda sem fibrose septal. Daí por diante, a fibrose septal se fez presente. CONCLUSÕES: Como os vermes morrem espontaneamente após o 15º dia da infecção, não apenas a origem, mas o posterior crescimento e a manutenção da fibrose septal dependem da presença dos ovos acumulados no fígado, os quais são os únicos elementos parasitários presentes após o 15º dia da infecção por C. hepatica no rato.

Role of partial hepatectomy on Capillaria hepatica-induced hepatic fibrosis in rats

It is known that hepatic fibrosis may regress following partial hepatectomy, since the hepatic parenchyma regenerates very rapidly, but not the excess of fibrous tissue. The present study evaluated this hypothesis by observing the behavior of systematized septal fibrosis induced by either 30 or 90-day-old Capillaria hepatica infection, in rats subjected to partial hepatectomy. The results revealed that the morphology of the fibrosis was unaffected, but its relative quantity within the microscope field appeared significantly decreased, as a consequence of the increased liver tissue mass following regeneration.

Sabe-se que a fibrose hepática pode sofrer uma redução em seqüência uma hepatectomia parcial, uma vez que o parênquima hepático se regenera muito rápido, mas não o excesso de tecido fibroso. O presente trabalho avalia esta hipótese ao observar como se comporta a fibrose septal sistematizada induzida pela Capillaria hepática no rato, após infecção de 30 ou 90 dias de duração, em animais submetidos à hepatectomia parcial. Os resultados revelaram que a fibrose em si mesma não foi afetada na sua morfologia, mas a sua quantidade relativa apareceu diminuída significativamente no campo microscópico como conseqüência do aumento da massa de tecido hepático pós-regeneração.

Capillaria hepatica in rats: focal parasitic hepatic lesions and septal fibrosis run independent courses

Capillaria hepatica causes two main lesions in the liver of rats: multifocal chronic inflammation, directly related to the presence of disintegrating parasites and their eggs, and a process of systematized septal fibrosis. The comparative behavior of these two lesions was investigated in rats experimentally infected with 600 embryonated eggs, following either corticosteroid treatment or specific antigenic stimulation, in an attempt to understand the relationship between these two lesions, and the pathogenesis of septal fibrosis. The two treatments differently modified the morphological aspects of the focal parasitic-related lesions, but did not interfere with the presentation of diffuse septal fibrosis, although a mild decrease in the degree of fibrosis occurred in corticoid-treated animals. These findings indicate that although the two lesions are C. hepatica induced, they are under different pathogenetic control, the induction of septal fibrosis being triggered during early infection to follow an independent pathway.

Regressão da fibrose hepática / Regression of hepatic fibrosis

Durante muito tempo, se acreditou que a fibrose hepática extensa e de longa duracão fosse um processo irreversível. As investigacões sobre o comportamento da fibrose hepática, nas formas avancadas da esquistossomose, vieram abalar este conceito e hoje em dia está se estabelecendo a nocão de que qualquer fibrose é reversível, inclusive aquela associada à cirrose hepática. O problema é identificar sua causa e removê-la. Embora, a fibrose hepática tenha per se pouca significacão fisiopatológica, sua gravidade está relacionada com as alteracões vasculares que ela encerra. O que dá ao assunto primordial importância são os indícios até aqui obtidos de que, a regressão da fibrose costuma se acompanhar de uma remodelacão das alteracões vasculares no seu interior. Mas, há peculiaridades relativas ao tipo anatômico e ao papel fisiológico que certas fibroses exibem, e tais peculiaridades podem interferir com o processo regressivo da mesma, o que pode significar que por vezes a fibrose pode se tornar permanente. Esses assuntos, alguns deles controversos, são aqui apresentados e discutidos.

Worm load and septal fibrosis of the liver in Capillaria hepatica-infected rats

Inocula, varying from 15 to 1,000 embryonated Capillaria hepatica eggs, were administered to young adult rats by gastric tube, in an attempt to investigate the influence of worm load in the production of septal fibrosis of the liver. Low doses of 15, 30 or 50 eggs were sufficient to produce septal fibrosis, but it appeared with variable degrees of intensity and always with focal distribution. Septal fibrosis became diffuse, progressive with time, and already well developed 40 days after infection, when 100 eggs or more were administered. However, higher inocula (200, 500 and 1,000 eggs) did not intensify septal fibrosis, although the number of parasitic focal lesions proportionally augmented

Proteoglycans and glycosaminoglycans synthesized by the hepatic granulomas isolated from schistosome-infected mice and by a granuloma-derived connective tissue cell line

1. This paper summarizes our studies on proteglycans and glycosaminoglycans in the hepatic fibrosis occurring in schistosomiasis. 2. We have compared proteglycans and glycosaminoglycans isolated from schistosomal fibrotic granulomas with those obtained from the cellular and extracellular compartments of a murine cell line derived from schistosome-induced granulomas, primary cell line "GR". 3. Our results have shown some biochemical and structural similarities between proteglycans and glycosaminoglycans extracted from granulomas and those synthesized and secreted by GR cells, suggesting that cells may be the major cell population involved in synthesis and accumulation of these molecules in the schistosomal periovular granulomas in liver. Furthermore, we have shown that GR cells can function as an extramedullary myelopoietic stroma that mediates a long-term myeloid proliferation through an autocrine mechanism where the interaction between myelopoietic growth factors and cell-surface heparan sulfate proteoglycans was characterized

Capillaria hepatica: a cause of septal fibrosis of the liver

Fine, long, fibrous septa were observed as a late change developing in the acinar zone III of the liver of rats experimentally infected with the helminth Capillaria hepatica. Hepatic septal fibrosis begun 30 days after inoculation of embryonated eggs into the stomach of rats and became clearly evident from the 40th day onwards. Experimental observation was undertaken for 170 days. Septal fibrosis increased progressively with time and was most marked when the parasitic nodules formed around larvae, disintegrating worms and eggs were involving. Septal fibrosis of the liver has not been previously recognized as a manifestation of hepatic capillariasis. The presence of sequestered parasite antigens, probably being slowly released within the liver, appears to be a major factor in the pathogenesis of hepatic septal fibrosis observed in rats with C. hepatica infection