Ghrelin and gastrointestinal wound healing. A new perspective for colorectal surgery1 1 Research performed at Department of Surgery, Experimental Surgery Laboratory, Universidade Federal de Santa Catarina, Florianopolis-SC, Brazil.

Humberto Fenner Lyra Junior Igor Kunze Rodrigues Leonardo de Lucca Schiavon Armando José D`Acâmpora About the authors

Introduction

Healing of intestinal anastomosis remains a challenge for surgeons, mainly after colon and rectal resections. Anastomotic leakage is the most feared and potentially fatal complication after colorectal surgery because usually results in high morbidity and mortality, increase length of stay, medical costs and is associated with poorer long-term oncological results11 Trencheva K, Morrissey KP, Wells M, Mancuso CA, Lee SW, Sonoda T, Michelassi F, Charlson ME, Milsom JW. Identifying important predictors for anastomotic leak after colon and rectal resection: prospective study on 616 patients. Ann Surg. 2013;257(1):108-13. PMID: 22968068.

2 Matthiessen P, Hallbook O, Rutegard J, Simert G, Sjodahl R. Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer: a randomized multicenter trial. Ann Surg. 2007;246(2):207-14. PMID: 17667498.

3 Kube R, Mroczkowski P, Granowski D, Benedix F, Sahm M, Schmidt U, Gastinger I, Lippert H, Study group Qualitatssicherung KR-K. Anastomotic leakage after colon cancer surgery: a predictor of significant morbidity and hospital mortality, and diminished tumour-free survival. Eur J Surg Oncol. 2010;36(2):120-4. PMID: 19775850.

4 Frye J, Bokey EL, Chapuis PH, Sinclair G, Dent OF. Anastomotic leakage after resection of colorectal cancer generates prodigious use of hospital resources. Colorectal Dis. 2009;11(9):917-20. PMID: 19175646.
-55 Krarup PM, Nordholm-Carstensen A, Jorgensen LN, Harling H. Association of comorbidity with anastomotic leak, 30-day mortality, and length of stay in elective surgery for colonic cancer: a nationwide cohort study. Dis Colon Rectum. 2015;58(7):668-76. PMID: 26200681.. The prevalence of anastomotic leakage has been reported to range from 1 to 26%11 Trencheva K, Morrissey KP, Wells M, Mancuso CA, Lee SW, Sonoda T, Michelassi F, Charlson ME, Milsom JW. Identifying important predictors for anastomotic leak after colon and rectal resection: prospective study on 616 patients. Ann Surg. 2013;257(1):108-13. PMID: 22968068.,22 Matthiessen P, Hallbook O, Rutegard J, Simert G, Sjodahl R. Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer: a randomized multicenter trial. Ann Surg. 2007;246(2):207-14. PMID: 17667498.,66 Frasson M, Flor-Lorente B, Rodriguez JL, Granero-Castro P, Hervas D, Alvarez Rico MA, Brao MJ, Sanchez Gonzalez JM, Garcia-Granero E, Group AS. Risk factors for anastomotic leak after colon resection for cancer: multivariate analysis and nomogram from a multicentric, prospective, national study with 3193 patients. Ann Surg. 2015;262(2):321-30. PMID: 25361221.

7 Alves A, Panis Y, Trancart D, Regimbeau JM, Pocard M, Valleur P. Factors associated with clinically significant anastomotic leakage after large bowel resection: multivariate analysis of 707 patients. World J Surg. 2002;26(4):499-502. PMID: 11910487.

8 Krarup PM, Jorgensen LN, Andreasen AH, Harling H, Danish Colorectal Cancer G. A nationwide study on anastomotic leakage after colonic cancer surgery. Colorectal Dis. 2012;14(10):e661-7. PMID: 22564292.

9 Lim M, Akhtar S, Sasapu K, Harris K, Burke D, Sagar P, Finan P. Clinical and subclinical leaks after low colorectal anastomosis: a clinical and radiologic study. Dis Colon Rectum. 2006;49(10):1611-9. PMID: 16990979.

10 Leichtle SW, Mouawad NJ, Welch KB, Lampman RM, Cleary RK. Risk factors for anastomotic leakage after colectomy. Dis Colon Rectum. 2012;55(5):569-75. PMID: 22513436.
-1111 Fujita F, Torashima Y, Kuroki T, Eguchi S. Risk factors and predictive factors for anastomotic leakage after resection for colorectal cancer: reappraisal of the literature. Surg Today. 2014;44(9):1595-602. PMID: 24006125.. Multiple factors are involved in healing process of colorectal anastomosis, including technical-related factors and patients-specific characteristics. Over the last few years, molecular aspects of wound healing process have been described and great interest is being given in the role of hormones in the reparative process. The aim of the present review is to provide a comprehensive analysis of the role of ghrelin`s therapy in the gastrointestinal anastomotic healing mainly in colorectal procedures.

Gastrointestinal healing process

Gastrointestinal healing process is a multifactorial and complex process that depends on a several local and systemic factors and have three distinct phases that begins immediately after the tissue damage1212 Iizuka M, Konno S. Wound healing of intestinal epithelial cells. World J Gastroenterol. 2011;17(17):2161-71. PMID: 21633524.

13 Thompson SK, Chang EY, Jobe BA. Clinical review: Healing in gastrointestinal anastomoses, part I. Microsurgery. 2006;26(3):131-6. PMID: 16518804.
-1414 Rijcken E, Sachs L, Fuchs T, Spiegel HU, Neumann PA. Growth factors and gastrointestinal anastomotic healing. J Surg Res. 2014;187(1):202-10. PMID: 24290527.. The complete healing process results in an optimal balance of all phases that are described below:

  • Inflammation or “lag” phase: It starts immediately after the tissue injury, until third postoperative day. The fibrin-based clot is created by the efflux of platelets and an increase of permeability promotes the migration of neutrophils resulting in a hemostasis and epithelial restitution;

  • Proliferation phase: Proliferation process begins in the wounded site with fibroblasts in the fourth postoperative day that becomes the major local cell type. Several growth factors acting in this period manly platelet-derived growth factor (PDGF), basic fibroblast growth factor (bFGF) and transforming growth factor (TGF-β). At this time the matrix established in the inflammatory phase is replaced with granulation tissue that promotes angiogenesis and high levels of oxygen and nutrients to satisfactory healing process;

  • Remodeling phase: Generally, after fourteen days the reorganization process occurs with decrease of macrophages and fibroblasts, thickening of collagen fibers and wound contraction leading to maturation state.

