Endothelin receptor changes during inflammation in the lung

University dissertation from Laboratory of Experimental Vascular Research Department of Clinical Sciences Lund University

Abstract: Endothelin-1 (ET-1) is an extremely potent smooth muscle spasmogen well known from the vascular system but also active within the airways. The importance of its proinflammatory and co-mitogenic properties has become increasingly evident, the endothelin system also having been shown to mimic the signal features of asthma, COPD and other pulmonary diseases. The present thesis concerns the role of the endothelin receptors: 1. Bronchial biopsies from patients with lung diseases that included a major inflammatory component (asthma bronchiale or COPD) showed a significantly lower ETA / ETB ratio than in the case of lung diseases with non-inflammatory states. This points to an up-regulation of the ETB receptors in the human bronchi during inflammatory processes in the lungs. 2. Functional studies of the mixed population of endothelin receptors found in the respiratory system and the vasculature were made simultaneously in isolated, perfused and ventilated lung preparations from rats. The potent contractile effect of ET-1 on the vascular side of the rat lung is mediated mainly by ETA receptors, whereas both ETA and ETB receptors are involved in conductance (Gaw) in the lung. Although there are distinct differences between the airways and the vasculature, activity in the one system influences activity in the other. The importance of how drugs and antagonists are administrated could be demonstrated. 3. At early stage of eosinophilic inflammation in airways in the rat lung induced by Sephadex, ET-1 and sarafotoxin 6c resulted in an increase in the maximum contractile effect and an increase (3.9 fold) in ETB receptor mRNA in the bronchial but not in the tracheal smooth muscle cells. This, together with a rise in ET-1 levels that was observed in BALF during inflammatory processes in the lung, can contribute synergistically in the long run to an acute hyper-reactivity and to remodeling processes. 4. Early changes in endothelin receptor expression in rat lung dye to smoking were studied. Nicotine had no effect per se but cigarette smoke particles increased the maximum contractility mediated by both ETA and ETB receptors. The ETA and ETB mRNA levels were unchanged, but a clear rise in ETA and ETB receptor protein in the bronchial smooth muscle cell layer could be observed. This supports the view that the increased contractility caused by cigarette smoke particles is due to a translational mechanism.

  This dissertation MIGHT be available in PDF-format. Check this page to see if it is available for download.