Hypercapnic acidosis attenuates pulmonary epithelial wound repair by an NF-kappaB dependent mechanism.
Thorax
; 64(11): 976-82, 2009 Nov.
Article
em En
| MEDLINE
| ID: mdl-19617214
ABSTRACT
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-kappaB (NF-kappaB), 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-kappaB 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 (P(CO(2))) 11 kPa) or normocapnia (pH 7.37, P(CO(2)) 5.5 kPa) and the rate of healing determined. Subsequent experiments investigated the role of hypercapnia versus acidosis and elucidated the role of NF-kappaB 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-kappaB compared with normocapnia. Buffering of the acidosis did not alter this inhibitory effect. Prior inhibition of NF-kappaB 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-kappaB dependent mechanism that may involve alterations in matrix metalloproteinase activity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acidose Respiratória
/
Cicatrização
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NF-kappa B
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Lesão Pulmonar Aguda
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Hipercapnia
Limite:
Humans
Idioma:
En
Revista:
Thorax
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Irlanda
País de publicação:
ENGLAND
/
ESCOCIA
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GB
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GREAT BRITAIN
/
INGLATERRA
/
REINO UNIDO
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SCOTLAND
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UK
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UNITED KINGDOM