Although the basic healing process is similar in the skin and in the gastrointestinal tract (GIT), there are some specific differences, which directly influence tissue repair. For example, there are three collagen subtypes (1, 3, 5) in the GI and only two (1, 3) in the skin. The collagen is produced by fibroblasts and smooth muscle cells in GI and only by fibroblasts in the skin. Anaerobic and aerobic bacteria are present in GI lumen whereas only aerobic in the skin. The collagenase activity is greater in the GI tract wound repair especially in the first three days and the anastomotic strength is weaker in this period. This condition does not occur in the skin repair. Anastomotic ischemia and tension-free suture are important and crucial factors in the healing process of GI tract and poor tissue perfusion strongly contributes for anastomotic dehiscence1414 Rijcken E, Sachs L, Fuchs T, Spiegel HU, Neumann PA. Growth factors and gastrointestinal anastomotic healing. J Surg Res. 2014;187(1):202-10. PMID: 24290527. (Table 1).

Table 1
Comparison between GI tract and skin healing process

Major factors affecting healing process in colorectal anastomosis

The reasons for anastomotic breakdown are unclear and several risk factors and clinical conditions have been reported in the genesis of colorectal anastomotic dehiscence66 Frasson M, Flor-Lorente B, Rodriguez JL, Granero-Castro P, Hervas D, Alvarez Rico MA, Brao MJ, Sanchez Gonzalez JM, Garcia-Granero E, Group AS. Risk factors for anastomotic leak after colon resection for cancer: multivariate analysis and nomogram from a multicentric, prospective, national study with 3193 patients. Ann Surg. 2015;262(2):321-30. PMID: 25361221.,1111 Fujita F, Torashima Y, Kuroki T, Eguchi S. Risk factors and predictive factors for anastomotic leakage after resection for colorectal cancer: reappraisal of the literature. Surg Today. 2014;44(9):1595-602. PMID: 24006125.. Generally, the risks can be stratified as patient-specific, technical-specific and low anastomosis risk factors.

Obesity is an independent risk factor for anastomotic leak (AL) and increase the risk of leakage up to 2.7 times when compared with non-obese patients66 Frasson M, Flor-Lorente B, Rodriguez JL, Granero-Castro P, Hervas D, Alvarez Rico MA, Brao MJ, Sanchez Gonzalez JM, Garcia-Granero E, Group AS. Risk factors for anastomotic leak after colon resection for cancer: multivariate analysis and nomogram from a multicentric, prospective, national study with 3193 patients. Ann Surg. 2015;262(2):321-30. PMID: 25361221.,1515 Tsukada K, Miyazaki T, Kato H, Masuda N, Fukuchi M, Fukai Y, Nakajima M, Ishizaki M, Motegi M, Mogi A, Sohda M, Moteki T, Sekine T, Kuwano H. Body fat accumulation and postoperative complications after abdominal surgery. Am Surg. 2004;70(4):347-51. PMID: 15098790.; this association has many hypotheses like tissue stricture and healing defect, increase of intraabdominal pressure and microcirculation damage. Nutritional status is another important factor. Many studies have demonstrated the correlation of low serum protein levels and AL showing a decrease of anastomotic complications with preoperative nutritional improvement66 Frasson M, Flor-Lorente B, Rodriguez JL, Granero-Castro P, Hervas D, Alvarez Rico MA, Brao MJ, Sanchez Gonzalez JM, Garcia-Granero E, Group AS. Risk factors for anastomotic leak after colon resection for cancer: multivariate analysis and nomogram from a multicentric, prospective, national study with 3193 patients. Ann Surg. 2015;262(2):321-30. PMID: 25361221.,88 Krarup PM, Jorgensen LN, Andreasen AH, Harling H, Danish Colorectal Cancer G. A nationwide study on anastomotic leakage after colonic cancer surgery. Colorectal Dis. 2012;14(10):e661-7. PMID: 22564292.,1010 Leichtle SW, Mouawad NJ, Welch KB, Lampman RM, Cleary RK. Risk factors for anastomotic leakage after colectomy. Dis Colon Rectum. 2012;55(5):569-75. PMID: 22513436..

Smoking and alcohol abuse are conditions that have also been associated with AL because they cause microvascular disease and ischemia and consequent anastomotic healing failure1616 Kingham TP, Pachter HL. Colonic anastomotic leak: risk factors, diagnosis, and treatment. J Am Coll Surg. 2009;208(2):269-78. PMID: 19228539.. Also, preoperative long-term steroid use strongly increase the rate of leakage of colorectal procedures when compared with non-steroid use1717 Konishi T, Watanabe T, Kishimoto J, Nagawa H. Risk factors for anastomotic leakage after surgery for colorectal cancer: results of prospective surveillance. J Am Coll Surg. 2006;202(3):439-44. PMID: 16500248.. Many studies have demonstrated that radiotherapy is another independent factor and is involved in anastomotic healing defect mainly in rectal resections probably by inducing an inflammatory response and local ischemia66 Frasson M, Flor-Lorente B, Rodriguez JL, Granero-Castro P, Hervas D, Alvarez Rico MA, Brao MJ, Sanchez Gonzalez JM, Garcia-Granero E, Group AS. Risk factors for anastomotic leak after colon resection for cancer: multivariate analysis and nomogram from a multicentric, prospective, national study with 3193 patients. Ann Surg. 2015;262(2):321-30. PMID: 25361221.,1616 Kingham TP, Pachter HL. Colonic anastomotic leak: risk factors, diagnosis, and treatment. J Am Coll Surg. 2009;208(2):269-78. PMID: 19228539. . Colorectal surgery series have demonstrated others patient-specific conditions involved in colonic anastomotic healing process like ASA status, perioperative transfusion and cardiovascular diseases that directly affects anastomosis formation and complete healing55 Krarup PM, Nordholm-Carstensen A, Jorgensen LN, Harling H. Association of comorbidity with anastomotic leak, 30-day mortality, and length of stay in elective surgery for colonic cancer: a nationwide cohort study. Dis Colon Rectum. 2015;58(7):668-76. PMID: 26200681.,66 Frasson M, Flor-Lorente B, Rodriguez JL, Granero-Castro P, Hervas D, Alvarez Rico MA, Brao MJ, Sanchez Gonzalez JM, Garcia-Granero E, Group AS. Risk factors for anastomotic leak after colon resection for cancer: multivariate analysis and nomogram from a multicentric, prospective, national study with 3193 patients. Ann Surg. 2015;262(2):321-30. PMID: 25361221..

