FIGURE 6.

Schematic representation of the role of NO in lung cancer. Cigarette smoke is a source of exogenous NO, irritants, and ROS that activates macrophages and epithelial cells of the airways to release cytokines that attract inflammatory cells to the lungs. In epithelial cells, the expression of the iNOS increases by proinflammatory stimuli such as IL-1β produced by macrophages. Patients with lung cancer show higher levels of F_ENO than healthy controls. An elevated NO generates nitrosative stress and amplification of inflammation. Although in physiological conditions, after DNA damage, NO activates p53 inducing apoptosis of cells, an excess of NO inactivates p53 function. In addition, higher concentrations of NO in the lung also downregulates caspase–3 activity and S-nitrosylation and stabilization of BCl-2 protein, all of them contributing to inhibition of apoptosis. Prolonged NO stimulation is additionally 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 created with Biorender.