Genetic and molecular mechanisms of pulmonary hypertension

Abstract

-Pulmonary arterial hypertension frequently occurs secondary to common cardiopulmonary diseases, and more rarely as a primary condition. Observations in animals and man have suggested genetic influences underlying the susceptibility to pulmonary hypertension. A gene underlying many cases of familial and apparently sporadic cases of primary pulmonary hypertension has now been identified, and a genetic approach to hypoxia-induced pulmonary hypertension promises to reveal new insights into the unique nature of the pulmonary circulation. The exploration of potential candidate genes influencing susceptibility and the identification of new genes promise new therapeutic approaches to the treatment of pulmonary hypertension. The unique nature of the pulmonary circulationThe main role of the pulmonary circulation is to deliver deoxygenated blood to the alveolar capillaries where gas exchange occurs. To achieve this vital role the pulmonary circulation has developed as a high flow, low resistance vascular bed to protect the thin blood-gas barrier from high intravascular pressures that would otherwise promote alveolar oedema formation. Consequently the mean pulmonary arterial pressure (~13mmHg) is approximately one fifth of the systemic arterial pressure, and because of the great capacity of the pulmonary circulation to recruit normally closed vessels, rarely rises above 30mmHg even at very high levels of cardiac output 1 . In contrast to the systemic circulation, the normal pulmonary circulation exhibits minimal resting tone, and appears to be almost maximally dilated under resting conditions. The maximum resistance in the pulmonary circulation lies in the precapillary arterioles, the site of some of the earliest pathological changes during the development of pulmonary hypertension. One of the intriguing features of the pulmonary circulation is vasoconstriction to hypoxia 2 , whereas the systemic circulation responds by vasodilatation. This mechanism, when localised to a particular lung segment or lobe, serves to preserve arterial oxygenation by reducing blood flow to underventilated lung regions, for example in pneumonia or acute asthma 3 . However, the importance of this role should not be overestimated, since it is only about 50% efficient at preserving arterial oxygenation in man and the intensity of hypoxic pulmonary vasoconstriction varies greatly between species. Indeed, it could be argued that the mechanism is a vestigial response representing the equivalent of the amphibian reflex that diverts blood flow from the lungs to the skin, which serves as an alternative organ of gas exchange during hibernation 4 ! Hypoxia-induced pulmonary hypertensionWhen alveolar hypoxia involves most of the lung and is prolonged, any usefulness of acute hypoxic pulmonary vasoconstriction is offset by a rise in pulmonary arterial pressure. This is accompanied by structural changes in small peripheral pulmonary arteries, consisting of increased wall thickness of muscular arteries and the appearance of new muscle in normally non...

A case of late diagnosis of Gaucher disease with lung involvement (case study)

“…Pulmonary hypertension is the most severe lung complication in Gaucher patients. Its exact pathophysiology is still debated [9,10]. Most of the described cases with severe lung disease, characterized by recurrent pulmonary infections and progressive dyspnea culminating in fatal respiratory insufficiency, were children.…”