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Title Ghrelin in critical illness
Authors Tathagat Narula, M.D. Ex-Fellow, Pulmonary Diseases Critical Care Medicine Respiratory Institute, Cleveland Clinic Foundation, Cleveland, OH Staff Physician, RCCSMA Baptist Medical Center, Jacksonville, FL Ph: 19042536910 Fax: 19042021120 Email: [email protected]
Bennett P. deBoisblanc, M.D. Professor of Medicine and Physiology Section of Pulmonary/Critical Care Medicine Department of Medicine LSU Health Sciences Center New Orleans, LA Participating Institutions Cleveland Clinic Foundation, Cleveland, OH RCCSMA, Jacksonville, FL Louisiana State University Health Sciences Center, New Orleans, LA
No financial support was used for this study Running Title: Ghrelin in critical illness Drafting the manuscript for important intellectual content: TN, BD
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AJRCMB Articles in Press. Published on 11-June-2015 as 10.1165/rcmb.2014-0226TR
Abstract Ghrelin, a recently described peptide, has attracted significant attention in recent years, primarily in the context of its endocrine and appetite regulating effects. The versatility of this peptide is manifested in a rapidly expanding body of literature highlighting its nonendocrine functions. This review summarizes the available data on the immunomodulatory as well as the non-immune-mediated effects of ghrelin that form the scientific basis of its role in critical illness.
1. Introduction The interrelationship between neuroendocrine regulation and regulation of immunity has been long recognized.1 Ghrelin, an endogenous ligand for the G-proteincoupled, growth hormone secretagogue receptor (GHSR 1a), is an appetite stimulant that also has regulatory effects on immunity. 2,3 Ghrelin signals the brain that it is time to eat, i.e. a preprandial rise in plasma ghrelin induces feeding behavior.4 Most of the early interest in ghrelin revolved around its role in regulating appetite, energy balance and gastric motility.5-7 However, the ability of ghrelin to attenuate inflammation has received recent attention. In this paper, we review the scientific basis for ghrelin’s immunomodulatory and non-immune mediated effects in critical illness. 2. Ghrelin Structural Features and Distribution The human ghrelin gene encodes a precursor 117 amino acid peptide – pre-proghrelin. This precursor peptide is proteolytically cleaved to the mature 28 amino acid ghrelin. Structurally, ghrelin has a unique n-octanoyl modification at the Serine 3 residue that is critical for activating its endogenous receptor, GHS-R1a.2, 8 The catalytic enzyme
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that attaches the octanoate to Serine-3 of ghrelin has been named Ghrelin-O Acyltransferase (GOAT), a member of the Membrane-Bound O-Acyltransferases (MBOATs) family.9 In addition to the acylated isoform, a desacylated form of ghrelin is also expressed. The des-acyl form, lacking the octanoyl at Ser 3, cannot bind to GHSR 1a and was initially considered biologically inactive. However, it is now known that both the acylated and des-acyl forms of ghrelin bind to common sites on cardiomyocytes and endothelial cells in vitro and work similarly to inhibit apoptosis. This suggests that both forms of ghrelin may bind and signal through a receptor other than GHS-R1a.10, 11 Studies in transgenic mice have shown suppression of the growth hormone-insulin-like growth factor 1 (GH-IGF1) axis with elevated des-acyl ghrelin levels. This suggests a potential role for des-acyl ghrelin as a counterbalance to the effects of acylated ghrelin, a known growth hormone inducer.12 Ghrelin release was initially localized to gastric X/A-like cells and pancreatic epsilon cells.13 However, subsequent studies have demonstrated that ghrelin and its receptor are widely expressed throughout several major organ systems and can modulate wide ranging biological actions such as glucose homeostasis, myocardial injury, neurogenesis, bone metabolism, reproductive function, memory and sleep. 11,14,15 In the context of immune modulation, ghrelin and its receptor, GHSR 1a have been localized to the spleen, thymus, T- and B-lymphocytes, neutrophils, monocytes and dendritic cells.10, 16-20 3. Ghrelin in Systemic Inflammation Plasma ghrelin concentration has been shown to increase in models of systemic inflammation, such as severe pancreatitis or acute colitis.21, 22 Similarly, elevated ghrelin
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levels has also been reported in humans in conditions such as inflammatory bowel diseases, ankylosing spondylitis, sepsis and cystic fibrosis.23-26 However, ghrelin does not appear to simply be an acute phase reactant that rises non-specifically in inflammatory conditions. Rather, its expression is complex. For example, plasma ghrelin has been found to be significantly lower at day 7 in rats with adjuvant-induced arthritis and lower in patients with rheumatoid arthritis when compared to controls.27 In experimental studies of human endotoxemia, ghrelin exhibits a biphasic response, increasing initially and then falling 2 h after the challenge to reach a nadir at 5 h.28 Finally, some studies have demonstrated elevated plasma ghrelin in critically ill patients compared to controls while other studies have shown lower levels.29,30 It is likely that the measurement of total ghrelin in lieu of the acylated and des-acylated isoforms contributes to some of these incongruous results, but there also exist significant gaps in our understanding of the confounding impact of nature, severity and stage of inflammatory illnesses on ghrelin expression. Immunomodulatory Effects of Ghrelin Ghrelin has potent inhibitory effects on the expression of proximal proinflammatory cytokines. Incubating human peripheral blood mononuclear cells (PBMCs) or human T cells with ghrelin, can inhibit the expression of Interleukin (IL)-1b, IL-6 and Tumor Necrosis Factor-alpha (TNF-a). Similar results are observed in vivo in murine models of lipopolysaccharide-induced endotoxemia.18 Mechanistically, these effects are mediated through myriad pathways. Pretreatment with ghrelin can attenuate TNF-a induced Nuclear Factor-Kappa B (NF-KB) production, that in turn controls the production and expression of many downstream chemotactic cytokines.31 Ghrelin can
