Keratinocyte growth factor protects against Clara cell injury induced by naphthalene
AÖ Yildirim, M Veith, T Rausch, B Müller… - European …, 2008 - Eur Respiratory Soc
AÖ Yildirim, M Veith, T Rausch, B Müller, P Kilb, LS Van Winkle, H Fehrenbach
European Respiratory Journal, 2008•Eur Respiratory SocAirway epithelial cells are exposed to environmental toxicants that result in airway injury.
Naphthalene (NA) causes site-selective damage to Clara cells in mouse distal airways. N-
terminally truncated recombinant human keratinocyte growth factor (ΔN23-KGF) protects
against acute lung injury. The present study investigated whether or not ΔN23-KGF protects
against NA-induced acute Clara cell damage by measuring airway responses specifically
and in order to identify underlying molecular mechanisms. Mice were treated with ΔN23 …
Naphthalene (NA) causes site-selective damage to Clara cells in mouse distal airways. N-
terminally truncated recombinant human keratinocyte growth factor (ΔN23-KGF) protects
against acute lung injury. The present study investigated whether or not ΔN23-KGF protects
against NA-induced acute Clara cell damage by measuring airway responses specifically
and in order to identify underlying molecular mechanisms. Mice were treated with ΔN23 …
Airway epithelial cells are exposed to environmental toxicants that result in airway injury. Naphthalene (NA) causes site-selective damage to Clara cells in mouse distal airways. N-terminally truncated recombinant human keratinocyte growth factor (ΔN23-KGF) protects against acute lung injury. The present study investigated whether or not ΔN23-KGF protects against NA-induced acute Clara cell damage by measuring airway responses specifically and in order to identify underlying molecular mechanisms.
Mice were treated with ΔN23-KGF or PBS 33 h prior to injection of 200 mg·kg body weight−1 NA. Lung function was analysed by head-out body plethysmography. Distal airways isolated by microdissection were assessed for cell permeability using ethidium homodimer-1. Immunohistochemistry of Clara cell-specific protein in conjunction with a physical dissector was used to quantify Clara cell numbers. RNA was isolated from frozen airways in order to analyse gene expression using quantitative RT-PCR.
ΔN23-KGF prevented NA-induced airflow limitation and Clara cell permeability, and resulted in twice as many Clara cells compared with PBS pre-treatment. ΔN23-KGF-pre-treated mice exhibited increased expression of proliferating cell nuclear antigen mRNA. Cytochrome P450 isoform 2F2, which converts NA into its toxic metabolite, was reduced by ∼50%.
The present results demonstrate that pre-treatment with N-terminally truncated recombinant human keratinocyte growth factor protects against naphthalene-induced injury. This suggests that N-terminally truncated recombinant human keratinocyte growth factor exerts its beneficial effect through a decrease in the expression of cytochrome P450 isoform 2F2.
European Respiratory Society