Normoxic cyclic GMP-independent oxidative signaling by nitrite enhances airway epithelial cell proliferation and wound healing

详细信息	查看全文 | 推荐本文 |

• 作者：Ling Wang^a ; Sheila A. Frizzell^a ; Xuejun Zhao^a ; ^b ; Mark T. Gladwin^a ; ^b ; ^{gladwinmt@upmc.edu}
• 关键词：Sodium nitrite ; Nitric oxide ; Cyclic GMP ; Cell proliferation ; Airway epithelium ; Hydrogen peroxide
• 刊名：Nitric Oxide
• 出版年：2012
• 期刊代码：181_10898603
• 类别：bio
• 出版时间：15 May, 2012
• 卷：26
• 期：4
• 页码：203-210
• 文件大小：775 K

摘要

The airway epithelium provides important barrier and host defense functions. Recent studies reveal that nitrite is an endocrine reservoir of nitric oxide (NO) bioactivity that is converted to NO by enzymatic reductases along the physiological oxygen gradient. Nitrite signaling has been described as NO dependent activation mediated by reactions with deoxygenated redox active hemoproteins, such as hemoglobin, myoglobin, neuroglobin, xanthine oxidoreductase (XO) and NO synthase at low pH and oxygen tension. However, nitrite can also be readily oxidized to nitrogen dioxide () via heme peroxidase reactions, suggesting the existence of alternative oxidative signaling pathways for nitrite under normoxic conditions. In the present study, we examined normoxic signaling effects of sodium nitrite on airway epithelial cell wound healing. In an in vitro scratch injury model under normoxia, we exposed cultured monolayers of human airway epithelial cells to various concentrations of sodium nitrite and compared responses to NO donor. We found sodium nitrite potently enhanced airway epithelium wound healing at physiological concentrations (from 1 渭M). The effect of nitrite was blocked by the NO and scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO). Interestingly, nitrite treatment did not increase cyclic guanosine monophosphate (cGMP) levels under these normoxic conditions, even in the presence of a phosphodiesterase 5 inhibitor, suggesting cGMP independent signaling. Consistent with an oxidative signaling pathway requiring hydrogen peroxide (H₂O₂)/heme-peroxidase/ signaling, the effects of nitrite were potentiated by superoxide dismutase (SOD) and low concentration H₂O₂, whereas inhibited completely by catalase, followed by downstream extracellular-signal-regulated kinase (ERK) 1/2 activation. Our data represent the first description of normoxic nitrite signaling on lung epithelial cell proliferation and wound healing and suggest novel oxidative signaling pathways involving nitrite-H₂O₂ reactions, possibly via the intermediary, .