title: In vivo hydroquinone exposure causes tracheal hyperresponsiveness due to TNF secretion by epithelial cells.
abstract: Hydroquinone (HQ) is the main oxidative substance in cigarette smoke and a toxic product of benzene biotransformation. Although the respiratory tract is an inlet pathway of HQ exposure, its effect on airway muscle responsiveness has not been assessed. We thus investigated the effects of low dose in vivo HQ-exposure on tracheal responsiveness to a muscarinic receptor agonist. Male Swiss mice were exposed to aerosolised 5% ethanol/saline solution (HQ vehicle; control) or 0.04 ppm HQ (1h/day for 5 days) and tracheal rings were collected 1h after the last exposure. HQ exposure caused tracheal hyperresponsiveness to methacholine (MCh), which was abolished by mechanical removal of the epithelium. This hyperresponsiveness was not dependent on neutrophil infiltration, but on tumour necrosis factor (TNF) secretion by epithelial cells. This conclusion was based on the following data: (1) trachea from HQ-exposed mice presented a higher amount of TNF, which was abrogated following removal of the epithelium; (2) the trachea hyperresponsiveness and TNF levels were attenuated by in vivo chlorpromazine (CPZ) treatment, an inhibitor of TNF synthesis. The involvement of HQ-induced TNF secretion in trachea mast cell degranulation was also demonstrated by the partial reversion of tracheal hyperresponsiveness in sodium cromoglicate-treated animals, and the in vivo HQ-exposure-induced degranulation of trachea connective tissue and mucosal mast cells, which was reversed by CPZ treatment. Our data show that in vivo HQ exposure indirectly exacerbates the parasympathetic-induced contraction of airway smooth muscle cells, mediated by TNF secreted by tracheal epithelial cells, clearly showing the link between environmental HQ exposure and the reactivity of airways.
authors.affiliation: Laboratory of Experimental Toxicology, Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo, Brazil.
authors.forename: Ana Lúcia Borges
authors.initials: AL
authors.lastname: Shimada
authors.forename: Adriana
authors.initials: A
authors.lastname: Lino-Dos-Santos-Franco
authors.forename: Simone Marques
authors.initials: SM
authors.lastname: Bolonheis
authors.forename: André
authors.initials: A
authors.lastname: Nakasato
authors.forename: Amílcar Sabino
authors.initials: AS
authors.lastname: Damazo
authors.forename: Wothan
authors.initials: W
authors.lastname: Tavares-de-Lima
authors.forename: Sandra Helena Poliselli
authors.initials: SH
authors.lastname: Farsky
mesh_terms: D000818:Animals; D002746:Chlorpromazine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006873:Hydroquinones / Q000009:adverse effects*; D008297:Male; D008407:Mast Cells / Q000187:drug effects; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000378:metabolism; D014132:Trachea / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D006873:Hydroquinones; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D002746:Chlorpromazine; C031927:hydroquinone