Keratinocyte growth factor protects against Clara cell injury induced by naphthalene.
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 (DeltaN23-KGF) protects against acute lung injury. The present study investigated whether or not DeltaN23-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 DeltaN23-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. DeltaN23-KGF prevented NA-induced airflow limitation and Clara cell permeability, and resulted in twice as many Clara cells compared with PBS pre-treatment. DeltaN23-KGF-pre-treated mice exhibited increased expression of proliferating cell nuclear antigen mRNA. Cytochrome P(450) isoform 2F2, which converts NA into its toxic metabolite, was reduced by approximately 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 P(450) isoform 2F2.
Yildirim
A O
AO
Clinical Research Group Chronic Airway Diseases, Medical Faculty, Philipps University Marburg, Hans-Meerwein Str.1, 35043 Marburg, Germany. ayildiri@med.uni-marburg.de
Veith
M
M
Rausch
T
T
Müller
B
B
Kilb
P
P
Van Winkle
L S
LS
Fehrenbach
H
H
D055371:Acute Lung Injury / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D055745:Bronchioles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism; D051523:Fibroblast Growth Factor 7 / Q000008:administration & dosage*; D051379:Mice; D009281:Naphthalenes / Q000633:toxicity; D010993:Plethysmography, Whole Body; D011994:Recombinant Proteins / Q000008:administration & dosage*
D009281:Naphthalenes; D011994:Recombinant Proteins; D051523:Fibroblast Growth Factor 7; C031721:naphthalene; D003577:Cytochrome P-450 Enzyme System; C110333:Cyp2f2 protein, mouse