• Peter J Barnes, Genki Kimura, Shouichi Eto, Takashi Masuko, Tadashi Kusama, and Yasuo Kizawa.
• Department of Physiology and Anatomy, Nihon University School of Pharmacy, Chiba, Japan.
• Chest. 2013 Jul 1;144(1):99-105.

BackgroundRNA virus infections, such as rhinovirus and respiratory syncytial virus, induce exacerbations in patients with COPD and asthma, and the inflammation is corticosteroid refractory. The main aim of this study is to establish a murine model induced by a Toll-like receptor 3 (TLR3) agonist, an RNA virus mimic, and investigate the response to corticosteroid.MethodsA/J mice were given polyinosinic-polycytidylic acid (poly[I:C]), a TLR3 agonist, intranasally, in the presence or absence of cigarette smoke exposure. Inflammatory cell accumulation and C-X-C motif chemokine (CXCL) 1, interferon (IFN), and CXCL10 production in BAL fluid (BALF) were determined by flow cytometry and enzyme-linked immunosorbent assay, respectively, and airway hyperresponsiveness (AHR) to histamine/methacholine was determined by a two-chambered, double-flow plethysmography system. BALB/c and C57BL/6J mice were also used for comparisons.ResultsIntranasal treatment of poly(I:C) significantly induced airway neutrophilia; production of CXCL1, IFN-β, and CXCL10; and necrotic cell accumulation in BALF. It also increased airway responsiveness to histamine or methacholine inhalation. This poly(I:C)-dependent airway inflammation and AHR was not inhibited by the corticosteroid fluticasone propionate (FP) (up to 0.5 mg/mL intranasal), although FP strongly inhibited lipopolysaccharide (TLR4 agonist)-induced airway neutrophilia. Furthermore, cigarette smoke exposure significantly increased TLR3 expression in murine lung tissue and exacerbated poly(I:C)-induced neutrophilia and AHR.ConclusionsThese results suggest that TLR3 stimulation is involved in corticosteroid-refractory airway inflammation in lung, which is enhanced by cigarette smoking, and this may provide a model for understanding virus-induced exacerbations in COPD and their therapy.

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