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also upregulate the expression of IL-10, an anti-inflammatory cytokine, by recruitment and augmentation of the protein kinase p38 MAPK, independent of its effects on NFKB.32, 33 Ghrelin may also inhibit more downstream proinflammatory cytokines, such as the transciption factor High-Mobility Group Protein B1 (HMGB1). 34, 35 High levels of systemic HMGB1 have been seen in humans and animals with severe sepsis. In a murine model of endotoxemia, delayed administration of ghrelin reduced circulating levels of HMGB1 and rescued from lethality.36 Ghrelin can also antagonize the pro-inflammatory protein, leptin. Leptin is a 16 kDa protein belonging to the type-1 cytokine family, that can induce a dose-dependent increase in IL-1b, IL-6, and TNF-a mRNA expression by human T-cells and PBMCs. At the functional level, leptin polarizes Th cytokine production towards a pro-inflammatory (Th1, IFN-γ ± IL-2) pathway.37, 38 The addition of ghrelin to cell cultures incubated with leptin results in inhibition of leptin-induced cytokine gene and protein expression and redirects T-cell differentiation towards an anti-inflammatory Th2-response (Figure 1)18, 32 These observations suggest that leptin and ghrelin, akin to their role in energy homeostasis, also have reciprocal functions in the immune system. The autonomic nervous system plays a significant role in immune regulation. Sympathetic responses tend to be pro-inflammatory while parasympathetic responses exert more anti-inflammatory effects.39 Lymphoid organs receive extensive sympathetic innervation and lymphocytes, macrophages, and other immune effector cells bear functional adrenoreceptors. In vitro, adrenergic agonists can modulate immune responses by altering Th1/Th2 lymphocyte proliferation, cytokine responses and antibody
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production.40 For example, in a rat model of polymicrobial sepsis by cecal ligation and puncture (CLP), nor-epinephrine released from the gut caused hepatocellular dysfunction by stimulating alpha 2 adrenoceptors on Kupffer cells. Downstream, this resulted in a marked increase in the release of TNF-a by Kupffer cells.41 Ghrelin administered 30 minutes before CLP significantly reduced norepinephrine and TNF-a 2 hours after CLP.3 Experimental evidence suggests that ghrelin administration also activates efferent vagal pathways with downstream cholinergic anti-inflammatory effects.42, 43 Ghrelin and Acute Respiratory Distress Syndrome (ARDS) The pathophysiology of ARDS involves many of the pro-inflammatory pathways influenced by ghrelin. Multiple studies have investigated the role of ghrelin in animal models of lung injury. In a rat model of sepsis, the administration of intravenous ghrelin down-regulated proinflammatory cytokine production in the lungs, markedly reduced lung neutrophilic infiltration, improved lung histology, increased pulmonary blood flow, and improved survival.44 Similar protective influences have been demonstrated in models with bleomycin-induced and pancreatitis-induced acute lung injury.45, 46 Ghrelin was recently shown to exert an anti-apoptotic effect on alveolar macrophages by inhibiting cJun N-terminal kinase (JNK) pathway.47,48 4. Effects of Ghrelin on Cardiovascular and Endothelial Function in Critical Illness Cardiovascular and endothelial dysfunction is common in critical illness and can adversely affect outcomes.49 Recent studies have indicated that cardiovascular system is an important target for ghrelin.50 In a rodent model of severe sepsis, ghrelin treatment improved cardiovascular stability as indicated by optimization of the rate of left ventricular pressure development, dP/dT, a global indicator of cardiac contractility.51
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Murine CLP models of sepsis are characterized by an early hyperdynamic phase and a late hypodynamic phase.52 The late hypodynamic phase is mediated by overexpression of the potent vasoconstrictor peptide, endothelin (ET)-1 leading to increased vascular resistance and decreased organ perfusion.53 Ghrelin inhibits ET-1 release in a dosedependent manner. Exogenous administration of ghrelin in the late hypodynamic phase of CLP mediated sepsis in rats reduces peripheral vascular resistance and improves organ perfusion. 54,55 Ghrelin’s pro-angiogenic influence on endothelial cell function also contributes to its protective cardiovascular effects. Angiogenesis in rat models of cardiac microvascular endothelial cells is induced by ghrelin mediated phosphorylation of ERK and Akt with downstream phosphorylation and activation of mTOR (mammalian target of Rapamycin), important signaling events for cellular growth, vascular proliferation and remodeling. Ghrelin ameliorates hypoxia-induced endothelial dysfunction and apoptosis in human pulmonary artery endothelial cells via similar promotion of Akt/mTOR phosphorylation.56, 57 It is known that impaired endothelial dysfunction is at least in part associated with decreased nitric oxide (NO) production.58 Ghrelin counteracts this by up regulating endothelial NO synthase phosphorylation thereby increasing NO release.57, 59 5. Effects of Ghrelin on Appetite and Gastrointestinal Function in Critical Illness In the acute phase of critical illness, endocrine adaptations impact energy and substrate consumption.60 Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance in humans, whereas elevated ghrelin inhibits insulin release. Exogenously administered ghrelin can elevate blood glucose levels by this effect.61, 62 In the chronic phase of critical illness, sustained hypercatabolism causes loss
