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O'Toole, D,Hassett, P,Contreras, M,Higgins, BD,McKeown, STW,McAuley, DF,O'Brien, T,Laffey, JG
2009
November
Thorax
Hypercapnic acidosis attenuates pulmonary epithelial wound repair by an NF-kappa B dependent mechanism
Published
()
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ACUTE LUNG INJURY RESPIRATORY-DISTRESS-SYNDROME ISCHEMIA-REPERFUSION INJURY BACTERIAL PNEUMONIA MATRIX METALLOPROTEINASES THERAPEUTIC HYPERCAPNIA CARBON-DIOXIDE GROWTH-FACTOR CELLS INHIBITION
64
976
982
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-kappa B (NF-kappa B), 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-kappa B 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-kappa B 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-kappa B compared with normocapnia. Buffering of the acidosis did not alter this inhibitory effect. Prior inhibition of NF-kappa B 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-kappa B dependent mechanism that may involve alterations in matrix metalloproteinase activity.
DOI 10.1136/thx.2008.110304
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