The most important technical-specific factors involved in healing process are mechanical and manual suturing, bowel preparation, proximal defunctioning stoma and anastomotic level. Although evidence are scarce, results comparing hand sewn versus stapled anastomosis found lower leak rates in the mechanical procedure in the majority of the series1818 Slesser AA, Pellino G, Shariq O, Cocker D, Kontovounisios C, Rasheed S, Tekkis PP. Compression versus hand-sewn and stapled anastomosis in colorectal surgery: a systematic review and meta-analysis of randomized controlled trials. Tech Coloproctol. 2016;20(10):667-76. PMID: 27554096.

19 Puleo S, Sofia M, Trovato MA, Pesce A, Portale TR, Russello D, La Greca G. Ileocolonic anastomosis: preferred techniques in 999 patients. A multicentric study. Surg Today. 2013;43(10):1145-9. PMID: 23111464.
-2020 Choy PY, Bissett IP, Docherty JG, Parry BR, Merrie A, Fitzgerald A. Stapled versus handsewn methods for ileocolic anastomoses. Cochrane Database Syst Rev. 2011(9):CD004320. PMID: 21901690.. This benefit is more evident in low an ultra-low colorectal anastomosis than in the colonic or ileocolic anastomosis. Diverting stoma also is a controversial condition because it does not act directly in the healing process; it only prevents major septic complications by diverting fecal stream and sometimes delays the fistula diagnosis in the postoperative period. Nowadays this procedure should be considered in patients who underwent low rectal anastomosis (below 6cm from anal verge), neoadjuvant radiotherapy and critically ill patients1010 Leichtle SW, Mouawad NJ, Welch KB, Lampman RM, Cleary RK. Risk factors for anastomotic leakage after colectomy. Dis Colon Rectum. 2012;55(5):569-75. PMID: 22513436.,1111 Fujita F, Torashima Y, Kuroki T, Eguchi S. Risk factors and predictive factors for anastomotic leakage after resection for colorectal cancer: reappraisal of the literature. Surg Today. 2014;44(9):1595-602. PMID: 24006125.,1616 Kingham TP, Pachter HL. Colonic anastomotic leak: risk factors, diagnosis, and treatment. J Am Coll Surg. 2009;208(2):269-78. PMID: 19228539..

Finally, mechanical bowel preparation remains a controversial perioperative condition in the processes of anastomotic dehiscence. The primary goals of mechanical cleansing are: to reduce the colonic bacterial load, decrease surgical site infection and improves the handling of the bowel leading to a better anastomotic healing2121 Saha AK, Chowdhury F, Jha AK, Chatterjee S, Das A, Banu P. Mechanical bowel preparation versus no preparation before colorectal surgery: a randomized prospective trial in a tertiary care institute. J Nat Sci Biol Med. 2014;5(2):421-4. PMID: 25097427.

22 Tajima Y, Ishida H, Yamamoto A, Chika N, Onozawa H, Matsuzawa T, Kumamoto K, Ishibashi K, Mochiki E. Comparison of the risk of surgical site infection and feasibility of surgery between sennoside versus polyethylene glycol as a mechanical bowel preparation of elective colon cancer surgery: a randomized controlled trial. Surg Today. 2016;46(6):735-40. PMID: 26319220.

23 Kiran RP, Murray AC, Chiuzan C, Estrada D, Forde K. Combined preoperative mechanical bowel preparation with oral antibiotics significantly reduces surgical site infection, anastomotic leak, and ileus after colorectal surgery. Ann Surg. 2015;262(3):416-25; discussion 23-5. PMID: 26258310.

24 Elnahas A, Urbach D, Lebovic G, Mamdani M, Okrainec A, Quereshy FA, Jackson TD. The effect of mechanical bowel preparation on anastomotic leaks in elective left-sided colorectal resections. Am J Surg. 2015;210(5):793-8. PMID: 26143605.

25 Chen M, Song X, Chen LZ, Lin ZD, Zhang XL. Comparing mechanical bowel preparation with both oral and systemic antibiotics versus mechanical bowel preparation and systemic antibiotics alone for the prevention of surgical site infection after elective colorectal surgery: a meta-analysis of randomized controlled clinical trials. Dis Colon Rectum. 2016;59(1):70-8. PMID: 26651115.
-2626 Haskins IN, Fleshman JW, Amdur RL, Agarwal S. The impact of bowel preparation on the severity of anastomotic leak in colon cancer patients. J Surg Oncol. 2016;114(7):810-3. PMID: 27634398.. A recent experimental study demonstrated a negative impact of bowel preparation on cellular proliferation and intracellular mechanisms and consequently on anastomotic healing2727 Brown SR, Ali MS, Williams M, Swisher JP, Rice WV, Coviello LC, Huitron SS, Davis KG. Cellular changes of the colon after mechanical bowel preparation. J Surg Res. 2015;193(2):619-25. PMID: 25277353.. Further researches are necessary to clarify and to set the best preoperative method for elective colorectal procedures.

