Abstract
Background/AimsDietary supplementation with transforming growth factor-beta (TGF-β) has been proven to minimize intestinal damage and facilitate regeneration after mucosal injury. In the present study, we evaluated the effects of oral TGF-β2 supplementation on intestinal structural changes, enterocyte proliferation and apoptosis following methotrexate (MTX)-induced intestinal damage in a rat and in a cell culture model.MethodsCaco-2 cells were treated with MTX and were incubated with increasing concentrations of TGF-β2. Cell apoptosis was assessed using FACS analysis by annexin staining and cell viability was monitored using Trypan Blue assay. Male rats were divided into four experimental groups: Control rats, CONTR- TGF-β rats were treated with diet enriched with TGF-β2, MTX rats were treated with a single dose of methotrexate, and MTX- TGF-β rats were treated with diet enriched with TGF-β2. Intestinal mucosal damage, mucosal structural changes, enterocyte proliferation and enterocyte apoptosis were determined at sacrifice. Real Time PCR and Western blot were used to determine bax and bcl-2 mRNA, p-ERK, β-catenin, IL-1B and bax protein expression.ResultsTreatment of MTX-pretreated Caco-2 cells with TGF-B2 resulted in increased cell viability and decreased cell apoptosis. Treatment of MTX-rats with TGF-β2 resulted in a significant increase in bowel and mucosal weight, DNA and protein content, villus-height (ileum), crypt-depth (jejunum), decreased intestinal-injury score, decreased level of apoptosis and increased cell proliferation in jejunum and ileum compared to the untreated MTX group. MTX-TGF-β2 rats demonstrated a lower bax mRNA and protein levels as well as increased bcl-2 mRNA levels in jejunum and ileum compared to MTX group. Treatment with TGF-β2 also led to increased pERK, IL-1B and β-catenin protein levels in intestinal mucosa.ConclusionsTreatment with TGF-β2 prevents mucosal-injury, enhances p-ERK and β-catenin induced enterocyte proliferation, inhibits enterocyte apoptosis and improves intestinal recovery following MTX-induced intestinal-mucositis in rats.
Highlights
Mucositis is the term used to describe the damage caused to mucous membranes of the alimentary tract by radiation and chemotherapy, in particular with drugs affecting DNA synthesis [1,2]
The epithelium in the small intestine is extremely sensitive to cytostatic drug treatment, since it is proliferating rapidly
Treatment is available for a small subset of patients suffering from mucositis, the majority rely on pain relief as their only treatment option [3]
Summary
Mucositis is the term used to describe the damage caused to mucous membranes of the alimentary tract by radiation and chemotherapy, in particular with drugs affecting DNA synthesis (such as fluorouracil, methotrexate, and cytarabine) [1,2]. The epithelium in the small intestine is extremely sensitive to cytostatic drug treatment, since it is proliferating rapidly. The loss of intestinal epithelial integrity causes pain and ulceration, vomiting, bloating, diarrhoea, symptoms of malabsorption, and an enhanced risk of bacteremia. Mucositis limits the patient’s ability to tolerate chemotherapy or radiation therapy, prolongs hospital stay, increases re-admission rates, compromises the patient’s nutritional status, affects the patient’s quality of life, and is occasionally fatal. Treatment is available for a small subset of patients suffering from mucositis, the majority rely on pain relief as their only treatment option [3]
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