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of lean body mass that may compromise vital functions, cause neuromuscular weakness, and delay recovery.63 Therapeutic interventions to correct these abnormalities theoretically offer opportunities to accelerate recovery and improve survival.64 Ghrelin’s ability to stimulate appetite, increase food intake, and improve clinical parameters in cachectic chronic illness states suggests it may have utility in augmenting the nutritional rehabilitation in the chronic stage of critically illness. 65-67 Intravenous infusion of ghrelin increases food intake in obese as well as lean humans.68 The orexigenic effects of ghrelin are believed to be mediated via the arcuate nucleus of the hypothalmus.4, 5 Ghrelin levels rise with fasting and fall after food ingestion.4 Ghrelin levels also rise and fall at traditional meal times during a 24-h fast suggesting that ghrelin may have a role in anticipating and preparing for the digestion and metabolism of the forthcoming meal.69 In this context, it is worth considering that the effect of feeding strategies on plasma ghrelin levels in the ICU may be different in tubefed patients compared to healthy humans. Investigations in healthy controls suggest that continuous tube feeding does not suppress appetite and food intake, whereas bolus tube feeds significantly reduce food intake and plasma ghrelin levels.70, 71 In critically ill patients with acute respiratory failure, a pilot study did not reveal any consistent relationships between plasma ghrelin and feeding strategy.72 The effects of exogenous ghrelin administration on appetite during the chronic phase of critical illness remain unknown. Gastric contractility is reduced and gastric emptying is delayed in 50% of mechanically ventilated patients.73, 74 Patients intolerant of gastric feedings generate less acylated ghrelin contributing to gastric hypomotility.75 Prokinetic effects of ghrelin have
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been observed in animal models of sepsis-induced gastroparesis.76 In humans with idiopathic or diabetic gastroparesis, exogenous administration of ghrelin accelerates gastric emptying.77 Hyperinsulinemia and insulin resistance are known to be associated with delayed gastric emptying.78 Ghrelin’s effects to suppress insulin secretion may contribute to its prokinetic properties.61 Synthetic non-peptide ghrelin agonists like TZP101 and TZP-102, have shown promise for the treatment of gastroparesis.79,80 6. Antimicrobial Effects of Ghrelin Bacterial load in the peritoneal fluid was significantly reduced in rats with CLPinduced sepsis who received exogenous ghrelin.44 Furthermore, ghrelin demonstrates dose-dependent in vitro bactericidal effects on E. coli.36 Both acylated and des-acylated forms of ghrelin were equipotent with regards to their antimicrobial actions. This effect was restricted to gram negative bacteria and was deemed a consequence of neutralization of negative bacterial cell charge with the cationic charge of the ghrelin molecule.81 7. Ghrelin and Sleep Critical illness is characterized by markedly deranged sleep architecture, sleep fragmentation, and temporal disorganization of circardian rhythm.82 Polysomnographic studies confirm that patients in the ICU have reduced restorative N3 and REM phases of sleep that contribute to short term and long term neurocognitive impairment.83-85 The pituitary-somatotropic axis, and specifically ghrelin signaling, plays a role in regulating sleep-wakefulness cycles.86, 87 Ghrelin receptors have been localized to suprachiasmatic nucleus, a key regulator of circardian rhythm.88,89 Data from human experiments in healthy subjects have demonstrated increases in sleep when ghrelin is administered to
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young males in the early part of the night.90 However, data from critically ill subjects are not available. 8. Human Clinical Trials of Ghrelin Administration Over the last few years, a multitude of studies have been published in which ghrelin was administered to humans. A recent review summarized 121 published articles in which ghrelin was administered to 1850 humans, both healthy and sick. Among these were patients with obesity, endocrinopathies, and end stage organ dysfunctions. The most reassuring finding from this review was that ghrelin appears to have a favorable shortterm safety profile, even in populations with serious co-morbidities. Mild adverse events occurred in approximately 20% of participants. The most common effect was transient flushing, which occurred in 10% of volunteers. Gastric rumbling and somnolence occurred in approximately 2% of patients. Serious adverse events such as pneumonia, enteritis, and lung cancer were extremely rare and difficult to attribute biologically to ghrelin administration.91 Summary Ghrelin is a relatively novel peptide with complex multi-systemic effects. In the context of inflammation, ghrelin seems to exert anti-inflammatory effects that are mediated by diverse pathways. Historically, targeting individual inflammatory mediators in complex critical illnesses like sepsis has failed to translate into improved outcomes. It is still unknown if targeting the somatotropic axis will be different. Interest in ghrelin in critical illness extends beyond its effects on inflammation, and encompasses it’s antimicrobial actions as well as its effects on metabolism and sleep.