Strategies for healing improvement of colorectal anastomosis

Therapeutic interventions for optimizing a healing anastomotic process have advanced in the last decades. Studies have demonstrated many options and parameters to achieve the best results in intestinal healing. Animal models, surgical techniques, pharmaceutical interventions and different segments of GI tract have been tested and demonstrated different results1414 Rijcken E, Sachs L, Fuchs T, Spiegel HU, Neumann PA. Growth factors and gastrointestinal anastomotic healing. J Surg Res. 2014;187(1):202-10. PMID: 24290527.,2828 Oines MN, Krarup PM, Jorgensen LN, Agren MS. Pharmacological interventions for improved colonic anastomotic healing: a meta-analysis. World J Gastroenterol. 2014;20(35):12637-48. PMID: 25253969..

Øines et al.2828 Oines MN, Krarup PM, Jorgensen LN, Agren MS. Pharmacological interventions for improved colonic anastomotic healing: a meta-analysis. World J Gastroenterol. 2014;20(35):12637-48. PMID: 25253969. in a recent meta-analysis identified seven therapeutic agents for improve the colonic anastomotic healing and that could be explored further. They stratified the agents in four categories: immunomodulators, miscellaneous, proteinase inhibitors and growth hormone (GH) factors.

In immunomodulators class, only ileoprost and tacrolimus demonstrated significant results, improving the anastomotic healing and increasing an early bursting pressure when compared with controls. None of the other tested substances showed benefits of anastomosis healing.

In experimental series, proteinase inhibitors agents have consistently demonstrated an improvement of anastomotic strength in the early postoperative days and are candidates for further studies. A single clinical trial showed that intravenous administration of aprotinin have reduced the anastomotic leakage in low colorectal anastomosis when compared with placebo group2929 Sheridan WG, Shandall AA, Alexander-Williams J, Keighley MR, Boulos PB, Young HL. A multicenter trial of the use of the proteolytic enzyme inhibitor aprotinin in colorectal surgery. Dis Colon Rectum. 1989;32(6):505-8. PMID: 2477204..

Miscellaneous category is represented by hyperbaric oxygen therapy (HBOT), hypothermia, antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs), hormones and GH factors as described below:

Oliveira et al.3030 Oliveira JC, Oliveira CH, Oliveira HE, Pereira A, Maraschin M, d'Acampora AJ. Effects of perioperative hypothermia and reactive oxygen species in the healing of colonic anastomosis in rats. Acta Cir Bras. 2014;29(11):742-7. PMID: 25424295.,3131 de Oliveira JC, de Oliveira CH, de Oliveira HE, Colombeli GL, De Bona Heck N, Pereira A, D'Acampora AJ. Effects of perioperative hypothermia on healing of anastomosis of the colon in rats. Int J Colorectal Dis. 2013;28(5):705-12. PMID: 23588874. reported a detrimental effect of perioperative hypothermia on the colonic anastomotic healing in animal models with decrease of inflammatory cytokines (IL-1, IL- 6, IL-10) and growth factors (IGF-1, VEGF) in the seventh and fourteenth postoperative days.

HBOT has been demonstrated as an important tool to improve the anastomotic healing in the ischemic and inflamed mucosa in colonic anastomosis by anti-infection effect and reducing an ischemia-reperfusion injury3232 Poyrazoglu Y, Topal T, Yuksel R, Bircan FS, Simsek K, Gocgeldi E, Ersoz N, Korkmaz A. Effects of hyperbaric oxygen and preconditioning on wound healing in colonic anastomoses. J Invest Surg. 2015;28(4):188-95. PMID: 26086171.

33 Boersema GS, Wu Z, Kroese LF, Vennix S, Bastiaansen-Jenniskens YM, van Neck JW, Lam KH, Kleinrensink GJ, Jeekel J, Lange JF. Hyperbaric oxygen therapy improves colorectal anastomotic healing. Int J Colorectal Dis. 2016;31(5):1031-8. PMID: 27041554.
-3434 Guzel S, Sunamak O, As A, Celik V, Ferahman M, Nuri MM, Gazioglu E, Atukeren P, Mutlu O. Effects of hyperbaric oxygen and Pgg-glucan on ischemic colon anastomosis. World J Gastroenterol. 2006;12(9):1421-5. PMID: 16552813.. The effect appears not to be limited to the direct influence of high oxygen levels, but also related to an increment of local production of inflammatory cytokines and consequently the inflammatory response.

NSAIDs have been associated with a high-risk of anastomotic leak after gastrointestinal and colorectal surgery. Some authors recommend that the NSAIDs should be abandoned after primary colonic anastomosis because of the increase of leak rate that has been consistently demonstrated in experimental and clinical studies3535 Rushfeldt CF, Agledahl UC, Sveinbjornsson B, Soreide K, Wilsgaard T. Effect of perioperative dexamethasone and different NSAIDs on anastomotic leak risk: a propensity score analysis. World J Surg. 2016;40(11):2782-9. PMID: 27386865.

36 Van Koughnett JA, Wexner SD. Surgery. NSAIDs and risk of anastomotic leaks after colorectal surgery. Nat Rev Gastroenterol Hepatol. 2014;11(9):523-4. PMID: 25069542.

37 Bitot V, Beaussier M. NSAIDs and risk of anastomotic leakage after gastrointestinal surgery. Presse Med. 2014;43(6 Pt 1):633-6. PMID: 24703741.

38 Klein M. Postoperative non-steroidal anti-inflammatory drugs and colorectal anastomotic leakage. NSAIDs and anastomotic leakage. Dan Med J. 2012;59(3):B4420. PMID: 22381097.

