Keratinocyte growth factor protects against Clara cell injury induced by naphthalene

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. Nterminally truncated recombinant human keratinocyte growth factor (DN23-KGF) protects against acute lung injury. The present study investigated whether or not DN23-KGF protects against NAinduced acute Clara cell damage by measuring airway responses specifically and in order to identify underlying molecular mechanisms.Mice were treated with DN23-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. DN23-KGF prevented NA-induced airflow limitation and Clara cell permeability, and resulted in twice as many Clara cells compared with PBS pre-treatment. DN23-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 ,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.

Clara cells drive eosinophil accumulation in allergic asthma

“…The experiments presented here support previous findings that NA-treatment efficiently induces apoptosis in the majority of Clara cells with no obvious cytotoxic side-effects on other cell types [26][27][28]. Importantly, mice with impaired Clara cells at the time of aerosol challenge showed strongly diminished eosinophil accumulation around the airways and in the BALF.…”

“…1a). NA induced Clara cell-specific death without any other cellular alteration or nonspecific cell death in the lungs as reported previously [26][27][28]. Within 24 h, extensive detachment of Clara cells from the basement membrane and almost complete denudation of the epithelium in some airways was observed ( fig.…”

Comparative gene expression profiling of post-natal and post-pneumonectomy lung growth

“…As these enzymes play a role in preventing damage through xenobiotics [25], one could speculate that in this early stage of life, interference by metabolism of xenobiotics would significantly damage the structure and that lower CYP levels prevent such damage. Regarding this point, the lack of Cyp2f2, which was downregulated 3.4-fold in P3 lungs, has been shown to have a protective role in naphthalene-induced Clara cell damage [26]. The downregulation of the microsomal epoxide hydrolase 1 (Ephx1), which also plays a role in detoxification, further supports this thesis.…”

Nerve growth factor induces type III collagen production in chronic allergic airway inflammation

“…Systematic uniform random sampling (SURS) was performed to obtain a representative collection of lung tissue samples. 19 After paraffin embedment, 3-mm sections were stained with hematoxylin and eosin. Collagen fibrils were detected by means of staining with Sirius Red (Sigma-Aldrich)/Fast Green (Rowley Biochemicals, Danvers, Mass).…”