title: Hypercapnic acidosis attenuates pulmonary epithelial stretch-induced injury via inhibition of the canonical NF-κB pathway.
abstract: BACKGROUND
  Hypercapnia, with its associated acidosis (HCA), is a consequence of respiratory failure and is also seen in critically ill patients managed with conventional "protective" ventilation strategies. Nuclear factor kappa-B (NF-κB), a pivotal transcription factor, is activated in the setting of injury and repair and is central to innate immunity. We have previously established that HCA protects against ventilation-induced lung injury in vivo, potentially via a mechanism involving inhibition of NF-κB signaling. We wished to further elucidate the role and mechanism of HCA-mediated inhibition of the NF-κB pathway in attenuating stretch-induced injury in vitro.
  
  
  METHODS
  Initial experiments examined the effect of HCA on cyclic stretch-induced inflammation and injury in human bronchial and alveolar epithelial cells. Subsequent experiments examined the role of the canonical NF-κB pathway in mediating stretch-induced injury and the mechanism of action of HCA. The contribution of pH versus CO2 in mediating this effect of HCA was also examined.
  
  
  RESULTS
  Pulmonary epithelial high cyclic stretch (22 % equibiaxial strain) activated NF-κB, enhanced interleukin-8 (IL-8) production, caused cell injury, and reduced cell survival. In contrast, physiologic stretch (10 % strain) did not activate inflammation or cause cell injury. HCA reduced cyclic mechanical stretch-induced NF-κB activation, attenuated IL-8 production, reduced injury, and enhanced survival, in bronchial and alveolar epithelial cells, following shorter (24 h) and longer (120 h) cyclic mechanical stretch. Pre-conditioning with HCA was less effective than when HCA was applied after commencement of cell stretch. HCA prevented the stretch-induced breakdown of the NF-κB cytosolic inhibitor IκBα, while IκBα overexpression "occluded" the effect of HCA. These effects were mediated by a pH-dependent mechanism rather than via CO2 per se.
  
  
  CONCLUSIONS
  HCA attenuates adverse mechanical stretch-induced epithelial injury and death, via a pH-dependent mechanism that inhibits the canonical NF-κB activation by preventing IκBα breakdown.
authors.affiliation: Discipline of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.|Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Shahd
authors.initials: S
authors.lastname: Horie
authors.affiliation: Discipline of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.|Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Bilal
authors.initials: B
authors.lastname: Ansari
authors.affiliation: Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.|Department of Anesthesia, Critical Illness and Injury Research Centre, Keenan Research Centre for Biomedical Science, St Michael's Hospital, University of Toronto, Toronto, Canada.
authors.forename: Claire
authors.initials: C
authors.lastname: Masterson
authors.affiliation: Discipline of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.|Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: James
authors.initials: J
authors.lastname: Devaney
authors.affiliation: Discipline of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.|Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Michael
authors.initials: M
authors.lastname: Scully
authors.affiliation: Discipline of Anaesthesia, School of Medicine, Clinical Sciences Institute, National University of Ireland, Galway, Ireland.|Regenerative Medicine Institute, National University of Ireland, Galway, Ireland.
authors.forename: Daniel
authors.initials: D
authors.lastname: O'Toole
authors.affiliation: Regenerative Medicine Institute, National University of Ireland, Galway, Ireland. laffeyj@smh.ca.|Department of Anesthesia, Critical Illness and Injury Research Centre, Keenan Research Centre for Biomedical Science, St Michael's Hospital, University of Toronto, Toronto, Canada. laffeyj@smh.ca.
authors.forename: John G
authors.initials: JG
authors.lastname: Laffey
keywords: Acute respiratory distress syndrome; Hypercapnic acidosis; Inflammation; Nuclear factor kappa-B; Repair; Ventilation-induced lung injury