Alterations in the proteome of the respiratory tract in response to single and multiple exposures to naphthalene

Abstract

Protein adduction is considered to be critical to the loss of cellular homeostasis associated with environmental chemicals undergoing metabolic activation. Despite considerable effort, our understanding of the key proteins mediating the pathologic consequences from protein modification by electrophiles is incomplete. This work focused on naphthalene-induced acute injury of respiratory epithelial cells and tolerance which arises after multiple toxicant doses to define the initial cellular proteomic response and later protective actions related to tolerance. Airways and nasal olfactory epithelium from mice exposed to 15 ppm NA either for 4 hrs (acute) or for 4 hrs/day × 7 days (tolerant) were used for label free protein quantitation by LC/MS/MS. Cyp2f2 and secretoglobin 1A1 are decreased dramatically in airways of mice exposed for 4 hrs, a finding consistent with the fact that P450's are localized primarily in Clara cells. A number of heat shock proteins and protein disulfide isomerases, which had previously been identified as adduct targets for reactive metabolites from several lung toxicants, were upregulated in airways but not olfactory epithelium of tolerant mice. Protein targets that are upregulated in tolerance may be key players in the pathophysiology associated with reactive metabolite protein adduction.

Naphthalene DNA adduct formation and tolerance in the lung

“…Since GSH conjugates are the primary mechanism of detoxification, tolerance exposures increase the ability of Club cells to detoxify NA metabolites before adducts form. Nevertheless, NA-protein adducts are much more plentiful than NA-DNA adducts [35,37,48]. While a decrease in the concentrations of reactive metabolites available could lead to reduced DNA- and protein adducts, the effects may be more pronounced for protein adducts than for DNA adducts, as the present study suggests.…”

Reaction products of hexamethylene diisocyanate vapors with “self” molecules in the airways of rabbits exposed via tracheostomy

“…Polymorphism in human SCGB1A1 is associated with reduced levels of protein and increased likelihood of developing asthma (Candelaria et al, 2005; Ku et al, 2011; Laing et al, 2000; Taniguchi et al, 2013). Of particular relevance to the present study are findings (Kultz et al, 2015) demonstrating uteroglobin as a reaction target for naphthalene, a xenobiotic metabolically activated within Clara cells. Kultz et al suggest chemical modification of proteins such as uteroglobin, which normally exhibit anti-inflammatory activity (Miele et al, 1987; Mukherjee et al, 2007; Ray et al, 2006; Shijubo et al, 2003; Vasanthakumar et al, 1988), may be key to the pathophysiology associated with certain xenobiotic exposures (Kultz et al, 2015).…”

“…Of particular relevance to the present study are findings (Kultz et al, 2015) demonstrating uteroglobin as a reaction target for naphthalene, a xenobiotic metabolically activated within Clara cells. Kultz et al suggest chemical modification of proteins such as uteroglobin, which normally exhibit anti-inflammatory activity (Miele et al, 1987; Mukherjee et al, 2007; Ray et al, 2006; Shijubo et al, 2003; Vasanthakumar et al, 1988), may be key to the pathophysiology associated with certain xenobiotic exposures (Kultz et al, 2015). Further investigation, beyond the scope of this study, will be needed to determine if human uteroglobin is also susceptible to HDI modification in vivo , and if so, its potential relevance to occupational exposure and/or disease pathogenesis.…”

Deconstructing the molecular architecture of olfactory areas using proteomics

“…Fifty percent of differential expressed proteins in OE were upregulated in both types of exposures. Interestingly, most proteins adducted by reactive NA metabolites were exclusively N ‐ or O ‐glycosylated in airway epithelium indicating a tissue‐specific difference in protein glycosylation .…”