Abstract
Adrenomedullin (AM) is a biologically active peptide which has been tested as a new therapy for inflammatory bowel disease (IBD) in animal models and in patients with severe ulcerative colitis. We used an inducible knockout (KO) mouse model for AM to evaluate the effects of endogenous levels of this peptide on the development and degree of pathogenesis of IBD. Acute colitis was induced in mice of both sexes by rectal instillation of 3 mg 2,4,6-trinitrobenzenesulfonic acid (TNBS) in 100 μL of 50% ethanol. Control mice received the same volume of saline in 50% ethanol. During the following 5 days, the weight and the disease severity index of all animals were recorded. After sacrifice, the inflammatory response was macroscopically assessed by analyzing the weight of the colon; by histomorphometrical analysis on histological sections; and by qRT-PCR determination of different inflammatory, adhesion, and regeneration molecules. TNBS administration caused a significantly more severe colitis in KO mice, and especially in females, when compared to wild type (WT) animals. Abrogation of the AM gene caused more severe diarrhea, accompanied by rectal bleeding, anorexia, and a significant increase of colon weight. Histological analysis of TNBS-treated KO mice showed large areas of lymphocyte infiltrates in the mucosa and submucosa, with loss of tissue architecture. No alterations were observed in the expression levels of inflammatory cytokines at the time of sacrifice; meanwhile lack of AM resulted in lower levels of some adhesion molecules and regeneration markers. Taken together, these results support the protective role of endogenous AM against the development of acute colitis, and that its effects are particularly beneficial on females.
Highlights
Gastrointestinal diseases are attracting renewed interest in biomedicine due to the increased incidence of newly diagnosed cases in recent years (Dahlhamer et al, 2016)
WT mice of both sexes treated with TNBS maintained body weight (Figures 1A,B; two way ANOVA; Tukey’s Multiple Comparison test (MCT), p > 0.05 TNBS-WT males (WTM) vs. Sham-WTM; p > 0.05 TNBS-WT females (WTF) vs. Sham-WTF) and only exhibited mild colitis symptoms when compared with their vehicle-treated WT littermates at day five (Figures 1C,D; two way ANOVA; Tukey’s MCT, p < 0.05 TNBSWTM vs. Sham-WTM; p < 0.05 TNBS-WTF vs. Sham-WTF)
KO males (KOM) mice treated with TNBS experienced a slight weight loss during the 2 days following rectal instillation when compared with their control vehicletreated counterparts (Figure 1A, two way ANOVA; Tukey’s MCT, p < 0.05), which paralleled the occurrence of harsher colitis symptoms (Figure 1C, two way ANOVA; Tukey’s MCT, p < 0.01)
Summary
Gastrointestinal diseases are attracting renewed interest in biomedicine due to the increased incidence of newly diagnosed cases in recent years (Dahlhamer et al, 2016). Epidemiologic studies revealed that the number of new IBD diagnoses is increasing all around the world (Ponder and Long, 2013; Dahlhamer et al, 2016). Incidence and prevalence ratios are similar for males and females in IBD, according to data of the “Centers for Disease Control and Prevention” in the United States UC is slightly more common in males, while Crohn’s disease is more frequent in women (CDC report, 2015). Prior observational studies have suggested a link between exogenous hormone use and risk of IBD (Khalili, 2016). Some studies have shown an association between oral contraceptive use and risk of CD, and menopausal hormone therapy and risk of UC (Khalili, 2016)
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