Original Research: Asthma |

Toll-like Receptor 3 Stimulation Causes Corticosteroid-Refractory Airway Neutrophilia and Hyperresponsiveness in MicePoly(I:C)-Induced Airway Neutrophilia

Genki Kimura, PhD; Keitaro Ueda, MSc; Shouichi Eto, MSc; Yuji Watanabe, MSc; Takashi Masuko, PhD; Tadashi Kusama, PhD; Peter J. Barnes, MD, FCCP; Kazuhiro Ito, DVM, PhD; Yasuo Kizawa, PhD
Author and Funding Information

From the Department of Physiology and Anatomy (Drs Kimura, Masuko, Kusama, and Kizawa and Messrs Ueda, Eto, and Watanabe), Nihon University School of Pharmacy, Funabashi, Chiba, Japan; and Airway Disease Section (Drs Barnes and Ito), National Heart and Lung Institute, Imperial College, London, England.

Correspondence to: Yasuo Kizawa, PhD, Department of Physiology and Anatomy, Nihon University School of Pharmacy, 7-7-1, Narashinodai, Funabashi, Chiba 274-8555, Japan; e-mail: kizawa.yasuo@nihon-u.ac.jp

Funding/Support: This research was funded by “High-Tech Research Center” Project for Private Universities (2007-2011): matching fund subsidy from MEXT (Japan; to Dr Kizawa).

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

Chest. 2013;144(1):99-105. doi:10.1378/chest.12-2610
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Background:  RNA 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.

Methods:  A/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.

Results:  Intranasal 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.

Conclusions:  These 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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