Apoptosis, Dysbiosis and Expression of Inflammatory Cytokines are Sequential Events in the Development of 5-Fluorouracil-induced Intestinal Mucositis in Mice.

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Apoptosis, Dysbiosis and Expression of Inflammatory Cytokines are Sequential Events in the Development of 5-Fluorouracil-induced Intestinal Mucositis in Mice.

Basic Clin Pharmacol Toxicol. 2017 Apr 04;:

Authors: Hamouda N, Sano T, Oikawa Y, Ozaki T, Shimakawa M, Matsumoto K, Amagase K, Higuchi K, Kato S

Abstract
The chemotherapeutic agent 5-fluorouracil (5-FU) causes intestinal mucositis with severe diarrhoea but the pathogenesis is not fully understood. In the present study, we investigated the pathogenic effects of 5-FU in mice, focusing on apoptosis, enterobacteria and inflammatory cytokines. Repeated administration of 5-FU caused severe intestinal mucositis on day 6, accompanied by diarrhoea and body weight loss. TNF-α expression increased one day after exposure to the drug, and spiked a second time on day 4, at which point myeloperoxidase activity and IL-1β expression also increased. Apoptotic cells were observed in intestinal crypts only on day 1. 5-FU also induced dysbiosis, notably decreasing the abundance of intestinal Firmicutes while increasing the abundance of Bacteroidetes and Verrucomicrobia. Twice-daily co-administration of oral antibiotics significantly reduced the severity of intestinal mucositis and dysbiosis, and blocked the increase in myeloperoxidase activity and cytokine expression on day 6, without affecting apoptosis and TNF-α upregulation on day 1. In cultured colonic epithelial cells, exposure to 5-FU also upregulated TNF-α expression. Collectively, the data suggest that crypt apoptosis, dysbiosis and expression of inflammatory cytokines are sequential events in the development of intestinal mucositis after exposure to 5-FU. In particular, 5-FU appears to directly induce apoptosis via TNF-α and to suppress intestinal cell proliferation, thereby resulting in degradation of the epithelial barrier, as well as in secondary inflammation mediated by inflammatory cytokines. This article is protected by copyright. All rights reserved.

PMID: 28374966 [PubMed - as supplied by publisher]

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