Abstract
Ghrelin is a growth hormone-releasing peptide, discovered in 1999 by Kojima et al.
Its potential role in inflammation and stress response is not yet clear. The purpose
of this study was to characterize perioperative levels of circulating ghrelin in relation
to different surgical procedures. The authors compared plasma ghrelin changes with
cortisol, cytokines, and acute-phase proteins. The prospective study was performed
on 22 patients with resection for colon cancer (group 1). Group 2, functioning as
a comparative group, consisted of 22 patients with elective laparotomic cholecystectomy.
Plasma concentrations of ghrelin, cortisol, tumor necrosis factor-α (TNF-α), interleukin-1β,
IL-6, IL-8, soluble IL-2 receptor, C reactive protein, and α1-antitrypsin were estimated
repeatedly during a 72-hour postoperative period. Data revealed significant elevation
of plasma ghrelin 24 hours after resection of coli (median 508.0 ng/l, interquartile
range 398.2-633.7 ng/l) in relation to both preoperative levels (317.6 ng/l, 253.4-355.1
ng/l, p<0.01) and group 2 maximal postoperative levels (386.2 ng/l, 324-432 ng/l,
p<0.05). Ghrelin levels returned to initial status 36-48 hours after surgery with
subsequent decline to subnormal levels. The regression coefficient was the highest
for ghrelin and TNF-α 24 hours after laparotomy (r=0.64, p<0.05) and for ghrelin and
IL-6 24 hours after surgery (r=0.56, p<0.05). Maximal postoperative levels of all
tested parameters except for cortisol and IL-1β differed significantly between both
patient groups at p<0.05. After large abdominal surgery, ghrelin shows itself as an
acute-phase reactant. The significant correlation between ghrelin and inflammatory
cytokines supposes their regulatory role in this period. Our comparison of more- and
less-invasive surgical procedures with similar nutritional restrictions argues for
a dominant role of inflammatory factors in postoperative ghrelin elevation.
Key words
acute phase response - C reactive protein - interleukin-6 - surgery - tumor necrosis
factor
References
- 1
Kojima M, Hosoda H, Date Y.
Ghrelin is a growth hormone releasing acylated peptide from stomach.
Nature.
1999;
402
656-660
- 2
Toorn FM van der, Janssen JA, Herder WW de, Broglio F, Ghigo E, Lely AJ van der.
Central ghrelin production does not substantially contribute to systemic ghrelin concentrations:
a study in two subjects with active acromegaly.
Eur J Endocrinol.
2002;
147
195-199
- 3
Dembinski A, Warzecha Z, Ceranowicz P, Tomaszewska R, Stachura J, Konturek SJ, Konturek PC.
Ghrelin attenuates the development of acute pancreatitis in rat.
J Physiol Pharmacol.
2003;
54
561-573
- 4
Muccioli G, Baragli A, Granata R, Papotti M, Ghigo E.
Heterogeneity of ghrelin/growth hormone secretagogue receptors. Toward the understanding
of the molecular identity of novel ghrelin/GHS receptors.
Neuroendocrinology.
2007;
86
143-146
- 5
Date Y, Shimbara T, Koda S, Toshinai K, Ida T, Murakami N, Miyazato M, Kokame K, Ishizuka Y,
Ishida Y, Kageyama H, Shioda S, Kangawa K, Nakazato M.
Peripheral ghrelin transmits orexigenic signals through the noradrenergic pathway
from the hindbrain to the hypothalamus.
Cell Metab.
2006;
4
323-331
- 6
Grossini E, Molinari C, Mary DA, Ghigo E, Bona G, Vacca G.
Intracoronary ghrelin infusion decreases coronary blood flow in anesthetized pigs.
Endocrinology.
2007;
148
806-812
- 7
Henriques-Coelho T, Roncon-Albuquerque Junior R, Lourenco AP, Baptista MJ, Oliveira SM,
Brandao-Nogueira A, Correia-Pinto J, Leite-Moreira AF.
Ghrelin reverses molecular, structural and hemodynamic alterations of the right ventricle
in pulmonary hypertension.
Rev Port Cardiol.
2006;
25
55-63
- 8
Levin F, Edholm T, Schmidt PT, Grybäck P, Jacobsson H, Degerblad M, Höybye C, Holst JJ,
Rehfeld JF, Hellström PM, Näslund E.
Ghrelin stimulates gastric emptying and hunger in normal-weight humans.
J Clin Endocrinol Metab.
2006;
91
3296-3302
- 9
Takeda R, Nishimatsu H, Suzuki E, Satonaka H, Nagata D, Oba S, Sata M, Takahashi M,
Yamamoto Y, Terauchi Y, Kadowaki T, Kangawa K, Kitamura T, Nagai R, Hirata Y.
Ghrelin improves renal function in mice with ischemic acute renal failure.
J Am Soc Nephrol.
2006;
17
113-121
- 10
Broglio F, Prodam F, Riganti F, Muccioli G, Ghigo E.
Ghrelin: from somatotrope secretion to new perspectives in the regulation of peripheral
metabolic functions.
Front Horm Res.
2006;
35
102-114
- 11
Stevanovic D, Milosevic V, Starcevic VP, Severs WB.
The effect of centrally administered ghrelin on pituitary ACTH cells and circulating
ACTH and corticosterone in rats.
Life Sci.
2007;
80
867-872
- 12
Pomerants T, Tillmann V, Karelson K, Jürimäe J, Jürimäe T.
