Abstract Background Disruption of the epithelial barrier is a key event in Ulcerative Colitis (UC) pathogenesis, leading to an increase in intestinal permeability and sustained mucosal inflammation. Prostaglandin D2 (PGD2), a member of the eicosanoid family of lipid mediators, is mainly released by mast cells (MC), known to be involved in UC inflammation. While biological effects of PGD2 could have a profound influence on many regulators of intestinal permeability, the evidence linking its activity to the pathogenesis of UC is still limited and conflicting. In order to address this gap in our understanding of the disease, we performed a series of ex vivo and in vitro studies. Results strongly suggest a complex and somewhat unexpected role of PGD2 Methods Colonic mucosal biopsies were obtained from 8 patients with UC and 8 healthy controls. Biopsies were mounted in Ussing chambers and transepithelial permeability was measured with or without treatment with PGD2 or MC degranulator A23187. Protein expression levels of PGD2 receptors PTGDR (DP1) and CRTH2 (DP2) in colon biopsies were measured by western blot. Mucosal infiltration of MC was assessed by counting the number of MC tryptase positive cells by immunofluorescence, while percentage of MC expressing DP1 and DP2 receptors was evaluated from double-staining with MC tryptase and each receptor separately. An in vitro model of Caco-2 was used to assess the effect of PGD2 on permeability in presence or absence of inflammation. Finally, the effect of PGD2 on MC activity was assessed by measuring the release of beta-hexosaminidase in human MC line HMC1 Results DP1 and DP2 expression was reduced in UC compared to control biopsies. The number of MC was increased in UC biopsies, together with the fraction of cells expressing DP2 receptor. In ex vivo experiments, PGD2 caused an increase in paracellular permeability in control biopsies and a decrease in transcellular permeability in UC biopsies. In in vitro experiments, PGD2 treatment caused an increase in both paracellular and transcellular permeability in inflamed model of Caco2 monolayer. PGD2 alone did non cause any effect on HMC1 degranulation, but was able to reduce HMC1 degranulation when added before A23187 treatment Conclusion Results support a role of PGD2 in the modulation of colonic mucosal permeability. However, the overall effect might be complex, considering that many cell types involved in the barrier function of the colonic mucosa express PGD2 receptors. Altogether, this study could have implication in both pathophysiology and future targeted treatments of UC Conflict of interest: Abruzzese, Vittorio: No conflict of interest Casado-Bedmar, Maite: No conflict of interest Myrelid, Pär: No conflict of interest Haapaniemi, Staffan: No conflict of interest Söderholm, Johan D.: No conflict of interest Keita, Åsa: No conflict of interest
Abruzzese et al. (2026) studied this question.