The role of nitric oxide in porcine models of asthma and acute lung injury

Abstract: Nitric oxide (NO) is a modulator of many important physiological processes in the body. It is produced endogenously in several cell types by a family of NO synthases (NOS). The lower respiratory tract is a part of the body that has received a lot of attention with regard to the role of NO, as this molecule seems to be involved in the inflammatory processes taking place in for instance asthma and the acute respiratory distress syndrome (ARDS). The purpose of this thesis was to establish models for inflammatory disorders of the respiratory tract in the pig and to characterise the role of NO in these models. The pig was chosen because of its size, and its physiological resemblance to humans. Interest was focused on two areas: the acute allergic reaction (as a model of the early phase of an allergic asthmatic attack) and acute lung injury (ALI, as a model of ARDS). A previously developed model for the acute allergic reaction was used in the first two studies. In this model pigs were sensitised with Ascaris suum allergen. Upon airway challenge with the allergen they react with acute bronchoconstriction and other reactions similar to an acute allergic reaction. In the first study it was found that inhibition of NOS enhanced the antigen -induced, but not the histamine-induced, acute airway reactions. This indicated a protective role of NO. Since histamine levels in bronchoalveolar lavage fluid were increased by pre- treatment with the NOS inhibitor L-NNA, it was proposed that one of the mechanisms through which NO could exert its protective effect is through down-regulation of histamine release from mast cells. In a next study the effects of inhalation of 20 p.p.m. of NO on the allergen -induced acute allergic reaction were studied. A protective effect of NO inhalation was found on arterial oxygenation and pulmonary arterial pressure. However, neither could a significant protective effect of NO inhalation on bronchoconstriction be observed, nor did inhaled NO affect histamine release by mast cells. This would indicate that it is mainly the endogenously produced NO that is responsible for the protective effects, and not high levels of exogenous NO. ALI and septic shock were induced in the pig by infusion of lipopolysaccharide (LPS). Pretreatment with metyrapone (a cortisol-synthesis inhibitor) severely enhanced LPS-induced ALI and septic shock and was therefore included in the subsequent sepsis studies. Inhalation of a low (0.2 p.p.m.) and a high (20 p.p.m.) dose of NO was shown to have protective effects on arterial oxygenation, whereas the high dose also improved pulmonary arterial pressure. The underlying inflammatory responses were not affected by NO. The reactivity of the bronchial circulation to increasing doses of NO was demonstrated to be severely reduced after 4 h of septic shock, whereas the reactivity of the pulmonary circulation was not affected. Infusion of the Gram-positive bacterial cell wall components peptidoglycan (PepG) and lipoteichoic acid (LTA) demonstrated that these two components act in synergy to induce ALI and septic shock in the pig. Despite haemodynamic similarities to Gram-negative (LPS) ALI and septic shock, marked differences were observed in the inflammatory mechanisms. In conclusion, inhalation of NO in two different models of inflammation of the lower respiratory tract resulted in protective effects on arterial oxygenation and pulmonary arterial pressure, but not on the inflammatory responses. Inhibition of endogenously produced NO resulted in an increased allergic reaction, including inflammatory responses. Therefore, it seems likely that it is the endogenously produced NO that plays a protective role in allergic inflammation, and not artificially administered inhaled NO. Induction of ALI and septic shock via infusion of LPS led to distinctly different observations in bronchial and pulmonary vascular reactivity to inhalation of NO. Bronchial vascular reactivity to NO inhalation was reduced, whereas pulmonary vascular reactivity remained. This may be an important observation, as the bronchial circulation is of importance in healing mechanisms during inflammation in the lower respiratory tract.