Abstract
Rhinovirus (RV) infections account for approximately two thirds of all virus-induced asthma exacerbations and often result in an impaired response to β2 agonist therapy. Using an in vitro model of RV infection, we investigated the mechanisms underlying RV-induced β2 adrenoceptor desensitization in primary human airway smooth muscle cells (ASMC). RV infection of primary human bronchial epithelial cells (HBEC) for 24 hours produced conditioned medium that caused β2 adrenoceptor desensitization on ASMCs without an effect on ASMCs viability. Less than 3 kDa size fractionation together with trypsin digestion of RV-induced conditioned medium did not prevent β2 adrenoceptor desensitization, suggesting it could potentially be mediated by a small peptide or lipid. RV infection of BECs, ASMCs and fibroblasts produced prostaglandins, of which PGE2, PGF2α and PGI2 had the ability to cause β2 adrenoceptor desensitization on ASMCs. RV-induced conditioned medium from HBECs depleted of PGE2 did not prevent ASMC β2 adrenoceptor desensitization; however this medium induced PGE2 from ASMCs, suggesting that autocrine prostaglandin production may be responsible. Using inhibitors of cyclooxygenase and prostaglandin receptor antagonists, we found that β2 adrenoceptor desensitization was mediated through ASMC derived COX-2 induced prostaglandins. Since ASMC prostaglandin production is unlikely to be caused by RV-induced epithelial derived proteins or lipids we next investigated activation of toll-like receptors (TLR) by viral RNA. The combination of TLR agonists poly I:C and imiquimod induced PGE2 and β2 adrenoceptor desensitization on ASMC as did the RNA extracted from RV-induced conditioned medium. Viral RNA but not epithelial RNA caused β2 adrenoceptor desensitization confirming that viral RNA and not endogenous human RNA was responsible. It was deduced that the mechanism by which β2 adrenoceptor desensitization occurs was by pattern recognition receptor activation of COX-2 induced prostaglandins.
Highlights
Acute exacerbations of asthma are the major cause of morbidity, mortality and health costs related to the disease
In contrast RV-induced conditioned medium from human bronchial epithelial cells (HBEC) resulted in a decreased isoprenaline induced cyclic adenosine monophosphate (cAMP) from airway smooth muscle cells (ASMC) compared to treatment with control conditioned medium and was indicative of b2 adrenoceptor (b2 AR) desensitization (p,0.05, Figure 1C)
We aimed to identify the responsible mediators and pathways which are involved and we confirmed that RV infection of primary HBEC produced conditioned medium that when used to treat ASMCs reduces isoprenaline induced cAMP, functionally causing b2 AR desensitization
Summary
Acute exacerbations of asthma are the major cause of morbidity, mortality and health costs related to the disease. Reddel and colleagues reported that in asthmatic adults, during a respiratory viral infection their exacerbation was characterized by reduced response to b2 agonists despite having good asthma control prior to infection, and a good response to b2 agonists prior to achieving good asthma control [3]. Rueter et al reported that asthmatic children responded less effectively to b2 agonist therapy in response to a viral-induced exacerbation in which RV was the most frequently identified virus [4]. These reports indicate that the underlying cause of this reduced response to b2 agonists during these exacerbations of asthma may be unique to a viral infection. The exact causes of exacerbations of asthma are unknown, it possible that functional impairment of the b2 adrenoceptor (b2 AR) may disrupt intrinsic bronchodilation through circulating epinephrine and result in airflow limitation characteristic of an exacerbation
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