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60. Vanhorebeek I, Van den Berghe G. The neuroendocrine response to critical illness is a dynamic process. Critical Care Clinics 2006; 22: 1-15, v. 61. Broglio F, Arvat E, Benso A, Gottero C, Muccioli G, Papotti M, van der Lely AJ, Deghenghi R, Ghigo E. Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. Journal of Clinical Endocrinology & Metabolism 2001; 86: 5083-5086. 62. Poykko SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA, Ukkola O. Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Diabetes 2003; 52: 2546-2553. 63. Carroll PV. Protein metabolism and the use of growth hormone and insulin-like growth factor-I in the critically ill patient. Growth Hormone & Igf Research 1999; 9: 400-413. 64. Vanhorebeek I, Van den Berghe G. Hormonal and metabolic strategies to attenuate catabolism in critically ill patients. Current Opinion in Pharmacology 2004; 4: 621-628. 65. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, Kennedy AR, Roberts GH, Morgan DG, Ghatei MA, Bloom SR. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000; 141: 4325-4328. 66. Druce MR, Neary NM, Small CJ, Milton J, Monteiro M, Patterson M, Ghatei MA, Bloom SR. Subcutaneous administration of ghrelin stimulates energy intake in healthy lean human volunteers. International Journal of Obesity 2006; 30: 293296.
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67. Nagaya N, Itoh T, Murakami S, Oya H, Uematsu M, Miyatake K, Kangawa K. Treatment of cachexia with ghrelin in patients with COPD. Chest 2005; 128: 1187-1193. 68. Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, Ghatei MA, Small C, Bloom SR. Ghrelin increases food intake in obese as well as lean subjects. International Journal of Obesity 2005; 29: 1130-1136. 69. Natalucci G, Riedl S, Gleiss A, Zidek T, Frisch H. Spontaneous 24-h ghrelin secretion pattern in fasting subjects: maintenance of a meal-related pattern. European Journal of Endocrinology 2005; 152: 845-850. 70. Stratton RJ, Stubbs RJ, Elia M. Short-term continuous enteral tube feeding schedules did not suppress appetite and food intake in healthy men in a placebo-controlled trial. J Nutrition 2003; 133: 2570-2576. 71. Stratton RJ, Stubbs RJ, Elia M. Bolus tube feeding suppresses food intake and circulating ghrelin concentrations in healthy subjects in a short-term placebocontrolled trial. American Journal of Clinical Nutrition 2008; 88: 77-83. 72. Narula T, Johnson K, Dwyer D, Rice TW, Summer RS, deBoisblanc BP. Relationship between serum ghrelin, feeding strategy, & outcomes in patients with acute respiratory failure. Am J Respir Crit Care Med 2010; 181: A6470. 73. Fruhwald S, Kainz J. Effect of ICU interventions on gastrointestinal motility. Current Opinion in Critical Care 2010; 16: 159-164. 74. Chapman M, Fraser R, Vozzo R, Bryant L, Tam W, Nguyen N, Zacharakis B, Butler R, Davidson G, Horowitz M. Antro-pyloro-duodenal motor responses to gastric and duodenal nutrient in critically ill patients. Gut 2005; 54: 1384-1390.
