Pharmacological modulation of cGMP levels by phosphodiesterase 5 inhibitors as a therapeutic strategy for treatment of respiratory pathology in cystic fibrosis

Abstract

The CFTR gene encodes a chloride channel with pleiotropic effects on cell physiology and metabolism. Here, we show that increasing cGMP levels to inhibit epithelial Na(+) channel in cystic fibrosis (CF) respiratory epithelial cells corrects several aspects of the downstream pathology in CF. Cell culture models, using a range of CF cell lines and primary cells, showed that complementary pharmacological approaches to increasing intracellular cGMP, by elevating guanyl cyclase activity though reduced nitric oxide, addition of cell-permeable cGMP analogs, or inhibition of phosphodiesterase 5 corrected multiple aspects of the CF pathological cascade. These included correction of defective protein glycosylation, bacterial adherence, and proinflammatory responses. Furthermore, pharmacological inhibition of phosphodiesterase 5 in tissues ex vivo or in animal models improved transepithelial currents across nasal mucosae from transgenic F508del Cftr(tm1Eur) mice and reduced neutrophil infiltration on bacterial aerosol challenge in Pseudomonas aeruginosa-susceptible DBA/2 mice. Our findings define phosphodiesterase 5 as a specific target for correcting a number of previously disconnected defects in the CF respiratory tract, now linked through this study. Our study suggests that phosphodiesterase 5 inhibition provides an opportunity for simultaneous and concerted correction of seemingly disparate complications in CF.

Inhaled phosphodiesterase type 5 inhibitors restore chloride transport in cystic fibrosis mice

“…Additionally, potential interest in PDE5 inhibitors to treat CF might be raised by the assumption that PDE5 inhibitors have a possible anti-inflammatory action [28][29][30]. In fact, it has been shown that application of sildenafil for 24 h to cultured CF bronchial epithelial cells exposed to Pseudomonas aeruginosa, a crucial pathogen responsible for the progressive loss of lung function in CF, reduced secretion of interleukin-8, a cytokine abnormally elevated in CF and responsible for neutrophil infiltrate and subsequent inflammatory cascade [29].…”

Effect of sildenafil on acrolein-induced airway inflammation and mucus production in rats

“…In a murine model of LPS-induced lung injury, sGC inhibition worsens lung inflammation, which can be reversed by a cell-permeable cGMP analogue [37]. In CF respiratory epithelial cells, increasing cGMP levels correct multiple aspects of the CF pathological cascade, including defective protein glycosylation, bacterial adherence and pro-inflammatory responses [14].…”

“…For instance, in guinea pig models of airway disease, sildenafil inhibits airway hyperreactivity, leukocyte infiltration and NO generation after allergen exposure and exposure to endotoxin [29]. In mice challenged with bacterial aerosol, sildenafil reduces lung neutrophil infiltration [14]. The current data showed that sildenafil pretreatment significantly reduced acrolein-induced leukocyte influx and NO generation, as well as TNF-a and CINC-1 release, in both the BALF and lung tissue, which could be attributed to the consequent reversed intracellular cGMP levels in the lung.…”

“…Sildenafil is now commonly used in clinical treatment for erectile dysfunction. Recently, it has been intensively studied in the treatment of pulmonary arterial hypertension [25,26], hyperoxia or hypoxia-induced lung injury [27,28] and airway diseases [14,29]. Thus, the aim of the present study was to examine the effect of sildenafil on airway inflammation, goblet cell metaplasia and mucin synthesis in a rat model induced by acrolein inhalation.…”

“…For example, it has been reported that cGMP signalling is involved in the downregulation of P-selectin expression and leukocyte recruitment in mice [13]. Pharmacologically increasing cGMP levels in CF respiratory epithelial cells can correct several aspects of the downstream pathology in CF [14]. cGMP analogues also have shown some anti-inflammatory activity through inhibiting lipopolysaccharide (LPS)-induced TNF-a secretion in both human monocytes and murine macrophages [15,16].…”