New Roles of Serotonin and Tachykinins in Intestinal Mucositis?
The paper by Matsumoto et al.  published in this issue of Digestive Diseases and Sciences reports an investigation of expression of 5-hydroxytrypamine (5HT) and tachykinins and their cognate receptors in an experimental model of mucositis of the mouse jejunum induced by the chemotherapeutic agent 5-fluorouracil (5-FU).
Mucositis is a serious adverse effect of common chemotherapeutic treatments. Damage to mucosa, prominent in the oral cavity (oral mucositis), also occurs in the esophagus, stomach, and small and large intestines (gastrointestinal mucositis). Gastrointestinal symptoms include pain, nausea and vomiting, ulceration, diarrhea, and rectal bleeding. Patients with mucositis often have to temporarily withdraw from chemotherapy, which can contribute to reduced cancer survival . Current guidelines for treatment of gastrointestinal mucositis include use of the oral histamine H2-receptor antagonist ranitidine or a proton pump inhibitor to reduce gastric injury. Loperamide is recommended for control of diarrhea; if loperamide fails, subcutaneous octreotide is also recommended . Mucosal damage was originally believed to result primarily from inhibition of epithelial cell proliferation, which reduces protection and repair of the mucosa. More recent evidence shows that chemotherapeutic agents stimulate nuclear factor-κB production; subsequent production of pro-inflammatory cytokines significantly induces mucositis . Therapy limiting intestinal mucosal damage is not in common use, primarily because suitable molecular targets have not been identified.
The publication by Matsumoto et al. builds on their previous findings that 5HT3 receptor antagonists reduce damage to mucosa, mucosal cytokine production, and enterocyte apoptosis caused by 5-FU in mice . Their latest paper reports that 5HT3 and neurokinin (NK) NK1 receptor expression were upregulated, mostly in lamina propria macrophage-like cells (CD11+) of the jejunum, of mice injected intraperitoneally with 5-FU for 5 days, investigated on the 5th day. The study also reports increased 5HT and tachykinin (substance P) content of small intestine homogenate, although the number of cells expressing these compounds was unchanged. The number of mucosal 5HT3 receptor immunoreactive nerve fibers also increased.
An important unanswered question is whether the results are clinically relevant, given that numerous studies have reported that 5HT3 receptors help modulate the immune–inflammatory axis. Rodents have only two genes encoding 5HT3 subunits whereas the human genome contains five 5-HT3 receptor-encoding genes, although the 5HT3C, 5HT3D, and 5HT3E subunits only express functional channels when co-expressed with 5HT3A . It is currently unclear whether any of the 5HT3 receptor subtypes are expressed on human macrophages. 5HT2B and 5HT7 were the only serotonin receptor-encoding genes expressed above background levels in human macrophages produced by treatment of peripheral monocytes with GM-CSF or M-CSF (granulocyte macrophage and macrophage colony-stimulating factors) . Kapellar et al.  detected immunoreactivity to 5HT3A, 5HT3C, 5HT3D, and 5HT3E in lamina propria immune cells in the human colon, although their identity was not verified. There is, however, good evidence that 5HT3 receptors are expressed on human monocytes, T cells, and mast cells, if not on macrophages themselves .
The importance of the results is that 5HT3 receptor antagonists, effective in reducing chemotherapy-induced nausea by blocking emetogenic pathways , may have additional mucosa-protective effects. Combined with results published previously by this group, the observations imply that activation of 5HT3 receptors on macrophages releases cytokines that contribute to the mucosal damage of mucositis. Further evidence in support of this theory might be obtained from experiments utilizing macrophage-deficient mice.
NK1 receptor antagonists protect against tachykinin-mediated hypersecretion and inflammatory responses in animal models of ileocolitis . The functional relevance of increased macrophage NK1 receptor expression in mucositis should be investigated, because NK1 receptor antagonists, for example aprepitant, are in use as anti-nauseants and might augment the anti-nausea and potential mucosa-protective activity of 5HT3 receptor antagonists, for example granisetron and odansetron.
In summary, current options for treatment of, or prevention of the development of, chemotherapy-induced gastrointestinal mucositis are limited. 5HT3 receptor antagonists and a NK1 receptor antagonist are already used clinically, alone or in combination, to reduce chemotherapy-induced nausea and are attractive options for reducing damage to mucosa. 5HT3 receptor antagonists, by reducing 5HT-induced cytokine production, may limit the contributions of pro-inflammatory cytokines to mucositis. Nevertheless, the effectiveness of 5HT3 and NK1 receptor antagonists in mucosa protection in human mucositis, as opposed to a mouse model, remains to be proved.
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