39 Rushfeldt CF, Sveinbjornsson B, Soreide K, Vonen B. Risk of anastomotic leakage with use of NSAIDs after gastrointestinal surgery. Int J Colorectal Dis. 2011;26(12):1501-9. PMID: 21833507.
-4040 Hazut O, Shaashua L, Benish M, Levi B, Sorski L, Benjamin B, Hoffman A, Zmora O, Ben-Eliyahu S. The effect of beta-adrenergic blockade and COX-2 inhibition on healing of colon, muscle, and skin in rats undergoing colonic anastomosis. Int J Clin Pharmacol Ther. 2011;49(9):545-54. PMID: 21888867.. This find is due to an effect on collagen metabolism leading to weakened tissue around the anastomosis and on the risk of thrombosis formation leading to a decrease of anastomotic blood flow and ischemic damage.

Experimental studies demonstrated controversial effects of perioperative antibiotics administration in the gastrointestinal wound healing process. There is no consistent results to recommend antibiotics for prevent anastomotic leakage2828 Oines MN, Krarup PM, Jorgensen LN, Agren MS. Pharmacological interventions for improved colonic anastomotic healing: a meta-analysis. World J Gastroenterol. 2014;20(35):12637-48. PMID: 25253969..

The hormones and GH factors therapy (erythropoietin, GH an IGF-1) have been studied and demonstrated important and promising results in gastrointestinal healing. Sorg et al.4141 Sorg H, Harder Y, Krueger C, Reimers K, Vogt PM. The nonhematopoietic effects of erythropoietin in skin regeneration and repair: from basic research to clinical use. Med Res Rev. 2013;33(3):637-64. PMID: 22430919. reviewed the erythropoietin effects in stages of reparative process and conclude that it increases the local levels of vascular endothelial growth factor (VEGF) and nitric oxide synthase (NOS) and consequently protects against ischemia damage particularly after surgical procedures and may lead to clinical benefits. Exogenous GH and IGF-1 increase the collagen levels in anastomotic area, but can presents local collateral effects as increasing the granulation tissue, leading a healing deficit and consequently an anastomotic leak2828 Oines MN, Krarup PM, Jorgensen LN, Agren MS. Pharmacological interventions for improved colonic anastomotic healing: a meta-analysis. World J Gastroenterol. 2014;20(35):12637-48. PMID: 25253969..

Recently, the exogenous administration ghrelin, an orexigenic peptide, was evaluated in the healing of colon anastomosis of rats resulting in a significant burst pressure improvement when compared with control group without collateral effects4242 Ceran C, Aksoy RT, Gulbahar O, Ozturk F. The effects of ghrelin on colonic anastomosis healing in rats. Clinics (Sao Paulo). 2013;68(2):239-44. PMID: 23525322.. These new approaches require further studies to determinate pathophysiology mechanisms and clinical applicability.

Ghrelin

Ghrelin was originally identified, purified and characterized by Kojima et al.4343 Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-60. PMID: 10604470. from rat stomach. Received notoriety, because is the first known endogenous ligand of GH-secretagogues receptor (GHS-R). It is a potent GH-releasing and appetite-stimulating peptide consisting of 28-amino acids, in which serine 3 position is modified by a fatty acid (n-octanioic acid) in the activated form4444 Kojima M, Kangawa K. Structure and function of ghrelin. Seikagaku. 2007;79(9):853-67. PMID: 17969325.,4545 Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85(2):495-522. PMID: 15788704..

The major forms of circulating ghrelin are n-octanoyl-modified and des-acyl ghrelin regulated by food intake and fasting conditions. The nonacylated form is inactive and circulates in amounts greater than acylated form4646 Sato T, Nakamura Y, Shiimura Y, Ohgusu H, Kangawa K, Kojima M. Structure, regulation and function of ghrelin. J Biochem. 2012;151(2):119-28. PMID: 22041973.. Experimental and clinical studies have reported ghrelin-producing cells and ghrelin mRNA expression in different tissues and organs as kidney, large bowel, rectum, small bowel, thyroid, human placenta, brain, adrenal, ovary, testis, heart and pancreas4747 Lyra HF, Jr., Schiavon Lde L, Vieira DS, Teive AM, Costa A, Onzi TR, Nau AL, d'Acampora AJ. Evaluation of immunohistochemical expression of ghrelin-producing rectal cells in Wistar rats receiving the cafeteria diet. Acta Cir Bras. 2013;28(8):614-8. PMID: 23896842.

48 Kurokawa T, Koshio M, Kaiya H, Hashimoto H, Nomura K, Uji S, Awaji M, Gen K, Tanaka H. Distribution of pepsinogen- and ghrelin-producing cells in the digestive tract of Japanese eel (Anguilla japonica) during metamorphosis and the adult stage. Gen Comp Endocrinol. 2011;173(3):475-82. PMID: 21827762.

49 Vitari F, Di Giancamillo A, Deponti D, Carollo V, Domeneghini C. Distribution of ghrelin-producing cells in the gastrointestinal tract of pigs at different ages. Vet Res Commun. 2012;36(1):71-80. PMID: 22281862.

50 Ghelardoni S, Carnicelli V, Frascarelli S, Ronca-Testoni S, Zucchi R. Ghrelin tissue distribution: comparison between gene and protein expression. J Endocrinol Invest. 2006;29(2):115-21. PMID: 16610236.
-5151 Gronberg M, Tsolakis AV, Magnusson L, Janson ET, Saras J. Distribution of obestatin and ghrelin in human tissues: immunoreactive cells in the gastrointestinal tract, pancreas, and mammary glands. J Histochem Cytochem. 2008;56(9):793-801. PMID: 18474938..

The two primary physiological functions of active form are release GH and increase the food intake. Additional effects also have been reported on cardiovascular system, gastrointestinal physiology, metabolism of glucose, lipids and bone4444 Kojima M, Kangawa K. Structure and function of ghrelin. Seikagaku. 2007;79(9):853-67. PMID: 17969325.

