Ghrelin, Diet, and Pulmonary Function

severe COPD. Br J Clin Pharmacol 2004; 57:388 –392 21 Wilson AM, Dempsey OJ, Coutie WJ, et al. Importance of drug-device interaction in determining systemic effects of inhaled corticosteroids [letter]. Lancet 1999; 353:2128 22 Derom E, Van De Velde V, Marissens S, et al. Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine monophosphate in asthmatic patients. Pulm Pharmacol Ther 2005; 60:335–342 23 Lee DKC, Fardon TC, Bates CE, et al. Airway and systemic effects of hydrofluoroalkane formulations of high dose ciclesonide and fluticasone in moderate persistent asthma. Chest 2005; 127:851– 860 24 Lee DK, Haggart K, Currie GP, et al. Effects of hydrofluoroalkane formulations of ciclesonide 400 microg once daily vs fluticasone 250 microg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma. Br J Clin Pharmacol 2004; 58:26 –33 Brian J. Lipworth, MD University of Dundee Dundee, Scotland Dr. Lipworth is Professor of Allergy and Pulmonology, Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee. The author and other members of the Asthma and Allergy Research Group have received financial support from Altana, Sanofi-Aventis, AstraZeneca, Schering Plough, GlaxoSmithKline, Innovata Biomed, Ivax, Merck, Cipla, and Neolab (who all manufacture inhaled steroids or other antiasthma products) for performing clinical trials, equipment, postgraduate training and education, attending scientific meetings, consulting, and giving lectures. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Brian J Lipworth, MD, Professor of Allergy and Pulmonology, Asthma and Allergy Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, DD1 9SY, Scotland, UK; e-mail: [email protected]

Ghrelin, Diet, and Pulmonary Function the 1970s and 1980s, many gut peptides D uring (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 secre-

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tion 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 hormoneindependent mechanism. In other studies,5–7 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 tissue8,9 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.5,10 –12 Chang et al13 reported improvement in survival with ghrelin treatment following isoproterenol-induced myocardial injury. Ghrelin decreased plasma lactate dehydrogenase activity, malondialdehyde levels, conjuEditorials

gated 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 normalweight 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 www.chestjournal.org

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. Gary P. Zaloga, MD, FCCP Indianapolis, IN Dr. Zaloga, is Medical Director, Methodist Research Institute, and Clinical Professor of Medicine, Indiana University School of Medicine. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml). Correspondence to: Gary P. Zaloga, MD, FCCP, Methodist Research Institute, 1812 N Capitol Ave, Wile Hall, Room 120, Indianapolis, IN 46202; e-mail: [email protected]

References 1 Kojima M, Hosoda H, Dale Y, et al. Ghrelin is a growthhormone-releasing acylated peptide from the stomach. Nature 1999; 402:656 – 660 2 Volante M, Fulcheri E, Allia E, et al. Ghrelin expression in fetal, infant, and adult human lung. J Histochem Cytochem 2002; 50:1013–1021 3 Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87:2988 –2991 4 Shimizu Y, Nagaya N, Teranishi Y, et al. Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats. Biochem Biophys Res Commun 2003; 310:830 – 835 5 Nagaya N, Uematsu M, Kojima M, et al. Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 2001; 104:1430 –1435 6 Wiley KE, Davenport AP. Comparison of vasodilators in human internal mammary artery: ghrelin is a potent physiological antagonist of endothelin-1. Br J Pharmacol 2002; 136:1146 –1152 7 Okumura H, Nagaya N, Enomoto M, et al. Vasodilatory effects of ghrelin, an endogenous peptide from the stomach. J Cardiovasc Pharmacol 2002; 39:779 –783 8 Henriques-Coelho T, Correia-Pinto J, Roncon-Albuquerque R, et al. Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotalineinduced pulmonary hypertension. Am J Physiol Heart Circ Physiol 2004; 287:H2885–H2890 9 Iglesias MJ, Pineiro R, Blanco M, et al. Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes. Cardiovasc Res 2004; 62:481– 488 10 Nagaya N, Kangawa K. Ghrelin improves left ventricular dysfunction and cardiac cachexia in heart failure. Curr Opin Pharmacol 2003; 3:146 –151 11 Nagaya N, Kojima M, Uematsu M, et al. Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am J Physiol Regul Integr Comp Physiol 2001; 280:R1483–R1487 12 King MK, Gay DM, Pan LC, et al. Treatment with a growth hormone secretagogue in a model of developing heart failure: CHEST / 128 / 3 / SEPTEMBER, 2005

