RNA virus infections, such as rhinovirus and respiratory syncytial virus, induce exacerbations in patients with chronic obstructive pulmonary disease (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, a RNA virus mimic, and investigate the response to corticosteroid.
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 CXCL1, IFNs and CXCL10 productions in bronchoalveolar lavage fluid (BALF) were determined by flow cytometry and ELISA, 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.
Intranasal treatment of poly(I:C) significantly induced airway neutrophilia, production of CXCL1, IFN-β and CXCL10, necrotic cell accumulation in BALF, and also increased airway responsiveness to histamine or methacholine inhalation. These poly(I:C)-dependent airway inflammation and AHR were not inhibited by the corticosteroid fluticasone propionate (FP; up to 0.5 mg/ml intranasal), although FP strongly inhibited LPS (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.
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.