Increased expression of endothelin-1 and endothelin receptor A in reflux esophagitis and Barrett's esophagus

Abstract

Barrett's esophagus (BE) is considered a complication of the inflammation provoked by acid and bile reflux. Endothelin-1 (ET-1) expresses in various cells during inflammatory process. However, the role of ET-1 in human inflamed and uninflamed esophageal tissue is unknown. The present study aimed to examine the expression of ET-1 and its receptors in human reflux esophagitis (RE) and BE. Endoscopic biopsies of normal squamous epithelium (NSE) (n = 20), RE (n = 22), and long segment BE (n = 14) were obtained. The segmental degree of endoscopic and histopathological inflammation was graded, and immunohistochemistry and real-time quantitative polymerase chain reaction were used to determine the expression of ET-1 and endothelin receptor A (ET(A)R) and endothelin receptor B (ET(B)R). ET-1 and ET(A)R messenger RNA (mRNA) levels were higher in RE than in NSE (3.25 ± 1.78 vs. 1.10 ± 0.71, P = 0.000; 2.13 ± 1.06 vs. 1.12 ± 0.64, P = 0.001, respectively). In BE, relative ET-1 mRNA levels in the proximal segment were higher than in the distal segment (3.03 ± 1.83 vs. 1.16 ± 0.70, P = 0.004) and in normal esophageal epithelium (P = 0.002). There was no significantly difference of ET(A)R mRNA levels between the proximal segment and the distal segment (1.99 ± 1.28 vs. 1.14 ± 0.67, P = 0.072). ET(B)R mRNA expression was unaltered between the groups. Furthermore, immunohistochemistry demonstrated that ET-1 expression increased significantly in RE (51.18 ± 30.14) compared with those in NSE (21.10 ± 18.17, P = 0.000) and in distal BE segment (28.02 ± 24.92, P = 0.022). There were more ET-1 positive cells in proximal BE segment (50.07 ± 25.88) than in distal BE segment (P = 0.030) and in NSE (P = 0.001). ET-1 expression increased in a stepwise manner with the growing degree of inflammation, and there were significant differences between mild, moderate, and marked degree esophagitis (36.08 ± 27.84, 65.86 ± 11.82, 98.00 ± 8.49, P = 0.003, respectively). However, expression of receptors remained unchanged. This study demonstrates that over-expression of ET-1 and ET(A)R in esophagitis may be related to the inflammatory process. ET-1 may play a significant role in the progression of Barrett's metaplasia.