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effects on ventricular and myocyte function. Circulation 2001; 103:308 –313 Chang L, Zhao J, Li GZ, et al. Ghrelin protects myocardium from isoproterenol-induced injury in rats. Acta Pharmacologica Sinica 2004; 25:1131–1137 Baldanzi G, Filigheddu N, Cutrupi S, et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002; 159:1029 –1037 Itoh T, Nagaya N, Yoshikawa M, et al. Elevated plasma ghrelin level in underweight patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 170:879 – 882 Nagaya N, Itoh T, Murakami S, et al. Treatment of cachexia with ghrelin in patients with COPD. Chest 2005; 128:1187– 1193

Quality, Quantity, or Both? Life After Lung Transplantation the past 20 years, lung transplantation has W ithin evolved as an effective therapy in the treatment of patients with advanced lung diseases. Unfortunately, long-term lung transplant outcomes remain disappointing compared to those in other solid organ transplant populations.1 The primary reason for the decreased lung transplant patient survival rate is the development of bronchiolitis obliterans syndrome (BOS), which is a condition of progressive airflow obstruction that is generally thought to reflect chronic lung rejection. Because of this limited survival of patients posttransplant, a greater understanding of the health-related quality of life (HRQOL) of lung transplant recipients is critical to evaluate the utility of this therapy. Both cross-sectional studies and prospective studies2–5 have confirmed that recipients’ experience improved HRQOL after lung transplantation on a variety of validated instruments. In fact, improvements in HRQOL are a major consideration in the decision to offer lung transplantation to patients with several endstage lung diseases, such as emphysema, in which the actual survival benefit of transplant has been questioned.6 While it is clear that lung transplantation can improve HRQOL, the specific factors that influence quality of life posttransplant have not been well-evaluated. Several studies2,7,8 have shown an association between objective measurements of posttransplant pulmonary function and HRQOL. The correlation of declining pulmonary function with the development of BOS is associated with decreased HRQOL.2,7,8 What is not clear, however, is the extent to which bilateral transplantation offers improved HRQOL compared to single-lung transplantation. We have previously shown9,10 that single-lung transplant recipients develop BOS at an earlier time compared to bilateral lung 1086

transplant recipients and that single-lung recipients are at risk for a number of unique complications, including native lung hyperinflation, malignancy, or infections. Thus, one might expect that single-lung transplant recipients should have a lower HRQOL compared to bilateral lung transplant recipients, which is consistent with results from a 2001 cross-sectional study11 of HRQOL in 255 lung recipients posttransplant. This is why the findings of Gerbase et al,12 which are presented in this issue of CHEST (see page 1371), are surprising. They compare posttransplant HRQOL among 44 lung transplant recipients (single lung transplants, 14; bilateral lung transplants, 30) who survived at least 2 years of posttransplant followup. Despite the improved FEV1 and lower incidence of BOS in bilateral transplant recipients compared to single-lung transplant recipients, respiratory diseasespecific HRQOL was not significantly different in the two transplant groups. However, there is a trend toward a difference favoring the bilateral transplant group when comparing the absolute mean difference between the two groups. The strengths of the study include the use of validated quality-of-life measurements for general well-being (visual analog scale) as well as the respiratory disease-specific St. George Respiratory Questionnaire (SGRQ), prospective measurements before and after transplantation, appropriate statistical methodology, and a median follow-up time of ⬎ 5 years. The findings of Gerbase et al12 raise the following important medical and ethical question: should single-lung transplantation be the standard of care for all diseases in which either single-lung or bilateral transplantation would be appropriate? The advantage of single-lung transplantation is obvious. With the limited donor lung supply, the prospect of offering single-lung transplants to two recipients, as opposed to one bilateral lung recipient, is appealing. However, before this question can be fully answered, we also need to consider the limitations of the work by Gerbase et al.12 First, the study was relatively small and included relatively few single-lung transplant recipients (n ⫽ 14). Second, there is a trend toward improved SGRQ scores in bilateral lung transplant recipients compared to single-lung transplant recipients at later time points (mean score at 5 years, 87 vs 71, respectively). The negative statistical results of the study could be a type II error related to underpowering (details regarding a formal power calculation were not provided). Third, the study only considers HRQOL but not quality-adjusted life years (QALYs). International registry data would suggest that long-term survival is superior among bilateral transplant recipients compared to single-lung transplant recipients. The results of the study by Gerbase et al12 would be Editorials