The expression on the iNOS increases by proinflammatory stimuli such as IL-1 produced by macrophages. Individuals with lung cancer show larger levels of FE NO than healthy controls. An elevated NO generates nitrosative tension and amplification of inflammation. Although in physiological situations, right after DNA harm, NO activates p53 inducing apoptosis of cells, an excess of NO inactivates p53 function. Moreover, higher concentrations of NO inside the lung also downregulates caspase activity and S-nitrosylation and stabilization of BCl-2 protein, all of them contributing to inhibition of apoptosis. Prolonged NO stimulation is in addition DYRK4 Inhibitor drug related to EMT by increasing vimentin and snail expression and decreasing E-cadherin levels. NO also enhances epithelial cell migration by caveolin-1 upregulation and angiogenesis by COX-2, PGE2, and VEGF upregulation. The image has been developed with Biorender.and cardiovascular diseases for their smooth muscle relaxation effect (Sandner, 2018). In COPD or asthma, these types of drugs have shown an anti-inflammatory impact (Mokry, 2017; Ren et al., 2020). Furthermore, aside from decreasing airway inflammation, sildenafil attenuates the mucus overproduction characteristic of each illnesses by means of the restoration of cGMP levels (Wang et al., 2009). In an animal model of COPD, sildenafil showed a reduction in lung harm. After exposure to tobacco smoke and bacterial inhalation, these animals showed an increase in each proliferation and apoptosis pathways in epithelial cells of bronchioles, suggesting that the pulmonary harm is associated with the abnormal repair from the airway epithelium. Treatment with sildenafil substantially reduces the apoptosis inside the bronchiolar epithelium decreasing the pulmonary harm (Ren et al., 2020). These benefits are in line with others that recommend that inhibition ofPDE5 can alleviate lung dysfunction and tobacco smoke-induced emphysema using the restoration on the NO-sGC-cGMP-PKG pathway and reduction of ROS (Milara et al., 2010; Seimetz et al., 2015). Even so, its efficacy is restricted in COPD and asthma because the sGC activation is decreased and, therefore, cGMP levels are also decreased. In these cases, even though the degradation of cGMP is inhibited, enough levels aren’t reached for the treatment of those pathologies (Evgenov et al., 2011; Sandner, 2018). In mutated F508del CF mice, inhaled exposure on the PDE5 inhibitors sildenafil, vardenafil, and tadalafil, results in restoration of chloride transport across the respiratory epithelium (Lubamba et al., 2011). Sildenafil acts in two techniques in human bronchial epithelial cells: by means of cGMP-dependent and cGMP-independent pathways. Through the cGMP-dependent pathway, sildenafil avoids cGMP degradation and therefore a rise of PKGFrontiers in Physiology www.frontiersin.orgJune 2021 Volume 12 ArticleBayarri et al.Nitric Oxide and Bronchial EpitheliumFIGURE 7 Scheme in the redox state in the sGC enzyme plus the IL-23 Inhibitor Accession modulatory drugs that act on the NO- sGC-cGMP pathway. Soon after oxidative pressure, the heme group is oxidized (Fe+3), along with the sGC enzyme is insensitive to NO. Additionally, the oxidized heme group loses affinity for the enzyme and is released. The drugs that could modulate this axis are NO donors, iNOS inhibitors, PDE5 inhibitors, and sGC modulators. sGC modulators increase the activity of sGC and thus the formation of cGMP independently of NO and are classified as stimulators or activators of sGC. Stimulators of sGC act when the heme group.