45 Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85(2):495-522. PMID: 15788704.
-4646 Sato T, Nakamura Y, Shiimura Y, Ohgusu H, Kangawa K, Kojima M. Structure, regulation and function of ghrelin. J Biochem. 2012;151(2):119-28. PMID: 22041973.,5252 Hosoda H, Kojima M, Kangawa K. Biological, physiological, and pharmacological aspects of ghrelin. J Pharmacol Sci. 2006;100(5):398-410. PMID: 16612045..

Three pathways control ghrelin-stimulated GH release: direct effect on pituitary cells, direct effect from the hypothalamus and indirect effect by vagus nerve pathway signaling which increases noradrenaline in the arcuate nucleus of the hypothalamus leading a central control of feeding behavior. This is an indirect pathway control because of the peptide do not pass the blood-brain barrier in the high levels4646 Sato T, Nakamura Y, Shiimura Y, Ohgusu H, Kangawa K, Kojima M. Structure, regulation and function of ghrelin. J Biochem. 2012;151(2):119-28. PMID: 22041973.,5353 Lemarie F, Beauchamp E, Legrand P, Rioux V. Revisiting the metabolism and physiological functions of caprylic acid (C8:0) with special focus on ghrelin octanoylation. Biochimie. 2016;120:40-8. PMID: 26253695.. Date et al.5454 Date Y, Murakami N, Toshinai K, Matsukura S, Niijima A, Matsuo H, Kangawa K, Nakazato M. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology. 2002;123(4):1120-8. PMID: 12360474. have demonstrated that vagotomy abolish fast-induced elevation of ghrelin plasma levels.

Effects of ghrelin in the gut

Protective effects of ghrelin have been demonstrated in different segments of the gut and for distinct conditions (Table 2).

Table 2
Protective ghrelin effects in the gut.

In gastric mucosa ghrelin administration reduces the damage evoked by ethanol, alendronate, oxidative stress (OS), gastric resection, acetic acid, diabetic inflammation and ischemia-reperfusion (I/R) state5555 Suzuki H, Matsuzaki J, Hibi T. Ghrelin and oxidative stress in gastrointestinal tract. J Clin Biochem Nutr. 2011;48(2):122-5. PMID: 21373264.. El Eter et al.5656 El Eter E, Al Tuwaijiri A, Hagar H, Arafa M. In vivo and in vitro antioxidant activity of ghrelin: attenuation of gastric ischemic injury in the rat. J Gastroenterol Hepatol. 2007;22(11):1791-9. PMID: 17914952. have reported an antioxidant effect of ghrelin in the gut by increasing nitric oxide (NO) release, leading to reduce ulceration, tissue congestion and increase vascular permeability and cellular infiltration.

In animal models, ghrelin administration has promoted acceleration on the healing of gastric and duodenal ulcers by releasing endogenous GH and IGF-1 and leading an increasing of mucosa blood flow and local cell proliferation rate5757 Ceranowicz P, Warzecha Z, Dembinski A, Sendur R, Cieszkowski J, Ceranowicz D, Pawlik WW, Kuwahara A, Kato I, Konturek PC. Treatment with ghrelin accelerates the healing of acetic acid-induced gastric and duodenal ulcers in rats. J Physiol Pharmacol. 2009;60(1):87-98. PMID: 19439811.. Warzecha et al.5858 Warzecha Z, Ceranowicz D, Dembinski A, Ceranowicz P, Cieszkowski J, Kuwahara A, Kato I, Dembinski M, Konturek PC. Ghrelin accelerates the healing of cysteamine-induced duodenal ulcers in rats. Med Sci Monit. 2012;18(5):BR181-7. PMID: 22534700. also have demonstrated an improvement of healing process in cisteamine-induced duodenal ulcers assessing reduction of mucosal OS and inflammatory response and reduction of mucosal OS and inflammatory response Ercan et al.5959 Ercan S, Basaranlar G, Gungor NE, Kencebay C, Sahin P, Celik-Ozenci C, Derin N. Ghrelin inhibits sodium metabisulfite induced oxidative stress and apoptosis in rat gastric mucosa. Food Chem Toxicol. 2013;56:154-61. PMID: 23439480. have reported decrease of apoptosis and OS in sodium metabisulfite induced gastric injury, suggesting that ghrelin treatment attenuates gastric injuries and could improve approaches against gastric mucosal injury.

Exogenous ghrelin prevents decreasing of the antioxidant glutathione in ileal I/R injury and attenuates excessive inflammation and intestinal damage in vagotomized rats after I/R gut-induced injury. It promotes activation of the cholinergic pathway by intracerebroventricular injection and results in inhibition of NF-kB activation in ileal mucosa and an increasing of antioxidative enzymes release (eg., superoxido dismutase, catalase and GSH peroxidase)6060 Sen LS, Karakoyun B, Yegen C, Akkiprik M, Yuksel M, Ercan F, Ozer A, Yegen BC. Treatment with either obestatin or ghrelin attenuates mesenteric ischemia-reperfusion-induced oxidative injury of the ileum and the remote organ lung. Peptides. 2015;71:8-19. PMID: 26032330.,6161 Wu R, Dong W, Ji Y, Zhou M, Marini CP, Ravikumar TS, Wang P. Orexigenic hormone ghrelin attenuates local and remote organ injury after intestinal ischemia-reperfusion. PLoS One. 2008;3(4):e2026. PMID: 18431503.. Intravenous ghrelin administration also induces inflammatory cytokines release, ameliorates intestinal barrier dysfunction and reduces neutrophil infiltration in I/R-induced intestinal injury in animal models6262 Zhang H, Cui Z, Luo G, Zhang J, Ma T, Hu N, Cui T. Ghrelin attenuates intestinal ischemia/reperfusion injury in mice by activating the mTOR signaling pathway. Int J Mol Med. 2013;32(4):851-9. PMID: 23877278.. Intraperitoneal administration of ghrelin has increased gastric acid secretion and protected against water immersion and restraint stress injury in experimental study6363 Sibilia V, Pagani F, Rindi G, Lattuada N, Rapetti D, De Luca V, Campanini N, Bulgarelli I, Locatelli V, Guidobono F, Netti C. Central ghrelin gastroprotection involves nitric oxide/prostaglandin cross-talk. Br J Pharmacol. 2008;154(3):688-97. PMID: 18414388.. Adami et al.6464 Adami M, Pozzoli C, Leurs R, Stark H, Coruzzi G. Histamine H(3) receptors are involved in the protective effect of ghrelin against HCl-induced gastric damage in rats. Pharmacology. 2010;86(5-6):259-66. PMID: 20975320. also have found protective effects in gastric lesions induced by intragastric administration of HCL in rats, this effect was abolished by prior administration of GHS-receptors antagonists and inhibition of histamine release.

