Irinotecan-induced mucositis is associated with mucus dysregulation and enteric nerve depletion — ASN Events

Irinotecan-induced mucositis is associated with mucus dysregulation and enteric nerve depletion (#26)

Daniel Thorpe 1 , Andrea Stringer 2 , Rachel Gibson 3 , Masooma Sultani 3 , Ross Butler 2
  1. School of Pharmacy & Medical Sciences , The University of South Australia, Adelaide, SA, Australia
  2. School of Pharmacy & Medical Sciences , The University of South Australia, Adelaide, SA, Australia
  3. Discipline of Anatomy and Pathology, The University of Adelaide, Adelaide, SA, Australia

Background: Irinotecan–induced mucositis is a major oncological problem. Goblet cells secrete mucus, protecting the intestinal mucosa, with secretion altered during mucositis. The enteric nervous system is involved in regulating gut motility and secretion. The aim of this study was to determine whether enteric nerves and goblet cells are altered following chemotherapy.
Methods: Dark Agouti (DA) rats were administered a single dose of 175 mg/kg of irinotecan intraperitoneally (ip) and 0.01mg/kg atropine subcutaneously (sc). Experimental and untreated control rats were killed at times 6, 24, 48, 72, 96 and 120 h after treatment. Duodenum, jejunum, ileum and colon samples were formalin fixed. Haematoxylin and eosin (H&E) staining, Alcian Blue-PAS staining, and immunohistochemistry with S-100 antibody (nerve marker) were carried out. Goblet cells (intact and cavitated) and nerve bundles and axons were counted. Statistical analysis was carried out using a Kruskal-Wallis test with Dunns post test.
Results: The percentage of cavitated goblet cells increased at 48h compared to controls in the duodenum, and increased at 72h compared with controls in the jejunum. The villous percentage of cavitated goblet cells increased significantly (p=0.0063, 95% CI) between control and 72h in the ileum, then decreased signficantly between 72h and 120h (p=0.0063, 95% CI). The percentage of cavitated goblet cells decreased compared to all other time points at 120h in the colon. There number of axons in the myenteric plexus decreased compared to controls, with an increase to control levels observed at later time points. Nerve bundles in the myenteric plexus of the jejunum decreased at 24h and 96h.
Conclusions: Irinotecan-induced mucositis is associated with increases in mucus secretion, and depletion of enteric nerves. These changes are likely to contribute to the pathophysiology of mucositis and associated diarrhoea through the dysregulation of neural signalling following enteric nerve damage.