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Background
Emphysema is a progressive disease characterized by irreversible airspace enlargement, followed by a decline in lung function [1]. The imbalance between elastase and anti-elastase activity [2], rupture of alveolar walls [3], and inflammation in the lung parenchyma [4] are some of the hallmarks of this disease. In addition to the well-known impact of emphysema on the lungs, extrapulmonary effects have also been described, such as pulmonary arterial hypertension, cor pulmonale, and changes in right ventricular structure and function [5]; skeletal muscle wasting [6]; and body weight loss [7]. These systemic manifestations are associated with increased risk of exacerbation and decreased survival [8].
The current therapeutic approach for emphysema is mainly focused on the use of bronchodilators, anti-inflammatory agents, and antibiotics [1]. To date, there has been no effective therapy able to modify the long-term decline in lung function. Therefore, a new pharmacological therapy able to reduce inflammation and remodelling, as well as mitigate the extrapulmonary effects associated with emphysema, might represent a potential disease-modifying strategy.
In this context, ghrelin, an endogenous ligand for the growth hormone secretagogue receptor (GHS-R) produced primarily by ghrelinergic cells in the stomach [9, 10], has direct effects on muscle anabolism and appetite stimulation [11, 12]. When administered exogenously, ghrelin has anti-inflammatory and anti-apoptotic effects [10], suppresses sympathetic activity [13], and induces vasodilation, followed by improvement of cardiac performance [14, 15]. Clinical studies have demonstrated that exogenous ghrelin administration is safe and can improve muscle strength, but its effects on cardiorespiratory parameters are unclear [16-18], which may be explained by small sample sizes [16, 19].
Recently, in a cigarette smoke-exposed rat model of emphysema, subcutaneous ghrelin administration was shown to increase body weight and improve respiratory function [20]. However, ghrelin was administered only during emphysema induction and not after emphysema was established, thus limiting the translational aspect of the study. Additionally, the role of ghrelin in cardiovascular impairment, which is associated with worse prognosis [16], was not evaluated.
We hypothesised that, in a well-established model of elastase-induced severe emphysema, with clearly observable lung damage and cor pulmonale, therapy with ghrelin might reduce pulmonary inflammation and remodelling, as well as improve lung mechanics and cardiac function.
Methods
Ethics statement
This study was approved by the Animal Ethics Committee of the Health...