Reversibility of cardiac fibrosis in mice chronically infected with Trypanosoma cruzi, under specific chemotherapy

Abstract

the untreated controls either infected with 21 SF or Colombian strain, showed inflammatory and fibrotic alterations that were mild to moderate with the 21 SF strain and intense with the Colombian strain. Redpicrosirius staining showed bundles of collagen in the interstitial space and around cardiac fibers. Increased deposits of matritial components and collagen fibers, macrophages and fibroblasts appeared at the ultrastructural examination. Deposits of fibronectin, laminin, pro-III and IV collagens were seen, most intense in those infected with the Colombian strain. Treated mice, parasitologically cured, presented clear-cut regression of the inflammatory lesions and of the interstitial matrix thickening. Mice infected with the Colombian strain and treated with MK-436, was parasitologically cured in 5/6 cases and showed mild inflammatory infiltration and fibrosis. The mice treated with Benznidazole (Colombian strain) did not cure and showed moderate fibrosis and inflammation. Treatment of the mice infected with the 21 SF with Benznidazole determined parasitological cure of all animals, that showed mild inflammation and fibrosis of the myocardium.(ABSTRACT TRUNCATED AT 400 WORDS)

Parasitological cure of Chagas disease: is it possible? Is it relevant?

“…2 -Current knowledge seems to indicate that eradication of T. cruzi from infected human patients and animals may be prerequisite to arrest the evolution of the disease and to avert its irreversible long-term consequences (Andrade et al 1991, 1996, Viotti et al 1994, Docampo & Schmuñis 1997, Kaplan et al 1997, Andrade & Zicker 1997, Urbina 1999. Thus, specific chemotherapeutic approaches should play an essential role in the successful clinical outcome of this parasitic disease.…”

“…4 -Effect of specific chemotherapy on the evolution of experimental and human Chagas disease: in experimental infections chemotherapy-induced parasite clearance leads to reversion not only of the inflammatory but also of the fibrotic heart lesions (Andrade et al 1991). Chronic chagasic patients subjected to antiparasitic treatment (benznidazole), although not parasitologically cured, had a marked reduction in the occurrence of electrocardiographic changes and a lower frequency of deterioration of their clinical condition (Viotti et al 1994).…”

Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification

“…In contrast, whether one or more of the autoimmune events described in experimental models and human cases of Chagas disease can contribute to, or aggravate, this pathology, has been more controversial and difficult to validate (Tarleton 2003a, b). The evidence supporting this viewpoint can be summarised as follows: (i) in recent years, more powerful and sensitive methods of parasite detection, such as immunohistochemistry and polymerase chain reaction (PCR), have demonstrated a higher frequency of T. cruzi antigens and parasite DNA in chronic lesions; also, a significant correlation between parasite persistence and tissue inflammation has been clearly documented; therefore, the supposed absence of parasites at or near sites of disease (the mainstay of the autoimmune theory), probably reflects the use of insensitive histological techniques in past decades (Tarleton & Zhang 1999); (ii) interventions that lessen the parasite burden, such as aetiologic treatment with benznidazole or nifurtimox, reduce clinical disease in humans (Viotti et al 2006, Fabbro et al 2007) and experimental animals (Andrade et al 1991, Garcia et al 2005, in contrast to immunosuppressive treatments/situations that clearly increase T. cruzi parasitemia (Rassi et al 1997) and usually aggravate the inflammatory response (Sartori et al 2007); (iii) reinfection or continued exposure (due to continued residence in areas of active transmission) seems to increase the parasite load and disease severity in experimental models and in human cases (Bustamante et al 2002, Storino et al 2002; (iv) although anti-self responses are encountered in T. cruzi infection, the nature of anti-self antibodies in experimental and human chronic Chagas disease is heterophilic, with a poor correlation with the heart lesions (i.e., there is no direct and definitive evidence that the immune reactions against the mimicked auto-antigens are actually pathogenic) (Tarleton 2003a, b); and (v) data supporting the direct involvement of either molecular mimicry or polyclonal activation in the pathogenesis of myocardial lesions ascribed to T. cruzi infection are sparse and inconclusive.…”

Fibrogenesis and collagen resorption in the heart and skeletal muscle of Calomys callosus experimentally infected with Trypanosoma cruzi: immunohistochemical identification of extracellular matrix components

“…An arbritary point scale was applied: (+) indicating mild focal or diffuse alterations; (++) moderate focal or diffuse and (+++) diffuse and severe alterations, as previously described (Andrade et al 1991).…”

“…According to Weber et al (1993), fibrillar collagen deposits in the myocardial interstitium are of paramount importance in the development of cardiac failure, and particularly of diastolic disfunction, in different cardiac diseases. The possibility of regression of fibrosis, already documented in the chronic infection of mice under chemotherapeutic treatment (Andrade et al 1991) has been described as spontaneously occurring in C. callosus, probably due to down regulation of delayed type hypersensitivity . However, other peculiarities of the present model must be investigated, including the sensitivity of the interstitial matrix components to spontaneous regression, regarding several types of collagen.…”