Hexarelin modulates lung mechanics, inflammation, and fibrosis in acute lung injury

Vanessa Zambelli; Laura Rizzi; Paolo Delvecchio; Elena Bresciani; Emanuele  Rezoagli; Laura Molteni; Ramona Meanti; Maria Serena Cuttin; Giorgio Bovo; Silvia Coco; Robert  J. Omeljaniuk; Vittorio Locatelli; Giacomo Bellani; Antonio Torsello

doi:10.33393/dti.2021.2347

Authors

Vanessa Zambelli Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy https://orcid.org/0000-0001-8002-5205
Laura Rizzi Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy https://orcid.org/0000-0002-3709-6574
Paolo Delvecchio Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy
Elena Bresciani Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy https://orcid.org/0000-0002-8247-276X
Emanuele Rezoagli Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy https://orcid.org/0000-0002-4506-7212
Laura Molteni Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy https://orcid.org/0000-0003-0510-9083
Ramona Meanti Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy https://orcid.org/0000-0002-9734-1025
Maria Serena Cuttin ASST Vimercate, Vimercate - Italy
Giorgio Bovo ASST Vimercate, Vimercate https://orcid.org/0000-0003-1189-6757
Silvia Coco Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy
Robert J. Omeljaniuk Department of Biology, Lakehead University, Thunder Bay, Ontario - Canada https://orcid.org/0000-0002-8500-6692
Vittorio Locatelli Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy
Giacomo Bellani Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy https://orcid.org/0000-0002-3089-205X
Antonio Torsello Department of Medicine and Surgery, University of Milano-Bicocca, Monza - Italy

DOI:

https://doi.org/10.33393/dti.2021.2347

Keywords:

ARDS, GHS , Hexarelin, Inflammation, Lung fibrosis

Abstract

Introduction: Acute respiratory distress syndrome (ARDS) is an acute form of diffuse lung injury characterized by (i) an intense inflammatory response, (ii) increased pulmonary vascular permeability, and (iii) the loss of respiratory pulmonary tissue. In this article we explore the therapeutic potential of hexarelin, a synthetic hexapeptide growth hormone secretagogue (GHS), in an experimental model of ARDS. Hexarelin has anti-inflammatory properties and demonstrates cardiovascular-protective activities including the inhibition of cardiomyocyte apoptosis and cardiac fibrosis, both of which may involve the angiotensin-converting enzyme (ACE) system.

Methods: In our experimental model, ARDS was induced by the instillation of 100 mM HCl into the right bronchus; these mice were treated with hexarelin (320 μg/kg, ip) before (Pre) or after (Post) HCl challenge, or with vehicle. Respiratory system compliance, blood gas analysis, and differential cell counts in a selective bronchoalveolar lavage (BAL) were determined 6 or 24 hours after HCl instillation. In an extended study, mice were observed for a subsequent 14 days in order to assess lung fibrosis.

Results: Hexarelin induced a significant improvement in lung compliance and a reduction of the number of total immune cells in BAL 24 hours after HCl instillation, accompanied with a lower recruitment of neutrophils compared with the vehicle group. At day 14, hexarelin-treated mice presented with less pulmonary collagen deposition compared with vehicle-treated controls.

Conclusions: Our data suggest that hexarelin can inhibit the early phase of the inflammatory response in a murine model of HCl-induced ARDS, thereby blunting lung remodeling processes and fibrotic development.

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References

Bellani G, Laffey JG, Pham T, et al; LUNG SAFE Investigators; ESICM Trials Group. Epidemiology, Patterns of Care, and Mortality for Patients with Acute Respiratory Distress Syndrome in Intensive Care Units in 50 Countries. JAMA. 2016;315(8):788-800. https://doi.org/10.1001/jama.2016.0291 PMID:26903337 DOI: https://doi.org/10.1001/jama.2016.0291

McNicholas BA, Rooney GM, Laffey JG. Lessons to learn from epidemiologic studies in ARDS. Curr Opin Crit Care. 2018;24(1):41-48. https://doi.org/10.1097/MCC.0000000000000473PMID:29135617 DOI: https://doi.org/10.1097/MCC.0000000000000473

Heymann DL, Shindo N; WHO Scientific and Technical Advisory Group for Infectious Hazards. COVID-19: what is next for public health? Lancet. 2020;395(10224):542-545. https://doi.org/10.1016/S0140-6736(20)30374-3 PMID:32061313 DOI: https://doi.org/10.1016/S0140-6736(20)30374-3

