Studies on nitric oxide in the respiratory system

Nitric oxide (NO) is formed in biological tissues and has regulatory functions in many organ systems. Endogenous NO has been found in exhaled air and NO is considered to have effects on the pulmonary circulation and bronchial tone, and to be one of the mediators for the circulatory adaptation at birth. Exogenous NO inhalation has been administered to patients with acute lung injury and pulmonary hypertension, but with varying responses and is not yet an approved therapy. The role of NO in the respiratory system is still unclear.

Objectives: A better understanding of NO in the respiratory system under normal- and pathophysiological conditions.

Material: Human adults with healthy and sick lungs. Premature and healthy term neonates. Several different animal species, domestic animals as well as wild animals at a zoo.

Methods: Endogenous airway NO concentrations were measured by chemiluminescence. Analysers with different response times and sampling flow rates were utilised in measurements of mixed exhaled air, after timed occlusions and in single breaths. Exhaled gas from different parts of the airways was studied. Two clinically used methods, chemiluminescence and electrochemical techniques, were evaluated by measurements in clinically relevant gas mixtures, containing up to 80 ppm NO in oxygen.

Results: The measured NO concentrations were dependent on sampling site, gas flow, and measuring technique. In adults, significant but low tracheal NO concentrations were measured, a few parts per billion (ppb), whereas nasal NO levels were several hundred times higher. All neonates, term as well as preterm infants, displayed high nasal NO concentrations, up to 4.6 parts per million (ppm) after timed occlusions already within a few minutes after birth, independent of mode of delivery. Nasal NO concentrations had increased 4-7 days after birth in term infants and were also related to the postconceptional age of the preterm infants. In animals we found a great difference in nasal NO concentrations between species. NO levels comparable with humans were only found in other primates (Rhesus monkey, chimpanzee and gorilla) and in elephant. Rhesus monkey and pig were studied in more detail and displayed quite different excretion pattern. Both chemiluminescence and electrochemical cells were found to be suitable for monitoring during NO inhalation therapy. Without precautions, toxic NO2 levels, up to 5 ppm, may be formed in a ventilatory circuit in hyperoxic NO-rich gas mixtures.

Conclusions. In humans, NO is excreted from the respiratory system with the highest concentrations from the nose. An autoinhalation from the upper to the lower airways is possible and might effect the pulmonary vessels. The high nasalNO concentrations, up to 4.6 ppm, found in neonates might be important for the circulatory adaptation at birth and indicates that at least some tissue is adapted to such NOlevels. Microbes is not a prerequisite for nasal NO excretion as it was found already within a few minutes after delivery by Caesarean section. The great species differences in nasal NO concentrations could not be related to differences in upper airway anatomy or living conditions. To extrapolate animal data to humans might be hazardous and so far only primates seem to be suitable for such studies.