endothelin-1 and Ulcer

Raynaud's phenomenon and digital ulcers (DUs) are frequent among systemic sclerosis (SSc) patients. Our aim was to investigate the diagnostic and predictive value for DU of endothelial dysfunction biomarkers (flow-mediated dilatation (FMD), serum levels of endothelin-1 (ET-1), and ADMA), angiogenic/angiostatic biomarkers (vascular endothelial growth factor (VEGF), endoglin, and endostatin), and nailfold videocapillaroscopy (NVC). We compared our results with a literature review. In a cohort study of 77 SSc patients, we followed two groups of patients: (i) naïve DU patients (39) and (ii) active DU at baseline (38 patients) for 3 years. Telangiectasia (p < 0.001) and diffuse disease subset (p = 0.001) were significantly more frequent in patients with active DU at enrolment. Additionally, NVC late scleroderma pattern (AUC 0.846, 95%CI 0.760-0.932), lower values of FMD (AUC 0.754, 95%CI 0.643-0.864), increased serum levels of ET-1 (AUC 0.758, 95%CI 0.649-0.866), ADMA (AUC 0.634, 95%CI 0.511-0.757), and endoglin as well as low VEGF serum levels (AUC 0.705, 95%CI 0.579-0.830) were significantly associated to new DU events in the 3-year follow-up. Cox regression analysis showed that FMD > 9.41 % (HR 0.37, 95%CI 0.14-0.99); ET-1 >11.85 pmol/L (HR 3.81, 95%CI 1.41-10.26) and late NVC pattern (HR 2.29, 95%CI 0.97-5.38) were independent predictors of DU recurrence. When estimating the probability of occurrence of first DU in naïve DU patients, only late NVC pattern (HR 12.66, 95%CI 2.06-77.89) was an independent predictor factor. In conclusion, late scleroderma patterns in NVC are the best independent predictors of SSc patients who are at risk of developing DU. Endothelial dysfunction assessed by FMD and ET-1 was also found to be an independent predictor of DU recurrence in a 3-year follow-up.

Topics: Adolescent; Adult; Aged; Antigens, CD; Biomarkers; Cohort Studies; Endoglin; Endothelin-1; Endothelium; Female; Fingers; Follow-Up Studies; Humans; Male; Microscopic Angioscopy; Middle Aged; Predictive Value of Tests; Prognosis; Prospective Studies; Raynaud Disease; Receptors, Cell Surface; Scleroderma, Systemic; Ulcer; Vascular Endothelial Growth Factor A; Young Adult

Endothelin (ET)-1 is a potent inducer of peptic ulcers. The roles of ET-1 in ulcer healing, however, have remained unclear, and these were investigated in mice. Gastric ulcers were induced in mice by serosal application of acetic acid. Three days later, mice were given a neutralizing ET-1 antibody or nonimmunized serum. The ulcer size, amount of fibrosis and myofibroblasts, and localization of ET-1 and ET(A/B) receptors were analyzed. To elucidate the mechanisms underlying the effects of ET-1, we examined the proliferation, migration, and release of growth and angiogenic factors in gastric myofibroblasts with or without ET-1. The expression of prepro-ET-1 (an ET-1 precursor) and ET-converting enzyme-1 was examined in gastric myofibroblasts using RT-PCR. Immunoneutralization of ET-1 delayed gastric ulcer healing. The areas of fibrosis and myofibroblasts were smaller in the anti-ET-1 antibody group than in the control. ET-1 was expressed in the gastric epithelium, myofibroblasts, and other cell types. ET(A) receptors, but not ET(B) receptors, were present in myofibroblasts. ET-1 increased proliferation and migration of gastric myofibroblasts. ET-1 stimulated the release of hepatocyte growth factor, VEGF, PGE(2), and IL-6 from gastric myofibroblasts. mRNA for prepro-ET-1 and ET-converting enzyme-1 was also expressed. ET-1 promotes the accumulation of gastric myofibroblasts and collagen fibrils at gastric ulcers. ET-1 also stimulates migration and proliferation of gastric myofibroblasts and enhances the release of growth factors, angiogenic factors, and PGE(2). Thus ET-1 has important roles not only in ulcer formation but also in ulcer healing via mobilizing myofibroblasts and inducing production of stroma-derived factors.

Topics: Angiogenesis Inducing Agents; Animals; Antibodies; Cell Movement; Cell Proliferation; Cytokines; Dose-Response Relationship, Drug; Endothelin-1; Fibroblasts; Gastric Mucosa; Growth Substances; Immunohistochemistry; Male; Mice; Mice, Inbred BALB C; Peptides, Cyclic; Placebos; Receptor, Endothelin A; Receptor, Endothelin B; Stomach; Stomach Ulcer; Time Factors; Ulcer

We investigated the effect of chronic alcohol ingestion on buccal mucosal ulcer healing by analyzing the interplay between mucosal expression of tumor necrosis factor-alpha (TNF-alpha), endothelin-1 (ET-1), and interleukin-4 (IL-4). Chronic ulceration was induced in rats maintained for 5 weeks on alcohol-containing or control liquid diet. In both groups, the ulcer onset was characterized by a massive increase (6.5-8.9-fold) in TNF-alpha and ET-1 (1.6-4.0-fold), and a decrease (1.4-1.5-fold) in IL-4. However, the group on the alcohol diet exhibited a 38.3% higher mucosal expression of TNF-alpha, a 26. 2% higher ET-1 level, and a 6.5% lower content of IL-4. While in both groups the ulcer healing was accompanied by an increase in buccal mucosal expression of IL-4, and a decline in ET-1 and TNF-alpha, the changes were significantly slower in the alcohol diet group and manifested by a 4 day delay in ulcer healing. The results suggest that chronic alcohol ingestion exerts detrimental effects on the buccal mucosal IL-4 expression, causing dysregulation of ET-1 production, induction of TNF-alpha, and triggering apoptotic events that delay the mucosal repair.

Topics: Acetic Acid; Animals; Apoptosis; Chronic Disease; Endothelin-1; Ethanol; Gene Expression; Interleukin-4; Mouth Mucosa; Rats; Rats, Sprague-Dawley; Time Factors; Tumor Necrosis Factor-alpha; Ulcer