Adrenomedullin Prevents Lung Injury after Hepatic Ischemia-Reperfusion Damage

  • Kürşat Dikmen Gazi University
  • Hasan Bostanci Gazi University
  • Aydin Yavuz Yildirim Beyazit University
  • Huseyin Gobut Yildirim Beyazit University
  • Murat Alper Diskapi Yildirim Bayezit Training and Education Hospital
  • Mustafa Kerem Gazi University
Keywords: Adrenomedullin, hepatic ischemia/reperfusion, lung injury

Abstract

Objective: Acute lung injury is a complication after hepatic ischemia/reperfusion (I/R) and might be responsible for high mortality rate. The aim of this study was to demonstrate that adrenomedulline administration may prevent lung injury after hepatic I / R by downregulation of proinflammatory cytokines. Materials and Methods: This study was performed by using 54 male Wistar rats. The rats were randomly allocated into 3 groups and in groups were randomly allocated into 1st, 2nd, and 4th hour subgroups. After I/R, AM (12μg/kg) was infused for 30 minute via portal vein. Blood and tissue samples were collected 1, 2 and 4 hour after reperfusion. Hepatic I/R induced lung injury, as characterized by lung edema, histopathologic changes and proinflammatory cytokines including tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels were evaluated. Results: The TNF-α enzyme activity in the first hour was found to be significantly higher in the I/R group than in the Sham and AM group (p=0.027 and p=0.041, respectively). The levels of TNF-α in the sham-operated group were similar in the AM group (p=0.310). Significant differences were found only in the second hour IL-6 measurements (p=0.038). Similar differences in caspase-9 enzyme activity in the sham-operated and AM group (p=0.291). Treatment with AM decreased lung injury after hepatic I/R as demonstrated by reduction in histologic damage. Conclusions: Acute lung injury was decreased by AM treatment after hepatic I/R injury.

Author Biographies

Kürşat Dikmen, Gazi University
Department of General Surgery
Hasan Bostanci, Gazi University
Department of General Surgery
Aydin Yavuz, Yildirim Beyazit University
Department of General Surgery
Huseyin Gobut, Yildirim Beyazit University
Department of General Surgery
Murat Alper, Diskapi Yildirim Bayezit Training and Education Hospital
Department of Pathology
Mustafa Kerem, Gazi University
Department of General Surgery

References

Ohashi I, Kaku R, Fuji H, Nakatsuka H, Matsumi M, Morita K. Severe acute pulmonary edema during living related liver transplantation surgery. Masui The Japanese journal of anesthesiology. 2004;53:925-8.

Yao W, Li H, Luo G, Li X, Chen C, Yuan D, Chi X, Xia Z, Hei Z. SERPINB1 ameliorates acute lung injury in liver transplantation through ERK1/2-mediated STAT3-dependent HO-1 induction. Free Radic Biol Med 2017; 108: 542-53.

Kimura N, Muraoka R, Horiuchi T, Tabo T, Uchinami M, Yokomachi J, et al. Intermittent hepatic pedicle clamping reduces liver and lung injury. The Journal of surgical research. 1998;78:11-7.

Chi X, Guo N, Yao W, Jin Y, Gao W, Cai J, Hei Z. Induction of heme oxygenase-1 by hemin protects lung against orthotopic autologous liver transplantation-induced acute lung injury in rats. J Transl Med 2016; 14: 35.

Chen Z, Ding T, Ma CG. Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice. Biochem Biophys Res Commun 2017; 493: 1143-50.

Chan KC, Lin CJ, Lee PH, CHen CF, Lai YL, Sun WZ, Cheng YJ. Propofol attenuates the decrease of dynamic compliance and water content in the lung by decreasing oxidative radicals released from the reperfused liver. Anesth Analg 2008; 107: 1284-9.

Liu Z, Wang Y, Wang Y, Ning Q, Zhang Y, Gong C, Zhao W, Jing G, Wang Q. Dexmedetomidine atten- uates inflammatory reaction in the lung tissues of septic mice by activating cholinergic anti-inflammatory pathway. Int Immunopharmacol 2016; 35: 210-216.

Cui J, Zhao H, Yi B, Zeng J, Lu K, Ma D. Dexmedetomidine attenuates Bilirubin-Induced lung alveolar epithelial cell death in vitro and in vivo. Crit Care Med 2015; 43: e356-e368.

Yang J, Wu R, Qiang X, Zhou M, Dong W, Ji Y, et al. Human adrenomedullin and its binding protein attenuate organ injury and reduce mortality after hepatic ischemia-reperfusion. Ann Surg. 2009;249:310-7.

Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, et al. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochemical and biophysical research communications. 1993;192:553-60.

Martinez A, Miller MJ, Unsworth EJ, Siegfried JM, Cuttitta F. Expression of adrenomedullin in normal human lung and in pulmonary tumors. Endocrinology. 1995;136:4099-105.

