Abstract
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 P 450 isoform 2F2. Copyright
| Original language | English (US) |
|---|---|
| Pages (from-to) | 694-704 |
| Number of pages | 11 |
| Journal | European Respiratory Journal |
| Volume | 32 |
| Issue number | 3 |
| DOIs | |
| State | Published - Sep 2008 |
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Keywords
- Airway epithelial injury
- Cytochrome P
- Keratinocyte growth factor
- Naphthalene
- Secretoglobin
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
- Medicine(all)
Cite this
Keratinocyte growth factor protects against Clara cell injury induced by naphthalene. / Yildirim, A. Ö; Veith, M.; Rausch, T.; Müller, B.; Kilb, P.; Van Winkle, L. S.; Fehrenbach, H.
In: European Respiratory Journal, Vol. 32, No. 3, 09.2008, p. 694-704.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Keratinocyte growth factor protects against Clara cell injury induced by naphthalene
AU - Yildirim, A. Ö
AU - Veith, M.
AU - Rausch, T.
AU - Müller, B.
AU - Kilb, P.
AU - Van Winkle, L. S.
AU - Fehrenbach, H.
PY - 2008/9
Y1 - 2008/9
N2 - 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 P 450 isoform 2F2. Copyright
AB - 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 P 450 isoform 2F2. Copyright
KW - Airway epithelial injury
KW - Cytochrome P
KW - Keratinocyte growth factor
KW - Naphthalene
KW - Secretoglobin
UR - http://www.scopus.com/inward/record.url?scp=51049113656&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=51049113656&partnerID=8YFLogxK
U2 - 10.1183/09031936.00155107
DO - 10.1183/09031936.00155107
M3 - Article
C2 - 18385170
AN - SCOPUS:51049113656
VL - 32
SP - 694
EP - 704
JO - European Respiratory Journal
JF - European Respiratory Journal
SN - 0903-1936
IS - 3
ER -