The Role of Soluble Guanylyl Cyclase in Chronic Obstructive Pulmonary Disease

Rationale: Soluble guanylyl cyclase (sGC), a cyclic guanosine 5'-monophosphate-generating enzyme, regulates smooth muscle tone and exerts antiinflammatory effects in animal models of asthma and acute lung injury. In chronic obstructive pulmonary disease (COPD), primarily caused by cigarette smoke (CS), lung inflammation persists and smooth muscle tone remains elevated, despite ample amounts of nitric oxide that could activate sGC. Objectives: To determine the expression and function of sGC in patients with COPD and in a murine model of COPD. Methods: Expression of sGC alpha 1, alpha 2, and beta 1 subunits was examined in lungs of never-smokers, smokers without airflow limitation, and patients with COPD; and in C57BL/6 mice after 3 days, 4 weeks, and 24 weeks of CS exposure. The functional role of sGC was investigated in vivo by measuring bronchial responsiveness to serotonin in mice using genetic and pharmacologic approaches. Measurements and Main Results: Pulmonary expression of sGC, both at mRNA and protein level, was decreased in smokers without airflow limitation and in patients with COPD, and correlated with disease severity (FEV1%). In mice, exposure to CS reduced sGC, cyclic guanosine 5'-monophosphate levels, and protein kinase G activity. sGC alpha 1(-/-) mice exposed to CS exhibited bronchial hyperresponsiveness to serotonin. Activation of sGC by BAY 58-2667 restored the sGC signaling and attenuated bronchial hyperresponsiveness in CS-exposed mice. Conclusions: Down-regulation of sGC because of CS exposure might contribute to airflow limitation in COPD.