Tuesday, November 5, 2013
Rhinovirus infection causes steroid resistance in airway epithelium through nuclear factor кB and c-Jun N-terminal kinase activation
Inhaled glucocorticoids are often highly effective in treating symptoms of asthma exacerbations, however they are ineffective at treating and preventing exacerbations brought on by rhinovirus infection, especially in children. Glucocorticoids act by binding to glucocorticoid receptors (GR) α which become activated and translocate to the nucleus, leading to the activation of down-stream anti-inflammatory pathways. Papi et al sought to determine the mechanistic actions of glucocorticoids during rhinovirus infection by studying factors in these anti-inflammatory pathways (J Allergy Clin Immunol 2013; 132(5): 1075-1085).
Using a variety of assays and human bronchial epithelial cells, the authors determined that the rhinovirus RV-16 reduces the ability of dexamethasone to inhibit the pro-inflammatory cytokine IL-1β induction of the chemokine CXCL8. They went on to show that there is an RV-16 dependent impairment of dexamethasone-induced GRα nuclear translocation that is mediated by the transcription factor NFкB p65 as well as the c-JUN N-terminal Kinase, JNK-1, both pro-inflammatory pathways. To solidify this finding, Papi attempted to reverse the RV-16 induced attenuation of GR nuclear translocation by dexamethasone with inhibitors of NFкB and JNK. Their results indicate that independently, both inhibitors partially rescued the impairment and the combination of both inhibitors totally restored dexamethasone sensitivity. The authors show that rhinovirus infection inhibits glucocorticoid mechanisms of action and impair both the transactivation and transrepression activities of dexamethasone, implying that rhinovirus infection targets an upstream aspect of GR activation.
These finding suggest a novel molecular mechanism for rhinoviruses, the biggest trigger of asthma exacerbations, to impair the ability of glucocorticoids to control airway inflammation. These data indicate a strategy through which rhinovirus infection can overcome the anti-inflammatory defense but also indicate approaches that might reverse this process. The discovery of completely inhibiting both NFкB and JNK pathways reverses glucocorticoid resistance identifies new therapeutic approaches for asthma and rhinoviruses in general for which there is no effective treatment available.
Questions for the authors:
Are there other markers or pathways that are involved that could be considered therapeutic approaches for treatment?
Yes, it is possible that the mechanisms by which rhinovirus inhibit corticosteroid activity involves the activation of other pro-inflammatory pathways, as 1) rhinovirus induces the production of multiple inflammatory mediators; 2) rhinovirus inhibits an upstream step of the mechanism of action of corticosteroids. We analyzed the keys/main mediators, but many other could be affected.
Could there be other pro-inflammatory cytokines that are up-regulated that amplify the effect of rhinoviruses?
Several pro-inflammatory mediators are induced by rhinovirus infection (Hansell TT. Lancet. 2013). They are likely affected by the mechanisms we described in the study as they are upstream steps of the mechanism of action of corticosteroids.
The severity of asthma symptoms is well known to be attenuated by inhaled corticosteroid (ICS) due to their anti-inflammatory effect. Long-acting β-agonists (LABA) and long acting muscarinic antagonists (LAMA) are current treatment options for patients that do not respond well to low dose ICSs. Using data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute’s Asthma Clinical Research Network’s Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid, Peters et al sought to determine individual and differential responses of asthmatic patients to salmeterol (LABA) and tiotropium (LAMA) when added to an inhaled corticosteroid, as well as predictors of a positive clinical response to the end points FEV₁, morning peak expiratory flow (PEF), and asthma control days (ACDs) (J Allergy Clin Immunol 2013; 132(5):1068-1074).
In the attempt to personalize the best treatment options for patients, investigators have used a variety of strategies, including the use of biomarkers, patient-specific and physiologic “predictors” and genetic/genomic approaches. Predictors of response that have been investigated by researchers include short-acting bronchodilators and leukotriene modifiers, but more recently, predicting the response to glucocorticoids, namely ICSs have contributed valuable insight into this framework. The author’s interest in long-acting bronchodilators, such as LABAs and LAMAs stems from the lack of information that has been published concerning these predictors of response, including intra-subject response of asthmatic patients treated with both a LABA and a LAMA.
Utilizing information from 210 asthmatic adults, the authors discovered that the use of tiotropium with a low dose of ICS resulted in a superior primary outcome compared to doubling the ICS alone, as assessed by improvement of morning PEF, evening PEF, a decrease in ACDs, and an increase in FEV₁. Salmeterol had a similar but less robust response, and subjects showed a differential response to tiotropium for FEV₁, but not for salmeterol. Furthermore, younger patients responded better to tiotropium in terms of ACDs. Peters also reports that large numbers of patients responded to either salmeterol or tiotropium, but not to both agents. This suggests that at the time of administration, different mechanisms were operating to produce airway constriction and symptoms in these 2 groups of patients. Finally, although the use of a short-acting bronchodilator did predict a positive response to a long-acting bronchodilator controller of the same class, albuterol response better predicted a response to tiotropium than did ipratropium.
While these findings need to be replicated in an independent study, the data suggest that asthmatics that have suboptimal asthma control using ICSs alone, with airway obstruction as demonstrated by a reduced FEV₁/FVC ratio, a positive response to albuterol, or both, should be good candidates for treatment with tiotropium as an add-on therapy. This could be used for patients where combination ICS-LABA therapy fails or when ICS monotherapy in inadequate for symptom control.