Effects of PKR inhibitor on poly (I:C)-induced exacerbation of severe asthma

Abstract

Respiratory viral infection is the most common cause for severe asthma exacerbation. The double-stranded RNA (dsRNA)-activated serine/threonine kinase R (PKR) is well characterized as an essential component of the innate antiviral response. Meanwhile, PKR phosphorylates e-IF2a, one of branches for unfolded protein response (UPR). However, to date, there is little information on its role the asthma exacerbation, especially in steroid-resistant severe asthma. In this study, we investigated whether PKR activation is involved in the induction of asthma exacerbation using a mouse model of acute asthma exacerbation induced by the administration of poly (I:C). We found that the administration of poly (I:C) aggravated the all severe asthmatic features compared to those in mice sensitized with ovalbumin (OVA) and lipopolysaccharide (LPS) and challenged with OVA (OVA LPS -OVA mice); the number of airway inflammatory cells in bronchoalveolar lavage (BAL) fluids, airway hyperresponsiveness, and the expression of Th2 cytokines, IL-17 and KC in lung tissues. Interestingly, the PKR expression was also more increased in lung tissues from OVA LPS -OVA mice treated with poly (I:C) than OVA LPS -OVA mice. Moreover, the phosphorylation of PKR in primary cultured tracheal epithelial cells was further enhanced in OVA LPS -OVA mice treated with poly (I:C). PKR inhibition using 2-AP attenuated these features of exacerbated severe asthma. This study indicates that PKR activation plays an important role the induction of acute exacerbation of severe neutrophilic asthma, highlighting the therapeutic potential of PKR inhibitor as a potent controller of acute asthma exacerbation in severe asthmatic patients.