PT  - JOURNAL ARTICLE
AU  - D O’Toole
AU  - P Hassett
AU  - M Contreras
AU  - B D Higgins
AU  - S T W McKeown
AU  - D F McAuley
AU  - T O’Brien
AU  - J G Laffey
TI  - Hypercapnic acidosis attenuates pulmonary epithelial wound repair by an NF-κB dependent mechanism
AID  - 10.1136/thx.2008.110304
DP  - 2009 Nov 01
TA  - Thorax
PG  - 976--982
VI  - 64
IP  - 11
4099  - http://thorax.bmj.com/content/64/11/976.short
4100  - http://thorax.bmj.com/content/64/11/976.full
SO  - Thorax2009 Nov 01; 64
AB  - 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.