Nitric oxide could promote development of Barrett's esophagus by S-nitrosylation-induced inhibition of Rho-ROCK signaling in esophageal fibroblasts
Nitric oxide could promote development of Barrett's esophagus by S-nitrosylation-induced inhibition of Rho-ROCK signaling in esophageal fibroblasts
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DOI：
10.1152/ajpgi.00124.2021
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发表时间：
2022-01-01
影响因子：
4.5
通讯作者：
Masamune, Atsushi
中科院分区：
文献类型：
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作者：
Fujiya, Taku;Asanuma, Kiyotaka;Masamune, Atsushi
Barrett‘s食道发生于胃食道反流病损伤的远端食道上皮的伤口愈合过程中。成纤维细胞分化为肌成纤维细胞、平滑肌细胞样表型和组织收缩是创面愈合的关键过程。目前尚无研究评价管腔内一氧化氮(NO)影响间质成纤维细胞Rho相关螺旋线圈形成蛋白激酶(Rho-ROCK)信号通路的机制。Rho-ROCK是组织收缩的关键因素，参与Barrett‘s食道的形成。利用成纤维细胞，我们进行了基于胶原的细胞收缩试验，并评价了Rho-ROCK信号在酸性胆盐和NO供体NOC-9中的影响。我们发现，NO抑制酸性胆盐诱导的细胞收缩，并伴随着磷酸化肌球蛋白轻链表达的减少和应力纤维的形成。NO直接使GTP-RhoA亚硝化，从而阻断Rho-Rock信号转导。此外，暴露于NO和Rho-ROCK信号抑制剂Y27632可降低α-SMA的表达，增加骨形态发生蛋白-4(BMP4)的表达和分泌。这些发现可能解释了BMP4在人Barrett‘s食管柱状上皮细胞和间质成纤维细胞中表达增加的原因。NO可通过阻断Rho-Rock信号通路损害创面收缩，促进Barrett‘s食道的发展。值得注意的是，Barrett’s食道是指胃食道反流病(GERD)损伤的食道上皮通过替换化生的柱状上皮而异常愈合的情况，但在Barrett‘s食道的发育过程中，很少有研究发现创面愈合。食管腔一氧化氮抑制了食道成纤维细胞的Rho-Rock信号通路，从而导致延迟组织收缩，这是伤口正常愈合的关键步骤。此外，这种抑制增加了组织BMP4的表达。伤口愈合不良可能与Barrett‘s食道有关。
Barrett's esophagus arises in the process of wound healing in distal esophageal epithelium damaged by gastroesophageal reflux disease. Differentiation of fibroblast into myofibroblasts, a smooth muscle cell-like phenotype and tissue contraction are crucial processes in wound healing. No study has evaluated mechanism by which luminal esophageal nitric oxide (NO) affect Rho-asso-ciated coiled coil-forming protein kinase (Rho-ROCK) signaling pathway, a key factor of tissue contraction, in stromal fibroblasts to develop Barrett's esophagus. Using esophageal fibroblasts, we performed collagen-based cell contraction assays and eval-uated influence of Rho-ROCK signaling in the exposure to acidic bile salts and NOC-9, which is an NO donor. We found that enhanced cell contraction induced by acidic bile salts was inhibited by NO, accompanied by decrease in phosphorylated myosin light chain expression and stress fiber formation. NO directly S-nitrosylated GTP-RhoA and consequently blocked Rho-ROCK sig-naling. Moreover, exposure to NO and Y27632, a Rho-ROCK signaling inhibitor, decreased alpha-SMA expression and increased bone morphogenetic protein-4 (BMP4) expression and secretion. These findings could account for the increased expression of BMP4 in the columnar epithelial cells and stromal fibroblasts in human Barrett's esophagus. NO could impair wound contraction by blocking the Rho-ROCK signaling pathway and promote the development of Barrett's esophagus.NEW & NOTEWORTHY Barrett's esophagus is the condition where esophageal epithelium damaged by gastroesophageal reflux disease (GERD) is abnormally healed via replacing of metaplastic columnar epithelium, but very few studies have conducted fo-cusing wound healing in the development of Barrett's esophagus. Esophageal luminal nitric oxide inhibits Rho-ROCK signaling pathway in esophageal fibroblasts, which leads to delay tissue contraction, a pivotal step in proper wound healing. Moreover, this inhibition increases tissue BMP4 expression. Impaired wound healing could be related to Barrett's esophagus.