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Keratinocyte growth factor protects against Clara cell injury induced by naphthalene

¹ Clinical Research Group "Chronic Airway Diseases", Medical Faculty, Philipps University of Marburg, Marburg, Germany, and ² Dept of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine and Center for Health and the Environment, University of California, Davis, CA, USA. ³ Both authors contributed equally to this study.

CORRESPONDENCE: A. Ö. Yildirim, Clinical Research Group "Chronic Airway Diseases", Medical Faculty, Philipps University Marburg, Hans-Meerwein Str.1, 35043 Marburg, Germany. Fax: 49 64212866095. E-mail: ayildiri{at}med.uni-marburg.de

Keywords: Airway epithelial injury, cytochrome P₄₅₀, keratinocyte growth factor, naphthalene, secretoglobin

Received: November 19, 2007
Accepted March 18, 2008

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 (N23-KGF) protects against acute lung injury. The present study investigated whether or not N23-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 N23-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.

N23-KGF prevented NA-induced airflow limitation and Clara cell permeability, and resulted in twice as many Clara cells compared with PBS pre-treatment. N23-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.