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75. Crona D, MacLaren R. Gastrointestinal hormone concentrations associated with gastric feeding in critically ill patients. Jpen: Journal of Parenteral & Enteral Nutrition 2012; 36: 189-196. 76. De Winter BY, De Man JG, Seerden TC, Depoortere I, Herman AG, Peeters TL, Pelckmans PA. Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice. Neurogastroenterology & Motility 2004; 16: 439-446. 77. Tack J, Depoortere I, Bisschops R, Verbeke K, Janssens J, Peeters T. Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis. Alimentary Pharmacology & Therapeutics 2005; 22: 847-853. 78. Kaji M, Nomura M, Tamura Y, Ito S. Relationships between insulin resistance, blood glucose levels and gastric motility: an electrogastrography and external ultrasonography study. Journal of Medical Investigation 2007; 54: 168-176. 79. Ejskjaer N, Vestergaard ET, Hellstrom PM, Gormsen LC, Madsbad S, Madsen JL, Jensen TA, Pezzullo JC, Christiansen JS, Shaughnessy L, Kosutic G. Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. Alimentary Pharmacology & Therapeutics 2009; 29: 1179-1187. 80. Ejskjaer N, Wo JM, Esfandyari T, Mazen Jamal M, Dimcevski G, Tarnow L, Malik RA, Hellstrom PM, Mondou E, Quinn J, Rousseau F, McCallum RW. A phase 2a, randomized, double-blind 28-day study of TZP-102 a ghrelin receptor agonist for diabetic gastroparesis. Neurogastroenterology & Motility 2013; 25: e140-150. 81. Min C, Ohta K, Kajiya M, Zhu T, Sharma K, Shin J, Mawardi H, Howait M, Hirschfeld J, Bahammam L, Ichimonji I, Ganta S, Amiji M, Kawai T. The
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antimicrobial activity of the appetite peptide hormone ghrelin. Peptides 2012; 36: 151-156. 82. Gehlbach BK, Chapotot F, Leproult R, Whitmore H, Poston J, Pohlman M, Miller A, Pohlman AS, Nedeltcheva A, Jacobsen JH, Hall JB, Van Cauter E. Temporal disorganization of circadian rhythmicity and sleep-wake regulation in mechanically ventilated patients receiving continuous intravenous sedation. Sleep 2012; 35: 1105-1114. 83. Friese RS, Diaz-Arrastia R, McBride D, Frankel H, Gentilello LM. Quantity and quality of sleep in the surgical intensive care unit: are our patients sleeping? Journal of Trauma-Injury Infection & Critical Care 2007; 63: 1210-1214. 84. Hopkins RO, Weaver LK, Pope D, Orme JF, Bigler ED, Larson LV. Neuropsychological sequelae and impaired health status in survivors of severe acute respiratory distress syndrome. American Journal of Respiratory & Critical Care Medicine 1999; 160: 50-56. 85. Mikkelsen ME, Christie JD, Lanken PN, Biester RC, Thompson BT, Bellamy SL, Localio AR, Demissie E, Hopkins RO, Angus DC. The adult respiratory distress syndrome cognitive outcomes study: long-term neuropsychological function in survivors of acute lung injury. American Journal of Respiratory & Critical Care Medicine 2012; 185: 1307-1315. 86. Steiger A. Neurochemical regulation of sleep. Journal of Psychiatric Research 2007; 41: 537-552. 87. Tolle V, Bassant MH, Zizzari P, Poindessous-Jazat F, Tomasetto C, Epelbaum J, Bluet-Pajot MT. Ultradian rhythmicity of ghrelin secretion in relation with GH,
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feeding behavior, and sleep-wake patterns in rats. Endocrinology 2002; 143: 1353-1361. 88. Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK. Expression of ghrelin receptor mRNA in the rat and the mouse brain.[Erratum appears in J Comp Neurol. 2006 Dec 1;499(4):690]. Journal of Comparative Neurology 2006; 494: 528-548. 89. Yannielli PC, Molyneux PC, Harrington ME, Golombek DA. Ghrelin effects on the circadian system of mice. Journal of Neuroscience 2007; 27: 2890-2895. 90. Kluge M, Schussler P, Bleninger P, Kleyer S, Uhr M, Weikel JC, Yassouridis A, Zuber V, Steiger A. Ghrelin alone or co-administered with GHRH or CRH increases non-REM sleep and decreases REM sleep in young males. Psychoneuroendocrinology 2008; 33: 497-506. 91. Garin MC, Burns CM, Kaul S, Cappola AR. Clinical review: The human experience with ghrelin administration. Journal of Clinical Endocrinology & Metabolism 2013; 98: 1826-1837.
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Figure Legends Figure 1: Hypothesized Ghrelin-Leptin Axis in Inflammation (with permission) Ghrelin appears to mediate anti-inflammatory effects on IL-1, TNF, and IL-6 cytokine expression by T cells and mononuclear cells, while leptin appears to promote inflammatory cytokine expression.
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Figure 1: Hypothesized Ghrelin-Leptin Axis in Inflammation (with permission) Ghrelin appears to mediate anti-inflammatory effects on IL-1, TNF, and IL-6 cytokine expression by T cells and mononuclear cells, while leptin appears to promote inflammatory cytokine expression. 188x123mm (72 x 72 DPI)
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Title Ghrelin in critical illness
Authors Tathagat Narula, M.D. Ex-Fellow, Pulmonary Diseases Critical Care Medicine Respiratory Institute, Cleveland Clinic Foundation, Cleveland, OH Staff Physician, RCCSMA Baptist Medical Center, Jacksonville, FL Ph: 19042536910 Fax: 19042021120 Email: [email protected]
Bennett P. deBoisblanc, M.D. Professor of Medicine and Physiology Section of Pulmonary/Critical Care Medicine Department of Medicine LSU Health Sciences Center New Orleans, LA Participating Institutions Cleveland Clinic Foundation, Cleveland, OH RCCSMA, Jacksonville, FL Louisiana State University Health Sciences Center, New Orleans, LA
No financial support was used for this study Running Title: Ghrelin in critical illness Drafting the manuscript for important intellectual content: TN, BD
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Abstract Ghrelin, a recently described peptide, has attracted significant attention in recent years, primarily in the context of its endocrine and appetite regulating effects. The versatility of this peptide is manifested in a rapidly expanding body of literature highlighting its nonendocrine functions. This review summarizes the available data on the immunomodulatory as well as the non-immune-mediated effects of ghrelin that form the scientific basis of its role in critical illness.
