Keratinocyte growth factor protects against Clara cell injury induced by naphthalene

¹ Clinical Research Group "Chronic Airway Diseases", Medical Faculty, Philipps-University Marburg, Germany
² Dept of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine and Center for Health and the Environment, University of California, Davis, California, 95615, USA

^* To whom correspondence should be addressed. E-mail: ayildiri{at}med.uni-marburg.de.

	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. N23-KGF protects against acute lung injury. This study investigated whether N23-KGF protects against NA-induced acute Clara cell damage by measuring airway responses specifically and to identify underlying molecular mechanisms.

Mice were treated with N23-KGF or PBS 33h prior to injection of 200 mg·kg^-1 NA. Lung function was analysed by head-out body plethysmography. Distal airways isolated by microdissection were assessed by ethidium homodimer-1 for cell permeability. Immunohistochemistry for Clara cell specific protein in conjunction with a physical disector was used to quantify Clara cell numbers. RNA was isolated from frozen airways to analyse gene expression by quantitative RT-PCR.

N23-KGF prevented NA-induced airflow limitation and Clara cell permeabilty, and resulted in twice as many Clara cells compared to PBS pre-treatment. N23-KGF pre-treated mice exhibited increased mRNA expression for proliferating cell nuclear antigen. Cytochrome P450 isoform 2F2 (CYP2F2), which converts NA into its toxic metabolite, was reduced by about 50%.

Our results demonstrate that pre-treatment with N23-KGF protects against NA-induced injury. We suggest that N23-KGF exerts its beneficial effect through a decrease in the expression of CYP2F2.