Down regulation of soluble guanylate cyclase contributes to bronchial hyperreactivity in asthma

We have used an ovalbumin (OVA) model of inflammatory airway disease to explore the role of soluble guanylyl cyclase (sGC) in bronchial hyperactivity (BHR) and inflammation associated with asthma. OVA treated mice exhibited a 60-80 % reduction in steady-state mRNA levels of sGC subunits compared to control mice as determined by real-time PCR. Similarly, protein levels of the sGC subunits were reduced by 50-70% in animals with asthma. In addition, inhibition of sGC activity using the selective inhibitor 1H-[1,2,4] oxydiazolo[4,3-ea]quinoxalin-1-one (ODQ) lead to increased basal bronchial tone and airway reactivity to methacholine. ODQ-treated mice, also exhibited a significant increase in macrophage number in the bronchiolar lavage (BAL) that was not accompanied by changes in lung histology and interleukin-13 production. These data indicate that sGC inhibition is accompanied by an inflammatory response that is qualitatively different from that observed in asthma (eosinophil infiltration and increased IL-13 production). We conclude that sGC inhibition contributes to the BHR seen in asthma.