1. Introduction The interrelationship between neuroendocrine regulation and regulation of immunity has been long recognized.1 Ghrelin, an endogenous ligand for the G-proteincoupled, growth hormone secretagogue receptor (GHSR 1a), is an appetite stimulant that also has regulatory effects on immunity. 2,3 Ghrelin signals the brain that it is time to eat, i.e. a preprandial rise in plasma ghrelin induces feeding behavior.4 Most of the early interest in ghrelin revolved around its role in regulating appetite, energy balance and gastric motility.5-7 However, the ability of ghrelin to attenuate inflammation has received recent attention. In this paper, we review the scientific basis for ghrelin’s immunomodulatory and non-immune mediated effects in critical illness. 2. Ghrelin Structural Features and Distribution The human ghrelin gene encodes a precursor 117 amino acid peptide – pre-proghrelin. This precursor peptide is proteolytically cleaved to the mature 28 amino acid ghrelin. Structurally, ghrelin has a unique n-octanoyl modification at the Serine 3 residue that is critical for activating its endogenous receptor, GHS-R1a.2, 8 The catalytic enzyme
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that attaches the octanoate to Serine-3 of ghrelin has been named Ghrelin-O Acyltransferase (GOAT), a member of the Membrane-Bound O-Acyltransferases (MBOATs) family.9 In addition to the acylated isoform, a desacylated form of ghrelin is also expressed. The des-acyl form, lacking the octanoyl at Ser 3, cannot bind to GHSR 1a and was initially considered biologically inactive. However, it is now known that both the acylated and des-acyl forms of ghrelin bind to common sites on cardiomyocytes and endothelial cells in vitro and work similarly to inhibit apoptosis. This suggests that both forms of ghrelin may bind and signal through a receptor other than GHS-R1a.10, 11 Studies in transgenic mice have shown suppression of the growth hormone-insulin-like growth factor 1 (GH-IGF1) axis with elevated des-acyl ghrelin levels. This suggests a potential role for des-acyl ghrelin as a counterbalance to the effects of acylated ghrelin, a known growth hormone inducer.12 Ghrelin release was initially localized to gastric X/A-like cells and pancreatic epsilon cells.13 However, subsequent studies have demonstrated that ghrelin and its receptor are widely expressed throughout several major organ systems and can modulate wide ranging biological actions such as glucose homeostasis, myocardial injury, neurogenesis, bone metabolism, reproductive function, memory and sleep. 11,14,15 In the context of immune modulation, ghrelin and its receptor, GHSR 1a have been localized to the spleen, thymus, T- and B-lymphocytes, neutrophils, monocytes and dendritic cells.10, 16-20 3. Ghrelin in Systemic Inflammation Plasma ghrelin concentration has been shown to increase in models of systemic inflammation, such as severe pancreatitis or acute colitis.21, 22 Similarly, elevated ghrelin
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levels has also been reported in humans in conditions such as inflammatory bowel diseases, ankylosing spondylitis, sepsis and cystic fibrosis.23-26 However, ghrelin does not appear to simply be an acute phase reactant that rises non-specifically in inflammatory conditions. Rather, its expression is complex. For example, plasma ghrelin has been found to be significantly lower at day 7 in rats with adjuvant-induced arthritis and lower in patients with rheumatoid arthritis when compared to controls.27 In experimental studies of human endotoxemia, ghrelin exhibits a biphasic response, increasing initially and then falling 2 h after the challenge to reach a nadir at 5 h.28 Finally, some studies have demonstrated elevated plasma ghrelin in critically ill patients compared to controls while other studies have shown lower levels.29,30 It is likely that the measurement of total ghrelin in lieu of the acylated and des-acylated isoforms contributes to some of these incongruous results, but there also exist significant gaps in our understanding of the confounding impact of nature, severity and stage of inflammatory illnesses on ghrelin expression. Immunomodulatory Effects of Ghrelin Ghrelin has potent inhibitory effects on the expression of proximal proinflammatory cytokines. Incubating human peripheral blood mononuclear cells (PBMCs) or human T cells with ghrelin, can inhibit the expression of Interleukin (IL)-1b, IL-6 and Tumor Necrosis Factor-alpha (TNF-a). Similar results are observed in vivo in murine models of lipopolysaccharide-induced endotoxemia.18 Mechanistically, these effects are mediated through myriad pathways. Pretreatment with ghrelin can attenuate TNF-a induced Nuclear Factor-Kappa B (NF-KB) production, that in turn controls the production and expression of many downstream chemotactic cytokines.31 Ghrelin can