Ghrelin proprieties in colonic healing has also been reported in different studies on colitis and inflammatory bowel diseases (IBD) showing several therapeutic effects and results depends on the type of colitis etiology and damage time6565 Tiaka EK, Manolakis AC, Kapsoritakis AN, Potamianos SP. Unraveling the link between leptin, ghrelin and different types of colitis. Ann Gastroenterol. 2011;24(1):20-8. PMID: 24714276..

Konturek et al.6666 Konturek PC, Brzozowski T, Engel M, Burnat G, Gaca P, Kwiecien S, Pajdo R, Konturek SJ. Ghrelin ameliorates colonic inflammation. Role of nitric oxide and sensory nerves. J Physiol Pharmacol. 2009;60(2):41-7. PubMed PMID: 19617644., in an experimental study, have assessed an anti-inflammatory effect of exogenous ghrelin administration in induced colitis due to the increasing of nitric oxide release by stimulation of COX-2-derived PGE2 and consequently improvement of mucosal healing.

Therapeutic effect of ghrelin in acute colitis was associated with reduced lipid peroxidation and TH1-induced inflammatory response, but these effects are less effective than in chronic colitis6767 Pamukcu O, Kumral ZN, Ercan F, Yegen BC, Ertem D. Anti-inflammatory effect of obestatin and ghrelin in dextran sulfate sodium-induced colitis in rats. J Pediatr Gastroenterol Nutr. 2013;57(2):211-8. PMID: 23549326.. Cheng et al.6868 Cheng J, Zhang L, Dai W, Mao Y, Li S, Wang J, Li H, Guo C, Fan X. Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis by inhibiting the activation of nuclear factor-kappa B. Biochem Biophys Res Commun. 2015;458(1):140-7. PMID: 25634696. have demonstrated a prevention of the breakdown of intestinal barrier function in dextran sulfate sodium-induced colitis in rats with reduction of transepithelial electrical resistance and tight junction expression, and bolstered tight junction structural integrity and regulated cytokine secretion6969 Matuszyk A, Ceranowicz D, Warzecha Z, Ceranowicz P, Fyderek K, Galazka K, Cieszkowski J, Bonior J, Jaworek J, Pihut M, Dembinski A. The influence of ghrelin on the development of dextran sodium sulfate-induced colitis in rats. Biomed Res Int. 2015;2015:718314. PMID: 26713317..

In IBD, serum ghrelin and obestatin levels are significantly higher in patients with active disease than in patients with remission, and colonic mucosal mRNA expression of ghrelin was also significantly higher in patients with active disease than in patients in remission mainly in Ulcerative Colitis (UC) suggesting as activity marker in UC7070 Jung JY, Jeong JB, Kim JW, Kim SH, Koh SJ, Kim BG, Lee KL. Circulating ghrelin levels and obestatin/ghrelin ratio as a marker of activity in ulcerative colitis. Intest Res. 2015;13(1):68-73. PMID: 25691845..

Maduzia et al.7171 Maduzia D, Matuszyk A, Ceranowicz D, Warzecha Z, Ceranowicz P, Fyderek K, Galazka K, Dembinski A. The influence of pretreatment with ghrelin on the development of acetic-acid-induced colitis in rats. J Physiol Pharmacol. 2015;66(6):875-85. PMID: 26769837. have reported protective effects of ghrelin in the large bowel in acetic acid-induced colitis with a reducing mucosal concentration of IL-1beta and malondialdehyde concentration, as well as decreased mucosal activity of myeloperoxidase improving anti-oxidative effects and healing process.

Matuszyk et al.7272 Matuszyk A, Ceranowicz P, Warzecha Z, Cieszkowski J, Ceranowicz D, Galazka K, Bonior J, Jaworek J, Bartus K, Gil K, Olszanecki R, Dembinski A. Exogenous ghrelin accelerates the healing of acetic acid-induced colitis in rats. Int J Mol Sci. 2016;17(9). PMID: 27598133. have assessed anti-inflammatory and healing effect in acetic acid-induced colitis in rats and the relationship between ghrelin and colonic healing, demonstrating faster regeneration of the colonic wall and reduction in colonic levels of IL-1beta, TNF-alpha and myeloperoxidase leading to curative effect on injured colonic tissue.

All these findings suggests that exogenous ghrelin protects and exerts beneficial anti-inflammatory and anti-oxidant effects in colonic mucosa, resulting in better intestinal mucosal healing and could be applied to ameliorate the results in colorectal surgery.

Ghrelin in abdominal and colorectal surgery

Experimental and clinical studies have been reported the influence of exogenous ghrelin in anastomotic healing, clinical recovery and postoperative ileus after abdominal procedures involving stomach, esophagus and colon7373 Stengel A, Goebel-Stengel M, Wang L, Shaikh A, Lambrecht NW, Rivier J, Tache Y. Abdominal surgery inhibits circulating acyl ghrelin and ghrelin-O-acyltransferase levels in rats: role of the somatostatin receptor subtype 2. Am J Physiol Gastrointest Liver Physiol. 2011;301(2):G239-48. PMID: 21636529.,7474 Koizumi M, Hosoya Y, Dezaki K, Yada T, Hosoda H, Kangawa K, Nagai H, Lefor AT, Sata N, Yasuda Y. Serum ghrelin levels partially recover with the recovery of appetite and food intake after total gastrectomy. Surg Today. 2014;44(11):2131-7. PMID: 24604119..

