Hypercapnic acidosis attenuates pulmonary epithelial wound repair by an NF-κB dependent mechanism
- D O’Toole1,2,
- P Hassett1,2,
- M Contreras1,2,
- B D Higgins1,2,
- S T W McKeown3,
- D F McAuley3,
- T O’Brien4,
- J G Laffey1,2,4
- 1Department of Anaesthesia, Clinical Sciences Institute, National University of Ireland, Galway, Ireland
- 2Lung Biology Group, National Centre for Biomedical Engineering Sciences, National University of Ireland, Galway, Ireland
- 3Respiratory Medicine Research Group, Centre for Infection and Immunity, The Queen’s University of Belfast, Belfast, UK
- 4Regenerative Medicine Institute, National University of Ireland, Galway, Ireland
- Correspondence to Professor J G Laffey, Department of Anaesthesia, Clinical Sciences Institute, National University of Ireland, Galway, Ireland;
- Received 29 October 2008
- Accepted 5 July 2009
- Published Online First 16 July 2009
Background: Hypercapnic acidosis exerts protective effects in acute lung injury but may also slow cellular repair. These effects may be mediated via inhibition of nuclear factor-κB (NF-κB), a pivotal transcriptional regulator in inflammation and repair.
Objectives: To determine the effects of hypercapnic acidosis in pulmonary epithelial wound repair, to elucidate the role of NF-κB and to examine the mechanisms by which these effects are mediated.
Methods: Confluent small airway epithelial cell, human bronchial epithelial cell and type II alveolar A549 cell monolayers were subjected to wound injury under conditions of hypercapnic acidosis (pH 7.0, carbon dioxide tension (Pco2) 11 kPa) or normocapnia (pH 7.37, Pco2 5.5 kPa) and the rate of healing determined. Subsequent experiments investigated the role of hypercapnia versus acidosis and elucidated the role of NF-κB and mitogen-activated protein kinases. The roles of cellular mitosis versus migration and of matrix metalloproteinases in mediating these effects were then determined.
Results: Hypercapnic acidosis reduced wound closure (mean (SD) 33 (6.3)% vs 64 (5.9)%, p<0.01) and reduced activation of NF-κB compared with normocapnia. Buffering of the acidosis did not alter this inhibitory effect. Prior inhibition of NF-κB activation occluded the effect of hypercapnic acidosis. Inhibition of ERK, JNK and P38 did not modulate wound healing. Hypercapnic acidosis reduced epithelial cell migration but did not alter mitosis, and reduced matrix metalloproteinase-1 while increasing concentrations of tissue inhibitor of metalloproteinase-2.
Conclusions: Hypercapnic acidosis inhibits pulmonary epithelial wound healing by reducing cell migration via an NF-κB dependent mechanism that may involve alterations in matrix metalloproteinase activity.
▸ Additional details and figures are published online only at http://thorax.bmj.com/content/vol64/issue11
This work was presented in part at the American Thoracic Society annual conference, Toronto, May 2008.
Funding This study was funded by the Health Research Board, Ireland (DO’T, BH, JGL) under the project grant award RP-2005-244.
Competing interests None.
DO’T and PH contributed equally to this paper.
Provenance and Peer review Not commissioned; externally peer reviewed.