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also upregulate the expression of IL-10, an anti-inflammatory cytokine, by recruitment and augmentation of the protein kinase p38 MAPK, independent of its effects on NFKB.32, 33 Ghrelin may also inhibit more downstream proinflammatory cytokines, such as the transciption factor High-Mobility Group Protein B1 (HMGB1). 34, 35 High levels of systemic HMGB1 have been seen in humans and animals with severe sepsis. In a murine model of endotoxemia, delayed administration of ghrelin reduced circulating levels of HMGB1 and rescued from lethality.36 Ghrelin can also antagonize the pro-inflammatory protein, leptin. Leptin is a 16 kDa protein belonging to the type-1 cytokine family, that can induce a dose-dependent increase in IL-1b, IL-6, and TNF-a mRNA expression by human T-cells and PBMCs. At the functional level, leptin polarizes Th cytokine production towards a pro-inflammatory (Th1, IFN-γ ± IL-2) pathway.37, 38 The addition of ghrelin to cell cultures incubated with leptin results in inhibition of leptin-induced cytokine gene and protein expression and redirects T-cell differentiation towards an anti-inflammatory Th2-response (Figure 1)18, 32 These observations suggest that leptin and ghrelin, akin to their role in energy homeostasis, also have reciprocal functions in the immune system. The autonomic nervous system plays a significant role in immune regulation. Sympathetic responses tend to be pro-inflammatory while parasympathetic responses exert more anti-inflammatory effects.39 Lymphoid organs receive extensive sympathetic innervation and lymphocytes, macrophages, and other immune effector cells bear functional adrenoreceptors. In vitro, adrenergic agonists can modulate immune responses by altering Th1/Th2 lymphocyte proliferation, cytokine responses and antibody
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production.40 For example, in a rat model of polymicrobial sepsis by cecal ligation and puncture (CLP), nor-epinephrine released from the gut caused hepatocellular dysfunction by stimulating alpha 2 adrenoceptors on Kupffer cells. Downstream, this resulted in a marked increase in the release of TNF-a by Kupffer cells.41 Ghrelin administered 30 minutes before CLP significantly reduced norepinephrine and TNF-a 2 hours after CLP.3 Experimental evidence suggests that ghrelin administration also activates efferent vagal pathways with downstream cholinergic anti-inflammatory effects.42, 43 Ghrelin and Acute Respiratory Distress Syndrome (ARDS) The pathophysiology of ARDS involves many of the pro-inflammatory pathways influenced by ghrelin. Multiple studies have investigated the role of ghrelin in animal models of lung injury. In a rat model of sepsis, the administration of intravenous ghrelin down-regulated proinflammatory cytokine production in the lungs, markedly reduced lung neutrophilic infiltration, improved lung histology, increased pulmonary blood flow, and improved survival.44 Similar protective influences have been demonstrated in models with bleomycin-induced and pancreatitis-induced acute lung injury.45, 46 Ghrelin was recently shown to exert an anti-apoptotic effect on alveolar macrophages by inhibiting cJun N-terminal kinase (JNK) pathway.47,48 4. Effects of Ghrelin on Cardiovascular and Endothelial Function in Critical Illness Cardiovascular and endothelial dysfunction is common in critical illness and can adversely affect outcomes.49 Recent studies have indicated that cardiovascular system is an important target for ghrelin.50 In a rodent model of severe sepsis, ghrelin treatment improved cardiovascular stability as indicated by optimization of the rate of left ventricular pressure development, dP/dT, a global indicator of cardiac contractility.51
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Murine CLP models of sepsis are characterized by an early hyperdynamic phase and a late hypodynamic phase.52 The late hypodynamic phase is mediated by overexpression of the potent vasoconstrictor peptide, endothelin (ET)-1 leading to increased vascular resistance and decreased organ perfusion.53 Ghrelin inhibits ET-1 release in a dosedependent manner. Exogenous administration of ghrelin in the late hypodynamic phase of CLP mediated sepsis in rats reduces peripheral vascular resistance and improves organ perfusion. 54,55 Ghrelin’s pro-angiogenic influence on endothelial cell function also contributes to its protective cardiovascular effects. Angiogenesis in rat models of cardiac microvascular endothelial cells is induced by ghrelin mediated phosphorylation of ERK and Akt with downstream phosphorylation and activation of mTOR (mammalian target of Rapamycin), important signaling events for cellular growth, vascular proliferation and remodeling. Ghrelin ameliorates hypoxia-induced endothelial dysfunction and apoptosis in human pulmonary artery endothelial cells via similar promotion of Akt/mTOR phosphorylation.56, 57 It is known that impaired endothelial dysfunction is at least in part associated with decreased nitric oxide (NO) production.58 Ghrelin counteracts this by up regulating endothelial NO synthase phosphorylation thereby increasing NO release.57, 59 5. Effects of Ghrelin on Appetite and Gastrointestinal Function in Critical Illness In the acute phase of critical illness, endocrine adaptations impact energy and substrate consumption.60 Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance in humans, whereas elevated ghrelin inhibits insulin release. Exogenously administered ghrelin can elevate blood glucose levels by this effect.61, 62 In the chronic phase of critical illness, sustained hypercatabolism causes loss
