Clostridium difficile is the major cause of antibiotic-associated colitis, a disease with significant morbidity and mortality. This study investigated the role of the haem oxygenase-1 (HO-1)/carbon monoxide (CO) pathway in C. difficile toxin A-induced enteritis in mice. The HO substrate haemin, zinc protoporphyrin IX (ZnPP IX), a specific HO-1 inhibitor, dimanganese decacarbonyl (DMDC), a CO donor, or an equivalent volume of their respective vehicles were injected subcutaneously 30 min prior to local challenge with toxin A (25 or 50 mg per ileal loop) or PBS. Intestinal ileal loop weight/length ratios were calculated 3 h later. Ileal tissues were collected for histological analysis and measurement of myeloperoxidase (MPO) activity, tumour necrosis factor alpha (TNF-a) and interleukin-1 beta (IL-1b) production by ELISA and immunohistochemistry for HO-1. Treatment of mice subjected to C. difficile toxin A (TcdA) with haemin or DMDC prevented oedema, mucosal disruption and neutrophil infiltration observed in histological analysis. It also decreased TcdAinduced MPO activity and TNF-a or IL-1b production. In contrast, the specific HO-1 inhibitor (ZnPP IX) exacerbated all these evaluated parameters. TcdA increased HO-1 expression as seen by immunohistochemistry. These results suggest that the HO-1/CO pathway exerts a protective role in TcdA-induced enteritis and that its pharmacological modulation might be important for the management of C. difficile-associated disease. INTRODUCTIONClostridium difficile is the major causative agent of antibiotic-associated diarrhoea. The main C. difficile virulence factors are two large exotoxins, toxin A (TcdA) and toxin B (TcdB), which show substantial sequence similarity and share common structural elements (Pothoulakis et al., 1986). A recent report demonstrated that, instead of TcdA, TcdB is actually the essential virulence factor for the development of C. difficileassociated disease (Lyras et al., 2009). However, by using a gene knockout system to inactivate the toxin genes permanently, Kuehne et al. (2010) found that C. difficile producing either one or both toxins showed cytotoxic activity in vitro that translated directly into virulence in vivo, re-establishing the importance of both toxins in the pathogenesis of C. difficile-associated disease. The mechanism of TcdA-induced enteritis involves toxin binding to enterocyte receptors, which leads to infiltration of the mucosa by neutrophils, degranulation of mast cells and activation of sensory and enteric nerves, resulting in enhanced intestinal secretion and motility (Brito et al., 2002b;Kelly et al., 1994a;Pothoulakis et al., 1998).Haem oxygenase (HO; EC 1.14.99.3) catalyses haem degradation to iron, carbon monoxide (CO) and biliverdin (BVD) (Abraham et al., 1988). Three isozymes have been identified: HO-2 and HO-3, which are constitutive forms (Maines et al., 1986;McCoubrey et al., 1997), and HO-1, which is induced by various stimuli such as haem, haemin, cytokines, mitogens, metals, reactive oxygen species, heat shock, UV ...
Este trabalho tenta aproximar-se da complexidade inerente à interseção entre Saúde Mental, Gênero e Violência através do entrelaçamento de olhares advindos da Psicanálise, da Saúde Pública, da Sociologia e da Filosofia. A hipótese sustentada a partir desta articulação de saberes é que o não lugar da fala na Atenção Primária expressa-se como uma violência institucional que toca, principalmente, as mulheres. Neste sentido, traçam-se três teses que se articulam e se reforçam mutuamente: 1) Não há espaço para fala na Atenção Primária do SUS; 2) A mulher, por sua posição na história das sociedades do Ocidente, tem sido sobrecarregada de papéis, o que gera uma identidade que aprisiona e faz sofrer; 3) A violência contra a mulher vincula-se à lógica da dominação que se entranha nas regras, nos valores e nas ideias que estruturam as instituições públicas e privadas. Como proposta para lidar com os problemas levantados, advoga-se pela adoção de uma epistemologia e de uma ética capazes de superar dualismos rasos e os resquícios da dominação masculina que atravessa e molda a sociedade e as instituições de saúde.
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