Effects of hypoxia on the human lung

A large number of animal studies have investigated the effects of hypoxia on the pulmonary vasculature and hypoxic pulmonary vasoconstriction (HPV) is now established as an important homeostatic mechanism for perfusion-ventilation matching in the lung. However, there is a conspicuous lack of studies investigating HPV in human pulmonary vascular preparations. In comparison to the pulmonary vasculature only a limited number of studies have previously investigated the effects of acute hypoxia on the airways. In this thesis the effects of hypoxia on the human pulmonary vasculature and airways was investigated in a number of ex vivo human lung models. In isolated human pulmonary arteries and veins and in ex vivo perfused and ventilated human lungs it was found that hypoxia caused a vasodilation. This finding is at variance with a large body of published literature and it is suggested that a neuronal mechanism could play an important role in the regulation of pulmonary vascular tone under hypoxic conditions in vivo which is not present in the ex vivo models used in this thesis. In exploring the effects of hypoxia on the pulmonary vasculature it was identified that the pulmonary veins could play a more significant role in the regulation of pulmonary vascular resistance than was previously believed. It was also found that exposure of the pulmonary veins to hypoxia precipitated a phasic activity which was suggestive of an automaticity and that the isolated human pulmonary vein model could therefore be used to investigate arrhythmic activity and the efficacy of new antiarrhythmic agents. Exposure of ex vivo perfused and ventilated human lungs to hypoxia caused a reduction in the rate of oedema formation and it is hypothesised that this effect could be mediated by an inhibition of pulmonary vascular endothelial cell contraction and an increase in endothelial barrier function. In isolated human bronchi and ex vivo human lungs hypoxia caused a robust and reversible bronchodilation. The mechanism of hypoxic bronchodilation (HBD) was investigated and it was found that HBD could be mediated by a reversal of the calcium sensitisation mechanism. This mechanism represents a significant therapeutic target for the future development of effective bronchodilator therapies which are not subject to the limitations of GPCR agonists (desensitisation). Studies investigating the effects of changing oxygen concentrations on bronchial tone identified that oxygen concentrations above ambient levels (21%) caused a robust contraction of human airways which could have significant implications for the clinical use of oxygen therapy in constrictive airway disease. In investigating the putative role of hydrogen sulphide (H₂S) as an oxygen sensor it was found that H₂S is an effective vasodilator and bronchodilator in the human lung and could have significant therapeutic potential in the treatment of human pulmonary disease. Further studies have been planned to build on the significant findings in this thesis.