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Indianapolis, IN
Dr. Zaloga, is Medical Director, Methodist Research Institute, and Clinical Professor of Medicine, Indiana University School of Medicine.
Correspondence to: Gary P. Zaloga, MD, FCCP, Methodist Research Institute, 1812 N Capitol Ave, Wile Hall, Room 120, Indianapolis, IN 46202; e-mail: gzaloga{at}clarian.org
During the 1970s and 1980s, many gut peptides (ie, cholecystokinin, bombesin, gastrin-releasing peptide, neuromedin B, glucagon) were linked to satiety. During the 1990s, leptin was recognized as a long-term adiposity signal that regulated food intake. In 1999, ghrelin (a 28 amino acid acyl-peptide) was first described by Kojima et al1 as the endogenous ligand to the receptor for growth hormone secretagogues, a group of molecules endowed with growth hormone-releasing activity. Ghrelin also serves as a peripheral signal from the stomach to the brain, informing the brain about gastric nutrient content. The primary sites of ghrelin action within the brain are the pituitary and hypothalamus. Ghrelin is synthesized primarily in enterochromaffin cells located mainly in the fundus of the stomach. Ghrelin secretion is increased by an empty stomach and signals the brain to increase food intake and release growth hormone. Stimulation of food intake by ghrelin is mediated via neuropeptide Y neurons in the hypothalamus. Due to its role in the regulation of food intake, much of the research on ghrelin relates to obesity. However, ghrelin may also play significant roles in wasting syndromes, such as occurs in patients with COPD. In these states, ghrelin may stimulate food intake while decreasing fat oxidation. In humans, circulating ghrelin levels are decreased in acute states of positive energy balance such as obesity and are increased during fasting and starvation.
Since ghrelin expression is restricted to GI foregut structures, Volante et al2 examined the bronchial tree (which is derived from the foregut). Neuroendocrine cells of fetal lungs contained large amounts of immunoreactive ghrelin and its messenger RNA. In contrast, the adult lung contained very little ghrelin. However, approximately 50% of pediatric and adult lungs expressed ghrelin receptors. The investigators of this study2 postulated that ghrelin played a role in lung development. Gnanapavan et al3 measured messenger RNA for ghrelin and its receptor in humans and also found the receptor to be expressed in lung tissue.
Shimizu et al4 reported that ghrelin improved endothelial dysfunction and increased endothelial nitric oxide expression through a growth hormone-independent mechanism. In other studies,567 ghrelin demonstrated potent vasodilator properties that were endothelium and growth hormone independent. Thus, at least one ghrelin signaling pathway appears to be involved in the regulation of vascular tone. Henriques-Coelho et al8 investigated endogenous production of ghrelin and its cardiac and pulmonary vascular effects in a rat model of pulmonary hypertension. Ghrelin was found to be produced in the heart, lung, and stomach of rats. In animals with pulmonary hypertension, pulmonary production of ghrelin was preserved and right ventricular production was increased 20-fold. Exogenous administration of ghrelin attenuated the development of pulmonary hypertension, right ventricular hypertrophy, vascular remodeling of the pulmonary arteries, and left ventricular dysfunction.
Interestingly, ghrelin and ghrelin receptors are also synthesized in cardiac tissue89 and possess beneficial cardiovascular effects. Ghrelin reduces cardiac afterload and increases cardiac output without increasing heart rate in normal individuals and in patients/animals with heart failure.5101112 Chang et al13 reported improvement in survival with ghrelin treatment following isoproterenol-induced myocardial injury. Ghrelin decreased plasma lactate dehydrogenase activity, malondialdehyde levels, conjugated diene release, and endothelin-1 levels induced by isoproterenol. Baldanzi et al14 report that ghrelin and des-acyl ghrelin inhibits doxorubicin/FAS/serum starvation induced apoptosis of cardiomyocytes and endothelial cells in vitro through activation of extracellular signal-regulated kinase-1/2 and Akt serine kinases. Thus, ghrelin may act as a survival factor within the cardiovascular system.
Itoh et al15 measured ghrelin levels in patients with COPD. Cachexia is common and is an independent risk factor for death in these patients. Ghrelin levels have been reported to be elevated in patients with cardiac cachexia, cancer cachexia, and anorexia nervosa. Itoh et al15 evaluated 50 patients with COPD and correlated results with body mass and pulmonary function. Plasma levels of ghrelin were significantly higher in COPD patients compared to control subjects. In addition, ghrelin levels were higher in underweight patients compared to normal-weight patients. Levels correlated negatively with body mass index and lean body mass. Circulating levels of tumor necrosis factor-
and norepinephrine were higher in COPD patients compared to control subjects and correlated positively with ghrelin levels. Plasma ghrelin levels were higher in patients with more severe disease. These results suggest the ghrelin is elevated in an attempt to compensate for the cachectin state and may represent a compensatory mechanism for catabolic-anabolic imbalance in cachectic patients with COPD.
On the basis of the above findings (ie, release of growth hormone, increased food intake, decreased fat oxidation, beneficial effects on pulmonary vasculature and heart), one could hypothesize that ghrelin might benefit patients with COPD through anabolic and organ protective actions. In this issue of CHEST (see page 1187), Nagaya et al16 evaluated ghrelin treatment in seven cachectic patients with COPD, and assessed the effect of ghrelin on both body mass and muscle function. Although the study was not blinded or controlled, was short term (3 weeks), and the sample size small, the results are provocative. Ghrelin increased growth hormone secretion, food intake, body weight, lean body mass, peripheral and respiratory muscle strength, Karnofsky status score, and walking distance. Ghrelin also attenuated sympathetic nervous system activity assessed with plasma norepinephrine levels. Importantly, results were consistent throughout the study parameters, and all were in beneficial directions. There were no adverse effects on glucose, insulin, and cortisol levels. Ghrelin was administered twice daily IV, and it is unclear whether similar results would also be obtained using subcutaneous injection. This study needs to be repeated in a larger population using appropriate control subjects and over longer time periods. It will also be important to evaluate other routes of ghrelin administration such as the subcutaneous route. However, results to date suggest that ghrelin represents a new and potentially beneficial treatment for patients with both advanced COPD and pulmonary hypertension. Additionally, decreased appetite is an important medical issue in the elderly and in many patients with chronic diseases. Ghrelin may be useful for appetite stimulation in these patients.
References
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