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of lean body mass that may compromise vital functions, cause neuromuscular weakness, and delay recovery.63 Therapeutic interventions to correct these abnormalities theoretically offer opportunities to accelerate recovery and improve survival.64 Ghrelin’s ability to stimulate appetite, increase food intake, and improve clinical parameters in cachectic chronic illness states suggests it may have utility in augmenting the nutritional rehabilitation in the chronic stage of critically illness. 65-67 Intravenous infusion of ghrelin increases food intake in obese as well as lean humans.68 The orexigenic effects of ghrelin are believed to be mediated via the arcuate nucleus of the hypothalmus.4, 5 Ghrelin levels rise with fasting and fall after food ingestion.4 Ghrelin levels also rise and fall at traditional meal times during a 24-h fast suggesting that ghrelin may have a role in anticipating and preparing for the digestion and metabolism of the forthcoming meal.69 In this context, it is worth considering that the effect of feeding strategies on plasma ghrelin levels in the ICU may be different in tubefed patients compared to healthy humans. Investigations in healthy controls suggest that continuous tube feeding does not suppress appetite and food intake, whereas bolus tube feeds significantly reduce food intake and plasma ghrelin levels.70, 71 In critically ill patients with acute respiratory failure, a pilot study did not reveal any consistent relationships between plasma ghrelin and feeding strategy.72 The effects of exogenous ghrelin administration on appetite during the chronic phase of critical illness remain unknown. Gastric contractility is reduced and gastric emptying is delayed in 50% of mechanically ventilated patients.73, 74 Patients intolerant of gastric feedings generate less acylated ghrelin contributing to gastric hypomotility.75 Prokinetic effects of ghrelin have
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been observed in animal models of sepsis-induced gastroparesis.76 In humans with idiopathic or diabetic gastroparesis, exogenous administration of ghrelin accelerates gastric emptying.77 Hyperinsulinemia and insulin resistance are known to be associated with delayed gastric emptying.78 Ghrelin’s effects to suppress insulin secretion may contribute to its prokinetic properties.61 Synthetic non-peptide ghrelin agonists like TZP101 and TZP-102, have shown promise for the treatment of gastroparesis.79,80 6. Antimicrobial Effects of Ghrelin Bacterial load in the peritoneal fluid was significantly reduced in rats with CLPinduced sepsis who received exogenous ghrelin.44 Furthermore, ghrelin demonstrates dose-dependent in vitro bactericidal effects on E. coli.36 Both acylated and des-acylated forms of ghrelin were equipotent with regards to their antimicrobial actions. This effect was restricted to gram negative bacteria and was deemed a consequence of neutralization of negative bacterial cell charge with the cationic charge of the ghrelin molecule.81 7. Ghrelin and Sleep Critical illness is characterized by markedly deranged sleep architecture, sleep fragmentation, and temporal disorganization of circardian rhythm.82 Polysomnographic studies confirm that patients in the ICU have reduced restorative N3 and REM phases of sleep that contribute to short term and long term neurocognitive impairment.83-85 The pituitary-somatotropic axis, and specifically ghrelin signaling, plays a role in regulating sleep-wakefulness cycles.86, 87 Ghrelin receptors have been localized to suprachiasmatic nucleus, a key regulator of circardian rhythm.88,89 Data from human experiments in healthy subjects have demonstrated increases in sleep when ghrelin is administered to
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young males in the early part of the night.90 However, data from critically ill subjects are not available. 8. Human Clinical Trials of Ghrelin Administration Over the last few years, a multitude of studies have been published in which ghrelin was administered to humans. A recent review summarized 121 published articles in which ghrelin was administered to 1850 humans, both healthy and sick. Among these were patients with obesity, endocrinopathies, and end stage organ dysfunctions. The most reassuring finding from this review was that ghrelin appears to have a favorable shortterm safety profile, even in populations with serious co-morbidities. Mild adverse events occurred in approximately 20% of participants. The most common effect was transient flushing, which occurred in 10% of volunteers. Gastric rumbling and somnolence occurred in approximately 2% of patients. Serious adverse events such as pneumonia, enteritis, and lung cancer were extremely rare and difficult to attribute biologically to ghrelin administration.91 Summary Ghrelin is a relatively novel peptide with complex multi-systemic effects. In the context of inflammation, ghrelin seems to exert anti-inflammatory effects that are mediated by diverse pathways. Historically, targeting individual inflammatory mediators in complex critical illnesses like sepsis has failed to translate into improved outcomes. It is still unknown if targeting the somatotropic axis will be different. Interest in ghrelin in critical illness extends beyond its effects on inflammation, and encompasses it’s antimicrobial actions as well as its effects on metabolism and sleep.
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Figure Legends Figure 1: Hypothesized Ghrelin-Leptin Axis in Inflammation (with permission) Ghrelin appears to mediate anti-inflammatory effects on IL-1, TNF, and IL-6 cytokine expression by T cells and mononuclear cells, while leptin appears to promote inflammatory cytokine expression.
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Figure 1: Hypothesized Ghrelin-Leptin Axis in Inflammation (with permission) Ghrelin appears to mediate anti-inflammatory effects on IL-1, TNF, and IL-6 cytokine expression by T cells and mononuclear cells, while leptin appears to promote inflammatory cytokine expression. 188x123mm (72 x 72 DPI)
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