Journal article
Normoxic cyclic GMP-independent oxidative signaling by nitrite enhances airway epithelial cell proliferation and wound healing
Nitric oxide, Vol.26(4), pp.203-210
05/15/2012
DOI: 10.1016/j.niox.2012.03.002
PMCID: PMC3854970
PMID: 22425780
Abstract
► Sodium nitrite potently enhanced airway epithelium wound healing. ► Nitrite does not increase cGMP levels under normoxic condition. ► Oxidative reactions with H2O2 and downstream ERK1/2 activation are involved.
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 (NO2) 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 1μM). The effect of nitrite was blocked by the NO and NO2 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/NO2 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, NO2.
Details
- Title: Subtitle
- Normoxic cyclic GMP-independent oxidative signaling by nitrite enhances airway epithelial cell proliferation and wound healing
- Creators
- Ling Wang - University of PittsburghSheila A. Frizzell - University of PittsburghXuejun Zhao - University of PittsburghMark T. Gladwin - University of Pittsburgh
- Resource Type
- Journal article
- Publication Details
- Nitric oxide, Vol.26(4), pp.203-210
- DOI
- 10.1016/j.niox.2012.03.002
- PMID
- 22425780
- PMCID
- PMC3854970
- NLM abbreviation
- Nitric Oxide
- ISSN
- 1089-8603
- eISSN
- 1089-8611
- Publisher
- Elsevier Inc
- Grant note
- name: NIH, award: R01HL098032, RO1HL096973, RC1DK085852, PO1HL103455
- Language
- English
- Date published
- 05/15/2012
- Academic Unit
- Orthopedics and Rehabilitation
- Record Identifier
- 9984303979102771
Metrics
8 Record Views