Garcia MA, Martin-Santamaria S, de Pascual-Teresa B, Ramos A, Julian M, Martinez A. Adrenomedullin: a new and promising target for drug discovery. Expert opinion on therapeutic targets. 2006;10:303-17.

Agorreta J, Zulueta JJ, Montuenga LM, Garayoa M. Adrenomedullin expression in a rat model of acute lung injury induced by hypoxia and LPS. American journal of physiology Lung cellular and molecular physiology. 2005;288:L536-45.

Itoh T, Obata H, Murakami S, Hamada K, Kangawa K, Kimura H, et al. Adrenomedullin ameliorates lipopolysaccharide-induced acute lung injury in rats. American journal of physiology Lung cellular and molecular physiology. 2007;293:L446-52.

Ge M, Yao W, Yuan D, Zhou S, Chen X, Zhang Y, Li H, Xia Z, Hei Z. Brg1-mediated Nrf2/HO-1 pathway activation alleviates hepatic ischemia-reperfusion injury. Cell Death Dis 2017; 8: e2841.

Takahashi K. Adrenomedullin from a pheochromocytoma to the eye: implications of the adrenomedullin research for endocrinology in the 21st century. The Tohoku journal of experimental medicine. 2001;193:79-114.

Dupuis J, Caron A, Ruel N. Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin. Clinical science (London, England : 1979). 2005;109:97-102.

Dwivedi AJ, Wu R, Nguyen E, Higuchi S, Wang H, Krishnasastry K, et al. Adrenomedullin and adrenomedullin binding protein-1 prevent acute lung injury after gut ischemia-reperfusion. Journal of the American College of Surgeons. 2007;205:284-93.

Thomaz NF, Koike MK, Abrahao MS, Carillo NF, Pereira RK, Machado JL, Montero EF. Ischemic preconditioning attenuates remote pulmonary in- flammatory infiltration of diabetic rats with an in- testinal and hepatic ischemia-reperfusion injury. Acta Cir Bras 2013; 28: 174-8.

Bae HB, Jeong CW, Li M, Kim HS, Kwak SH. Effects of urinary trypsin inhibitor on lipopolysaccha- ride-induced acute lung injury in rabbits. Inflam- mation 2012; 35: 176-82.

Chan LP, Liu C, Chiang FY, Wang LF, Lee KW, Chen WT, Kuo PL, Liang CH. IL-8 promotes inflamma- tory mediators and stimulates activation of p38 MAPK/ERK-NF-kappaB pathway and reduction of JNK in HNSCC. Oncotarget 2017; 8: 56375- 88.

Teoh NC. Hepatic ischemia reperfusion injury: Contemporary perspectives on pathogenic mechanisms and basis for hepatoprotection-the good, bad and deadly. Journal of gastroenterology and hepatology. 2011;26 Suppl 1:180-7.

Colletti LM, Green M. Lung and liver injury following hepatic ischemia/reperfusion in the rat is increased by exogenous lipopolysaccharide which also increases hepatic TNF production in vivo and in vitro. Shock (Augusta, Ga). 2001;16:312-9.

Carrizo GJ, Wu R, Cui X, Dwivedi AJ, Simms HH, Wang P. Adrenomedullin and adrenomedullin-binding protein-1 downregulate inflammatory cytokines and attenuate tissue injury after gut ischemia-reperfusion. Surgery. 2007;141:245-53.

Kerem M, Bedirli A, Pasaoglu H, Ofluoglu E, Yilmazer D, Salman B, et al. Effect of adrenomedullin on hepatic damage in hepatic ischaemia/reperfusion injury in rats. Liver international : official journal of the International Association for the Study of the Liver. 2008;28:972-81.

Wu R, Zhou M, Wang P. Adrenomedullin and adrenomedullin binding protein-1 downregulate TNF-alpha in macrophage cell line and rat Kupffer cells. Regulatory peptides. 2003;112:19-26.

Yang S, Zhou M, Fowler DE, Wang P. Mechanisms of the beneficial effect of adrenomedullin and adrenomedullin-binding protein-1 in sepsis: down-regulation of proinflammatory cytokines. Critical care medicine. 2002;30:2729-35.

Remick DG, Bolgos GR, Siddiqui J, Shin J, Nemzek JA. Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days. Shock (Augusta, Ga). 2002;17:463-7.

Galani V, Tatsaki E, Bai M, Kitsoulis P, Lekka M, Nakos G, et al. The role of apoptosis in the pathophysiology of Acute Respiratory Distress Syndrome (ARDS): an up-to-date cell-specific review. Pathology, research and practice. 2010;206:145-50.

Sata M, Kakoki M, Nagata D, Nishimatsu H, Suzuki E, Aoyagi T, et al. Adrenomedullin and nitric oxide inhibit human endothelial cell apoptosis via a cyclic GMP-independent mechanism. Hypertension (Dallas, Tex : 1979). 2000;36:83-8.

Published
2019-03-25
Section
Original Research