Rationale: Hypercapnic acidosis exerts direct protective effects in lung injury models, but may also slow cellular repair. Hypercapnic acidosis inhibits activation of nuclear factor-κB (NF-κB), a pivotal transcriptional regulator of genes involved in inflammation and repair.
Objectives: We sought to determine the effects of hypercapnic acidosis in pulmonary epithelial wound repair, and determine the role of NF-κB in mediating these effects.
Methods: Confluent small airway epithelial cell, human bronchial epithelial (HBE) cell and type II alveolar A549 cell monolayers were subjected to wound injury, and incubated under conditions of hypercapnic acidosis (pH 7.0, PCO2 11KPa) or normocapnia (pH 7.37, PCO2 5.5KPa), and the rate of healing determined. Subsequent experiments investigated the role of hypercapnia versus acidosis, and elucidated the role of NF-κB, MAP kinases and matrix metalloproteinases in mediating these effects of hypercapnic acidosis.
Results: Hypercapnic acidosis reduced wound closure (33 ± 6.3% versus 64 ± 5.9%, P < 0.01), and reduced activation of NF-κB, compared to control conditions. 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 inhibition of wound repair was dependent on reduced cell migration. Hypercapnic acidosis reduced matrix metalloproteinase-1 and increased TIMP-2 concentrations.
Conclusions: Hypercapnic acidosis inhibits pulmonary epithelial wound healing via inhibition of NF-κB activation, and involving alteration of expression of matrix metalloproteinases.