Περίληψη:
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.
Συγγραφείς:
Glynos, Constantinos
Dupont, Lisa L.
Vassilakopoulos, Theodoros
and Papapetropoulos, Andreas
Brouckaert, Peter
Giannis,
Athanassios
Joos, Guy F.
Bracke, Ken R.
Brusselle, Guy G.