Ghrelin response to acute aerobic exercise in boys at different stages of puberty.
Horm Metab Res.
2006;
38
752-757
- 13
Popovic V, Duntas LH.
Leptin TRH and ghrelin: Influence on energy homeostasis at rest and during exercise.
Horm Metab Res.
2005;
37
533-537
- 14
Maruna P, Gürlich R, Rosická M.
Ghrelin and leptin elevation in postoperative intraabdominal sepsis.
Eur Surg Res.
2005;
37
354-359
- 15
Mariani LM, Fusco A, Turriziani M, Veneziani A, Marini MA, Lorenzo A de, Bertoli A.
Transient increase of plasma ghrelin after laparoscopic adjustable banding in morbid
obesity.
Horm Metab Res.
2005;
37
242-245
- 16
Shimizu Y, Nagaya N, Isobe T, Imazu M, Okumura H, Hosoda H, Kojima M, Kangawa K, Kohno N.
Increased plasma ghrelin level in lung cancer cachexia.
Clin Cancer Res.
2003;
9
774-778
- 17
Corbetta S, Peracchi M, Cappiello V, Lania A, Lauri E, Vago L, Beck-Peccoz P, Spada A.
Circulating ghrelin levels in patients with pancreatic and gastrointestinal neuroendocrine
tumors: identification of one pancreatic ghrelinoma.
J Clin Endocrinol Metab.
2003;
88
3117-3120
- 18 Maruna P, Gürlich R, Fraško R, Chachkhiani I.
Leptin in acute phase response. In Ferrera LA (Ed). Body mass index and health. New York: Nova Science Publishers
2006: 97-117
- 19
Avram AM, Jaffe CA, Symons KV, Barkan AL.
Endogenous circulating ghrelin does not mediate growth hormone rhythmicity or response
to fasting.
J Clin Endocrinol Metab.
2005;
90
2982-2987
- 20
Otto B, Tschop M, Heldwein W, Pfeiffer AF, Diederich S.
Endogenous and exogenous glucocorticoids decrease plasma ghrelin in humans.
Eur J Endocrinol.
2004;
151
113-117
- 21
Wu R, Zhou M, Cui X, Simms HH, Wang P.
Ghrelin clearance is reduced at the late stage of polymicrobial sepsis.
Int J Mol Med.
2003;
12
777-781
- 22
Chang L, Zhao J, Yang J, Zhang Z, Du J, Tang C.
Therapeutic effects of ghrelin on endotoxic shock in rats.
Eur J Pharmacol.
2003;
473
171-176
- 23
Wang L, Basa NR, Shaikh A, Luckey A, Heber D, St-Pierre DH, Tache Y.
LPS inhibits fasted plasma ghrelin levels in rats: role of IL-1 and PGs and functional
implications.
Am J Physiol Gastrointest Liver Physiol.
2006;
291
G611-G620
- 24
Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Fujimiya M, Katsuura G, Makino S,
Fujino MA, Kasuga M.
A role of ghrelin in neuroendocrine and behavioral responses to stress in mice.
Neuroendocrinology.
2001;
74
143-147
- 25
Sibilia V, Lattuada N, Rapetti D, Pagani F, Vincenza D, Bulgarelli I, Locatelli V,
Guidobono F, Netti C.
Ghrelin inhibits inflammatory pain in rats: involvement of the opioid system.
Neuropharmacology.
2006;
51
497-505
- 26
Ueta Y, Ozaki Y, Saito J, Onaka T.
Involvement of novel feeding-related peptides in neuroendocrine response to stress.
Exp Biol Med (Maywood).
2003;
228
1168-1174
- 27
Nagaya N, Uematsu M, Kojima M, Date Y, Nakazato M, Okumura H, Hosoda H, Shimizu W,
Yamagishi M, Oya H, Koh H, Yutani C, Kangawa K.
Elevated circulating level of ghrelin in cachexia associated with chronic heart failure:
relationships between ghrelin and anabolic/catabolic factors.
Circulation.
2001;
104
2034-2038
- 28
Otero M, Nogueiras R, Lago F, Dieguez C, Gomez-Reino JJ, Gualillo O.
Chronic inflammation modulates ghrelin levels in humans and rats.
Rheumatology (Oxford).
2004;
43
306-310
- 29
Chang L, Du JB, Gao LR, Pang YZ, Tang CS.
Effect of ghrelin on septic shock in rats.
Acta Pharmacol Sin.
2003;
24
45-49
- 30
Wu R, Dong W, Zhou M, Cui X, Hank Simms H, Wang P.
Ghrelin improves tissue perfusion in severe sepsis via downregulation of endothelin-1.
Cardiovasc Res.
2005;
68
318-326
- 31
Zhao D, Zhan Y, Zeng H, Moyer MP, Mantzoros CS, Pothoulakis C.
Ghrelin stimulates interleukin-8 gene expression through protein kinase C-mediated
NF-kappaB pathway in human colonic epithelial cells.
J Cell Biochem.
2006;
97
1317-1327
Correspondence
Assoc. Prof. P. MarunaMD, PhD
Institute of Pathological Physiology of the 1st Faculty of Medicine UK
U nemocnice 5
128 08 Prague 2
Czech Republic
Phone: +420/224/96 28 00
Fax: +420/224/91 97 80
Email: maruna@LF1.cuni.cz