Therapeutic use of gas phase nitric oxide (NO) has several important applications in medicine. In addition to its well-known vasodilator action, NO is a potent and endogenous antimicrobial agent normally present at moderate levels (200-1000 ppbv) in the airways/sinuses of healthy individuals, which helps preventing chronic upper airway and lung infections. Since its first medical application >20 years ago, inhaled nitric oxide (iNO) has become a mainstay of intensive care for lung failure patients and it is essential in neonatology, lung transplantation, and pulmonary hypertension. It is also used in pneumonia, acute respiratory distress syndrome (ARDS), and potentially to treat of pulmonary tuberculosis and malaria. With the widespread hospital use of iNO there is a great potential for use of iNO also in the home for treating chronic pulmonary infections related to chronic obstructive pulmonary disease (COPD, ca. 11.5 million cases in US) and chronic rhino sinusitis (CRS, ca. 31 million cases in US). Further, while cases of cystic fibrosis (CF) is less common (ca. 30,000 cases), CF patients possess a genetic defect that greatly reduces NO levels liberated by airway epithelial cells, resulting in very high risk of infection. However, iNO therapy is presently exceedingly expensive (>$3,000 per day) owing to costly NO cylinders and the associated instability of NO in such gas tanks. Therefore, current NO delivery technology is both too expensive and non-portable for potential routine use for in-home care. Using funding from an exploratory R21 grant, our research team has developed a completely new and very attractive method for light-activated NO generation directly from solid phase S-nitrosothiols (RSNO) type NO donors. We have demonstrated that light-activated feedback-controlled release of NO can be achieved precisely from RSNO loaded polymer films combined with variable LED lighting. An amperometric NO selective sensor can provide signals for a feedback circuit to control the LED light intensity to achieve a target level of NO in the output air (or O2) stream. We have identified the main parameters affecting the efficiency of NO release from such films and for minimizing the emitted levels of toxic NO2 gas. In this R01 grant our team will further study the possibilities of scaling up the light-activated NO generation system. We will test the purity of the generated NO gas and the composition of the residual solid decomposition products in order to determine light triggered reaction mechanism of the NO release from the solid state RSNO species. We will study the antimicrobial and cytotoxic properties of the generated NO gas on bacteria infected human epithelial cells and in CFTR knockout mice. This new photochemical gas phase NO generation approach will be very attractive and much lower in cost than using current iNO delivery systems employing high pressure gas tanks. Indeed, photochemically generated NO could eventually be safely extended to in-home use for certain clinical situations (e.g., CF, COPD, CRS and ARDS) to prevent and treat chronic lung infections.
Chronic obstructive pulmonary disease (COPD) and chronic rhinosinusitis (CRS) together affect an estimated 15% of the US population and both diseases are associated with frequent respiratory tract infections. Cystic fibrosis (CF) affects a much smaller number of patients (30,000), but their risk of severe infection is greater and long-term prognosis is much poorer than patients with COPD or CRS. Each of these disorders has been linked to abnormally low levels of nitric oxide (NO), a potent endogenous antimicrobial/antiviral agent, within the airways of those afflicted with these diseases. Through the research described in this application, we will develop a very inexpensive and simple photochemical gas phase NO generating system for potential use at home by COPD, CRS and CF patients.