Role of the haem oxygenase/carbon monoxide pathway in Clostridium difficile toxin A-induced enteritis in mice

C. A. Medeiros, C. A. Warren, R. Freire, C. A. Vieira, B. B. Lima, M. L. Vale, R. A. Ribeiro, M. H. Souza, G. A. Brito
2011 Journal of Medical Microbiology  
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
more » ... 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.
doi:10.1099/jmm.0.028910-0 pmid:21372182 fatcat:cs3zfs2zc5ggdo5zni3u5iaydm