Ranieri VM, Rubenfeld GD, Thompson BT, et al; ARDS Definition Task Force. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526-2533. PMID:22797452 DOI: https://doi.org/10.1001/jama.2012.5669

Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342(18):1334-1349. https://doi.org/10.1056/NEJM200005043421806 PMID:10793167 DOI: https://doi.org/10.1056/NEJM200005043421806

Bachofen M, Weibel ER. Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med. 1982;3(1):35-56. https://doi.org/10.1016/S0272-5231(21)00143-X PMID:7075161 DOI: https://doi.org/10.1016/S0272-5231(21)00143-X

Sibilia V, Torsello A, Pagani F, et al. Effects of hexarelin against acid-independent and acid-dependent ulcerogens in the rat. Peptides. 2004;25(12):2163-2170. https://doi.org/10.1016/j.peptides.2004.08.001 PMID:15572206 DOI: https://doi.org/10.1016/j.peptides.2004.08.001

Locatelli V, Rossoni G, Schweiger F, et al. Growth hormone-independent cardioprotective effects of hexarelin in the rat. Endocrinology. 1999;140(9):4024-4031. https://doi.org/10.1210/endo.140.9.6948 PMID:10465272 DOI: https://doi.org/10.1210/endo.140.9.6948

Biagini G, Torsello A, Marinelli C, et al. Beneficial effects of desacyl-ghrelin, hexarelin and EP-80317 in models of status epilepticus. Eur J Pharmacol. 2011;670(1):130-136. https://doi.org/10.1016/j.ejphar.2011.08.020 PMID:21914437 DOI: https://doi.org/10.1016/j.ejphar.2011.08.020

Conte E, Camerino GM, Mele A, et al. Growth hormone secretagogues prevent dysregulation of skeletal muscle calcium homeostasis in a rat model of cisplatin-induced cachexia. J Cachexia Sarcopenia Muscle. 2017;8(3):386-404. https://doi.org/10.1002/jcsm.12185 PMID:28294567 DOI: https://doi.org/10.1002/jcsm.12185

Bresciani E, Pitsikas N, Tamiazzo L, et al. Feeding behavior during long-term hexarelin administration in young and old rats. J Endocrinol Invest. 2008;31(7):647-652. https://doi.org/10.1007/BF03345618 PMID:18787385 DOI: https://doi.org/10.1007/BF03345618

Mao Y, Tokudome T, Kishimoto I. The cardiovascular action of hexarelin. J Geriatr Cardiol. 2014;11(3):253-258. PMID:25278975

Torsello A, Bresciani E, Ravelli M, et al. Novel domain-selective ACE-inhibiting activity of synthetic growth hormone secretagogues. Pharmacol Res. 2012;66(4):317-324. https://doi.org/10.1016/j.phrs.2012.06.006 PMID:22732396 DOI: https://doi.org/10.1016/j.phrs.2012.06.006

Deng W, Deng Y, Deng J, et al. Losartan attenuated lipopolysaccharide-induced lung injury by suppression of lectin-like oxidized low-density lipoprotein receptor-1. Int J Clin Exp Pathol. 2015;8(12):15670-6. PMID: 26884836

Torsello A, Bresciani E, Rossoni G, et al. Ghrelin plays a minor role in the physiological control of cardiac function in the rat. Endocrinology. 2003;144(5):1787-1792. https://doi.org/10.1210/en.2002-221048 PMID:12697684 DOI: https://doi.org/10.1210/en.2002-221048

Amigoni M, Bellani G, Scanziani M, et al. Lung injury and recovery in a murine model of unilateral acid aspiration: functional, biochemical, and morphologic characterization. Anesthesiology. 2008;108(6):1037-1046. https://doi.org/10.1097/ALN.0b013e318173f64fPMID:18497604 DOI: https://doi.org/10.1097/ALN.0b013e318173f64f

Amigoni M, Bellani G, Zambelli V, et al. Unilateral acid aspiration augments the effects of ventilator lung injury in the contralateral lung. Anesthesiology. 2013;119(3):642-651. https://doi.org/10.1097/ALN.0b013e318297d487 PMID:23681142 DOI: https://doi.org/10.1097/ALN.0b013e318297d487

Zambelli V, Bellani G, Borsa R, et al. Angiotensin-(1-7) improves oxygenation, while reducing cellular infiltrate and fibrosis in experimental Acute Respiratory Distress Syndrome. Intensive Care Med Exp. 2015;3(1):44. https://doi.org/10.1186/s40635-015-0044-3PMID:26215809 DOI: https://doi.org/10.1186/s40635-015-0044-3

