Search

The pathogenesis of reflux esophagitis results from an imbalance between aggressive factors damaging the esophagus and the natural antireflux barriers. The local renin-angiotensin system (RAS) exists in esophageal mucosa, however, its contribution to the mechanism of esophageal integrity has not been clarified. Angiotensin-(1-7) (Ang-(1-7)) which is an important component of the RAS, was recently implicated in gastroprotection but its effect on damage induced by reflux esophagitis (RE) has not been explored. We evaluated the possible protective effect of Ang-(1-7) against mucosal lesions induced by the acute RE induced in anesthetized rats by ligating of the pylorus and the limiting ridge (transitional region between the forestomach and the corpus of stomach). Rats were pretreated 30 min before induction of RE either with 1) vehicle (saline), 2) Ang-(1-7) (5 75 μg/kg i.p.), 3) Ang-(1-7) (50 μg/ kg i.p.) without and with A 779 (2.5 mg/kg i.p.), a selective antagonist of Ang-(1-7) Mas receptor, 4) Ang 1-7 (50 μg/kg i.p.) without and with capsaicin (125 mg/kg s.c.) to induce functional ablation of sensory nerves, and 5) antisecretory treatment with PPI inhibitor, pantoprazole (10 mg/kg i.g.). Four hrs after induction of esophagitis, the damage was graded with mucosal lesion index (LI) from 0-6, the esophageal blood flow (EBF) was determined by H2-gas clearance technique and the RT-PCR expression and plasma levels of proinflammatory cytokines IL-1β and TNF-α was determined by ELISA. The esophageal LI and wet weight in esophagitis were significantly higher and the EBF was decreased by 35% as compared with the intact mucosa Pretreatment with Ang-(1-7) which in intact rats increased the EBF by 25% without any damage and alteration in plasma IL-1β and TNF-α levels, almost completely prevented, similarly as pantoprazole, the esophageal mucosal injury and significantly increased EBF by about 18% as compared to that in vehicle-controls with RE. The esophagoprotective effects and the rise in EBF induced by Ang-(1-7) were completely abolished by A779. Capsaicin denervation which by itself failed to affect the esophageal lesions, also reduced the esophagoprotective and hyperemic effects of Ang-(1-7) and both protection and hyperemia were restored by co-treatment with CGRP (10 μg/kg s.c.). Ang(1-7) significantly decreased the RE-induced increase in mRNA expression and plasma IL1β and TNF-α levels and these effects were also abolished by pretreatment with A779 and capsaicin-sensory denervation. We conclude that Ang-(1-7), a potent vasodilatatory member of angiotensin family peptides, exhibits esophagoprotection against the esophageal damage induced by reflux esophagitis via mechanism involving activation of Mas receptor, the stimulation of sensory nerves releasing of vasodilatatory CGRP and the suppression of expression and release of IL-1β and TNF-α.

Purpose: Radiation therapy is an important modality for cancer treatment as well as chemotherapy and surgery. It has been reported that radiation proctitis occurs in 5 20% of cases treated with pelvic radiation for cancers such as cervical cancer and prostatic cancer. The most common symptom of radiation procitis is rectal bleeding, and it often impairs QOL and sometimes requires blood transfusion. The pathological findings of radiation proctitis are characterized by abnormal angiogenesis and the bleeding from the abnormal vessels. However, the mechanisms by which radiation proctitis develops in humans are totally unknown. Therefore, in this study, the expression profiles of angiogenic factors were analyzed to clarify their role in the etiology of radiation proctitis. Patients and Methods: Eight patients with radiation proctitis (M/F, 6/2; average age, 67 ± 10.4 years) and 8 healthy volunteers (M/F, 5/3; average age, 65.3 ± 7.6 years) were enrolled. Diagnosis of radiation proctitis was made according to the criteria by Cavci et al. Rectal biopsy samples were endoscopically taken and frozen. The protein lysates of the tissues were incubated with biotin-labeled antibody. Then, they were reacted with the antibody array membrane, incubated with streptavidin-horseradish peroxidase (HRP), and visualized using a luminescent image analyzer. Total RNA was extracted from the tissues and reverse transcribed into cDNA. Then, Taqman real-time PCR was performed to evaluate the mRNA level of each factor. Immunohistochemistry was performed using the labeled streptavidin biotin (LSAB) method. Results: Antibody array analysis revealed 2.127.31-fold higher expression levels of angiogenin, FGF1, endoglin, MMP-8, uPA and maspin in radiation proctitis tissues compared with normal rectal mucosa. The mRNA levels of angiogenin, FGF1, maspin, MMP-8, endoglin, and uPA were significantly higher in radiation proctitis tissues than in normal rectal tissues (P < 0.05), indicating that these angiogenic factors were overexpressed by transcriptional activation. Immunohistochemical staining showed strong expression of angiogenin and maspin in rectal epithelia, MMP-8 and uPA in infiltrating lymphocytes, FGF1 in fibroblasts, and endoglin in endothelial cells. The major angiogenic factor, VEGF, was not overexpressed in radiation proctitis tissue compared with the normal rectal mucosa (0.91 1.32-fold). Conclusion: Our results suggest that in radiation proctitis, MMP-8 and uPA cooperatively degrade the extracellular matrix (ECM) and basement membrane to provide space for angiogenesis. Simultaneously, angiogenin and FGF1 promote endothelial cell proliferation, and endoglin induces vessel formation, culminating in angiogenesis. Inhibitors of angiogenic factors such as angiogenin and FGF1 may be effective for treating radiation proctitis.