Adachi et al.7575 Adachi S, Takiguchi S, Okada K, Yamamoto K, Yamasaki M, Miyata H, Nakajima K, Fujiwara Y, Hosoda H, Kangawa K, Mori M, Doki Y. Effects of ghrelin administration after total gastrectomy: a prospective, randomized, placebo-controlled phase II study. Gastroenterology. 2010;138(4):1312-20. PMID: 20060830. have showed in a randomized controlled phase II trial with 21 patients, that ghrelin postoperative administration leads a decrease of body weight loss in ghrelin group after total gastrectomy when compared with placebo group (P=0.044), because of the orexigenic and prokinetic effects. Takigushi et al.7676 Takiguchi S, Miyazaki Y, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Miyata H, Hosoda H, Kangawa K, Mori M, Doki Y. Impact of synthetic ghrelin administration for patients with severe body weight reduction more than 1 year after gastrectomy: a phase II clinical trial. Surg Today. 2016;46(3):379-85. PMID: 26019019. also have demonstrated that postoperative administration of synthetic ghrelin in gastrectomized patients improve oral food intake (P=0.039) and body weight gain (P=0.037) after one year of procedure when compared with control group in a recent clinical trial.

Popescu et al.7777 Popescu I, Fleshner PR, Pezzullo JC, Charlton PA, Kosutic G, Senagore AJ. The Ghrelin agonist TZP-101 for management of postoperative ileus after partial colectomy: a randomized, dose-ranging, placebo-controlled clinical trial. Dis Colon Rectum. 2010;53(2):126-34. PMID: 20087086. in a phase 2b study with 236 patients have reported accelerated motility recovery of the upper and lower gastrointestinal tract in the group that received an intravenous infusion of ghrelin agonist TZP-101 after partial colectomies, with less adverse events within 72 hours of postoperative period when compared to placebo. Takata et al.7878 Takata A, Takiguchi S, Miyazaki Y, Miyata H, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Mori M, Kangawa K, Doki Y. Randomized phase II study of the anti-inflammatory effect of ghrelin during the postoperative period of esophagectomy. Ann Surg. 2015;262(2):230-6. PMID: 25361222.,7979 Takata A, Takiguchi S, Murakami K, Miyazaki Y, Miyata H, Takahashi T, Kurokawa Y, Yamasaki M, Nakajima K, Mori M, Kangawa K, Doki Y. Effects of ghrelin administration on the early postoperative inflammatory response after esophagectomy. Surg Today. 2015;45(8):1025-31. PMID: 25377269. have reported less pulmonary complications and decreasing of C-reactive protein and IL-6 levels and consequently reduction of systemic inflammatory response syndrome duration in the postoperative period in patients undergoing esophagectomy that received continuous infusion of ghrelin when compared with saline group (P=0.0065).

The postoperative antifibrotic effects of ghrelin were also demonstrated by Bianchi et al.8080 Bianchi E, Boekelheide K, Sigman M, Lamb DJ, Hall SJ, Hwang K. Ghrelin ameliorates adhesions in a postsurgical mouse model. J Surg Res. 2016;201(1):226-34. PMID: 26850207. in growth hormone secretagogue receptor-knockout (GHSR KO) mice, that received postoperative intraperitoneal administration of ghrelin, and had significantly reduction of postoperative adhesion formation (P < 0.001) when compared with control group. The improvement of postsurgical outcomes were confirmed by measuring collagen I protein levels via Western blot analysis and demonstrating that this effect is mediated by the GHSR-1a receptor8080 Bianchi E, Boekelheide K, Sigman M, Lamb DJ, Hall SJ, Hwang K. Ghrelin ameliorates adhesions in a postsurgical mouse model. J Surg Res. 2016;201(1):226-34. PMID: 26850207..

Recently, Ceran et al.4242 Ceran C, Aksoy RT, Gulbahar O, Ozturk F. The effects of ghrelin on colonic anastomosis healing in rats. Clinics (Sao Paulo). 2013;68(2):239-44. PMID: 23525322. in an experimental study have reported another promising clinical effect of ghrelin. They have assessed a beneficial effect of postoperative ghrelin administration on the healing of colonic anastomoses in rats when compared with controls. They have showed an increasing in the bursting pressure and hidroxyproline levels in the ghrelin group on the seventh postoperative day. This results was associated with increase of fibroblasts efflux, local collagen synthesis and consequently an increasing of the burst pressure. All these findings evidences a potential benefit for abdominal procedures and new investigations should be performed to elucidate the real role of this peptide in the healing process, especially in colonic anastomosis.

In Table 3, summarizes the main clinical and experimental studies investigating the relationship between exogenous ghrelin administration and postoperative protective effects.

Table 3
Proposed postoperative protective effects of ghrelin in GI procedures.

Conclusions

Data available in the literature shows numerous proprieties and action mechanisms of ghrelin, not only in feeding or in GH releasing, but also in remodeling cellular process that could be essential in the majority of the abdominal procedures. Advances have recently been made in our understanding of the relationship between ghrelin and the pathophysiology of wound healing process, oxidative state and inflammatory response. These beneficial interactions in the anastomotic healing process and protective tissue effects represent opportunities for the evaluation of new therapeutic strategies focused on the gastrointestinal surgery.

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  • Financial source:

    none

  • 1
    Research performed at Department of Surgery, Experimental Surgery Laboratory, Universidade Federal de Santa Catarina, Florianopolis-SC, Brazil.

Publication Dates

  • Publication in this collection
    Mar 2018

History

  • Received
    27 Nov 2017
  • Reviewed
    26 Jan 2018
  • Accepted
    28 Feb 2018
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