Muc-2–Deficient Mice Display a Sex-Specific, COX-2–Related Impairment of Gastric Mucosal Repair

Abstract

Mucus is known to contribute significantly to the prevention and repair of mucosal damage throughout the gastrointestinal tract. Although not normally expressed in the stomach, mucin-2 (MUC-2, encoded by the MUC2 gene) is expressed in certain disease states. The aim of this study was to determine in a mouse model whether the absence of Muc-2 would result in impaired susceptibility to and healing of gastric mucosal injury. Acute gastric damage was induced in mice deficient in Muc-2 and in wild-type controls, through oral administration of indomethacin. Chronic gastric ulcers were induced by serosal application of acetic acid. The extent of injury and the extent of healing of the damage over time were examined in both models. Indomethacin administration caused similar levels of gastric damage in Muc-2-deficient and wild-type mice, but the erosions healed more slowly in the former. Acetic acid-induced gastric ulcers were initially similar in size in Muc-2-deficient and wildtype mice of both sexes, but ulcer healing was significantly impaired in male Muc-2-deficient mice. Induction of cyclooxygenase-2 in the stomach, in response to indomethacin-or acetic acid-induced ulceration, was significantly reduced in male Muc-2-deficient mice. This phenomenon, and the sex specificity, was also apparent in bone marrow-derived macrophages stimulated with endotoxin. These results demonstrate a marked impairment of gastric mucosal repair in male Muc-2-deficient mice that may be related to an insufficient induction of cyclooxygenase-2, an enzyme known to contribute to mucosal repair.

Chemokine expression of oral fibroblasts and epithelial cells in response to artificial saliva

“…Theoretically, the increased CXCL8, CXCL1, and CXCL2 expression by gingival fibroblasts upon exposure to artificial saliva with mucins attract cells of the innate immune system that in turn advance the healing process. In support of this assumption, chronic gastric ulcer healing was significantly impaired in male mucin 2-deficient mice [30]. Moreover, administration of mucin 3-epidermal growth factor-like domains reduced mucosal ulceration in experimental acute colitis [31].…”

Acetic acid induces cell death: An in vitro study using normal rat gastric mucosal cell line and rat and human gastric cancer and mesothelioma cell lines

“…Rat gastric epithelial cell line (RGM-1, Riken Kagaku, Kyoto, Japan), rat gastric carcinoma cell line (RGK-1), human gastric cancer cell line (KATO III, Riken Kagaku), and human mesothelioma cell lines (ACC-MESO1: RIKEN BioResource Center, Tsukuba, Japan, and MSTO-211H: ATCC, Manassas, VA, USA) were used. [9][10][11][12] Both RGM-1 and RGK-1 cells were maintained in DMEM/F-12 (Wako, Osaka, Japan) medium, whereas KATO III cells and mesothelioma cells were maintained in RPMI 1640 medium (Wako). All media were supplemented with heatinactivated 10% fetal bovine serum (Biowest, Nuaille, France), and 100 U/mL of penicillin and 100 U/mL of streptomycin at 37°C under 5% CO2 in air.…”

Hypoxia-inducible factor 1 in dendritic cells is crucial for the activation of protective regulatory T cells in murine colitis

“…This association may result from a compensatory protective mechanism in the intestinal epithelium, because mucins are also involved in mucosal repair. 54,55 Therapeutic strategies may be derived for models of IBD to use hydroxylase inhibitors that provided various protective effects in IBD. 56 Systemically applied hydroxylase inhibitors not only affect the gut epithelium but also immune cells like neutrophils, T cells, and DCs.…”