Activation of sGC induces the generation of cyclic guanosine

Activation of sGC induces the generation of cyclic guanosine monophosphate (cGMP), phosphorylation of protein kinase G (PKG) and changes in activity of effector proteins such as phosphodiesterases (PDE), ion channels and ion pumps [43]. This pathway eventually leads to dilation of bromophenol blue (bronchodilation) or vessels (vasodilation). In patients with asthma, bronchodilation is impaired, despite the presence of large amounts of NO in the airways that could activate sGC and cause relaxation of the smooth muscle. In a murine model of allergic asthma, the levels of sGC α1, α2 and β1 were reduced in the lungs, both on mRNA and protein level [44]. Mice treated with the selective sGC inhibitor ODQ had increased airway reactivity to methacholine compared with sham-treated mice [44]. This finding suggests that sGC could be inhibited in patients with asthma, leading to the observed airway hyperresponsiveness. Also in patients with COPD, the lungs contain ample amounts of NO, but the airway tone remains elevated [14]. Patients with COPD have decreased pulmonary mRNA and protein levels of sGC which are correlated with disease severity [45]. The levels of sGC are also decreased in CS-exposed mice [45] CS-exposed mice deficient for the sGC α1 subunit had a significantly higher airway resistance compared with CS-exposed wild-type mice (Fig. 1). These results indicate that sGC downregulation due to CS exposure in humans and mice, emerges as an alternative pathophysiological mechanism of the airway hyperresponsiveness.
Phosphodiesterase 5 (PDE5) degrades cGMP to GMP; thereby impairing the downstream effects of cGMP (Fig. 1). Sildenafil, a short-acting inhibitor of PDE5, is already on the market for erectile dysfunction and pulmonary arterial hypertension and induces smooth muscle relaxation. Tadalafil is a long-acting inhibitor of PDE5. The effect of PDE5 inhibition was analyzed in guinea pigs exposed to lipopolysaccharide (LPS) and in sensitized guinea pigs exposed to ovalbumin [46]. Pretreatment with sildenafil inhibited the LPS-induced airway hyperreactivity, influx of leukocytes and generation of NO. Exposure to ovalbumin caused early- and late-phase asthma responses which were not affected by sildenafil. However, AHR to histamine, leukocyte influx in BAL and increased NO metabolites in BAL were significantly attenuated in OVA-exposed mice after treatment with sildenafil [46]. In a rat model of acrolein (a component of cigarette smoke) exposure, sildenafil suppressed the acrolein-induced airway inflammation and mucus production [47]. CS-exposed mice have increased PDE5 protein levels in the lung compared with air-exposed mice [45]. These results suggest that PDE5 inhibitors have a therapeutic potential in airway diseases such as asthma and COPD. However, in contrast to OVA-challenged guinea pigs [46], OVA-challenged mice treated with sildenafil did not affect airway inflammation [48]. PDE5 inhibitors have not yet been tested in asthma or COPD for their anti-inflammatory properties. In contrast, PDE5 inhibitors have been investigated in patients with COPD and (concomitant) pulmonary hypertension. Treating patients with COPD-associated pulmonary hypertension with sildenafil or tadalafil did not improve exercise capacity or quality of life [49], [50].
Therapy
Concluding remarks
Acknowledgments This work was supported by the Concerted Research Action of the University of Ghent (BOF 14-GOA-027; Ghent, Belgium), by the Fund for Scientific Research Flanders (Project G.0195.09 and G.0194.10; Brussels, Belgium) and by the Interuniversity Attraction Poles Program/Belgian State/Belgian Science Policy (P7/30; Brussels, Belgium). L.L. Dupont is a beneficiary from a Bijzonder Onderzoeksfonds Research grant from Ghent University. K.R. Bracke is a Postdoctoral Fellow of the Fund for Scientific Research Flanders. C. Glynos was supported by EU grant (Call: FP7-REGPOT2011-1): “establishment of a centre of excellence for structured-based drug target characterization: strengthening the research capacity of South-Eastern Europe” (SEE-DRUG, www.seedrug.upatras.gr). P. Brouckaert is supported by the COST Action BM1005 (European Network on Gasotransmitters).