Tager AM, Kradin RL, LaCamera P, et al. Inhibition of pulmonary fibrosis by the chemokine IP-10/CXCL10. Am J Respir Cell Mol Biol. 2004;31(4):395-404. https://doi.org/10.1165/rcmb.2004-0175OC PMID:15205180 DOI: https://doi.org/10.1165/rcmb.2004-0175OC

Broglio F, Benso A, Valetto MR, et al. Growth hormone-independent cardiotropic activities of growth hormone-releasing peptides in normal subjects, in patients with growth hormone deficiency, and in patients with idiopathic or ischemic dilated cardiomyopathy. Endocrine. 2001;14(1):105-108. https://doi.org/10.1385/ENDO:14:1:105 PMID:11322491 DOI: https://doi.org/10.1385/ENDO:14:1:105

Soubrier F, Alhenc-Gelas F, Hubert C, et al. Two putative active centers in human angiotensin I-converting enzyme revealed by molecular cloning. Proc Natl Acad Sci USA. 1988;85(24):9386-9390. https://doi.org/10.1073/pnas.85.24.9386 PMID:2849100 DOI: https://doi.org/10.1073/pnas.85.24.9386

Georgiadis D, Beau F, Czarny B, Cotton J, Yiotakis A, Dive V. Roles of the two active sites of somatic angiotensin-converting enzyme in the cleavage of angiotensin I and bradykinin: insights from selective inhibitors. Circ Res. 2003;93(2):148-154. https://doi.org/10.1161/01.RES.0000081593.33848.FC PMID:12805239 DOI: https://doi.org/10.1161/01.RES.0000081593.33848.FC

Katugampola SD, Pallikaros Z, Davenport AP. [125I-His(9)]-ghrelin, a novel radioligand for localizing GHS orphan receptors in human and rat tissue: up-regulation of receptors with athersclerosis. Br J Pharmacol. 2001;134(1):143-149. https://doi.org/10.1038/sj.bjp.0704228PMID:11522606 DOI: https://doi.org/10.1038/sj.bjp.0704228

Nagaya N, Miyatake K, Uematsu M, et al. Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J Clin Endocrinol Metab. 2001;86(12):5854-5859. https://doi.org/10.1210/jcem.86.12.8115 PMID:11739451 DOI: https://doi.org/10.1210/jcem.86.12.8115

Kuba K, Imai Y, Ohto-Nakanishi T, Penninger JM. Trilogy of ACE2: a peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters. Pharmacol Ther. 2010;128(1):119-128. https://doi.org/10.1016/j.pharmthera.2010.06.003 PMID:20599443 DOI: https://doi.org/10.1016/j.pharmthera.2010.06.003

Bulgarelli I, Tamiazzo L, Bresciani E, et al. Desacyl-ghrelin and synthetic GH-secretagogues modulate the production of inflammatory cytokines in mouse microglia cells stimulated by beta-amyloid fibrils. J Neurosci Res. 2009;87(12):2718-2727. https://doi.org/10.1002/jnr.22088PMID:19382238 DOI: https://doi.org/10.1002/jnr.22088

Fukuda Y, Ishizaki M, Masuda Y, Kimura G, Kawanami O, Masugi Y. The role of intraalveolar fibrosis in the process of pulmonary structural remodeling in patients with diffuse alveolar damage. Am J Pathol. 1987;126(1):171-182. PMID:3812636

Aggarwal NR, King LS, D’Alessio FR. Diverse macrophage populations mediate acute lung inflammation and resolution. Am J Physiol Lung Cell Mol Physiol. 2014;306(8):L709-L725. https://doi.org/10.1152/ajplung.00341.2013 PMID:24508730 DOI: https://doi.org/10.1152/ajplung.00341.2013

Peiris JS, Yuen KY, Osterhaus AD, Stöhr K. The severe acute respiratory syndrome. N Engl J Med. 2003;349(25):2431-2441. https://doi.org/10.1056/NEJMra032498 PMID:14681510 DOI: https://doi.org/10.1056/NEJMra032498

Blackwell TS, Tager AM, Borok Z, et al. Future directions in idiopathic pulmonary fibrosis research. An NHLBI workshop report. Am J Respir Crit Care Med. 2014;189(2):214-222. https://doi.org/10.1164/rccm.201306-1141WS PMID:24160862 DOI: https://doi.org/10.1164/rccm.201306-1141WS