Adrenomedullin binding improves catecholamine responsiveness and kidney function in resuscitated murine septic shock

Intensive Care Medicine Experimental - 2013
Katja Wagner1, Ulrich Wachter1, J. Vogt1, Angelika Scheuerle2, Oscar McCook1, Sandra Weber1, Michael Gröger1, Bettina Stahl1, Michael Georgieff1, Peter Möller2, Andreas Bergmann3, Frauke Hein3, Enrico Calzia1, Peter Radermacher1, Florian Wagner1
1Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Klinik für Anästhesiologie, Ulm, 89081, Germany
2Institut für Pathologie, Universitätsklinikum, Albert-Einstein-Allee 23, Ulm, 89081, Germany
3Adrenomed AG, Hennigsdorf, 16761, Germany

Tóm tắt

Abstract Purpose Adrenomedullin (ADM) has been referred to as a double-edged sword during septic shock: On one hand, ADM supplementation improved organ perfusion and function, attenuated systemic inflammation, and ultimately reduced tissue apoptosis and mortality. On the other hand, ADM overproduction can cause circulatory collapse and organ failure due to impaired vasoconstrictor response and reduced myocardial contractility. Since most of these data originate from un-resuscitated shock models, we tested the hypothesis whether the newly developed anti-ADM antibody HAM1101 may improve catecholamine responsiveness and thus attenuate organ dysfunction during resuscitated murine, cecal ligation and puncture (CLP)-induced septic shock. Methods Immediately after CLP, mice randomly received vehicle (phosphate-buffered saline, n = 11) or HAM1101 (n = 9; 2 μg·g−1). Fifteen hours after CLP, animals were anesthetized, mechanically ventilated, instrumented, and resuscitated with hydroxyethylstarch and continuous i.v. norepinephrine to achieve normotensive hemodynamics (mean arterial pressure > 50 to 60 mmHg). Results HAM1101 pretreatment reduced the norepinephrine infusion rates required to achieve hemodynamic targets, increased urine flow, improved creatinine clearance, and lowered neutrophil gelatinase-associated lipocalin blood levels, which coincided with reduced expression of the inducible nitric oxide synthase and formation of peroxynitrite (nitrotyrosine immunostaining) in the kidney and aorta, ultimately resulting in attenuated systemic inflammation and tissue apoptosis. Conclusions During resuscitated murine septic shock, early ADM binding with HAM1101 improved catecholamine responsiveness, blunted the shock-related impairment of energy metabolism, reduced nitrosative stress, and attenuated systemic inflammatory response, which was ultimately associated with reduced kidney dysfunction and organ injury.

Từ khóa


Tài liệu tham khảo

Mittra S, Hyvelin JM, Shan Q, Tang F, Bourreau JP: Role of cyclooxygenase in ventricular effects of adrenomedullin: is adrenomedullin a double-edged sword in sepsis? Am J Physiol Heart Circ Physiol 2004, 286: H1034-H1042.

Wang P, Ba ZF, Cioffi EG, Bland KI, Chaudry IH: The pivotal role of adrenomedullin in producing hyperdynamic circulation during the early stage of sepsis. Arch Surg 1998, 133: 1298–1304. 10.1001/archsurg.133.12.1298

Yang S, Zhou M, Chaudry IH, Wang P: Novel approach to prevent the transition from the hyperdynamic phase to the hypodynamic phase of sepsis. Role of adrenomedullin and adrenomedullin binding protein-1. Ann Surg 2002, 236: 625–633. 10.1097/00000658-200211000-00013

Wu R, Higuchi S, Dong W, Ji Y, Zhou M, Marini CP, Ravikumar TS, Wang P: Reversing established sepsis in rats with human vasoactive hormone adrenomedullin and its binding protein. Mol Med 2009, 15: 28–33.

Ertmer C, Morelli A, Rehberg S, Lange M, Hucklenbruch C, Van Aken H, Booke M, Westphal M: Exogenous adrenomedullin prevents and reverses hypodynamic circulation and pulmonary hypertension in ovine endotoxaemia. Br J Anaesth 2007, 99: 830–836. 10.1093/bja/aem295

Temmesfeld-Wollbrück B, Brell B, Dávid I, Dorenberg M, Adolphs J, Schmeck B, Suttorp N, Hippenstiel S: Adrenomedullin reduces vascular hyperpermeability and improves survival in rat septic shock. Intensive Care Med 2007, 33: 703–710. 10.1007/s00134-007-0561-y

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. Crit Care Med 2002, 30: 2729–2735. 10.1097/00003246-200212000-00018

Talero E, Di Paola R, Emanuela M, Esposito E, Virginia M, Cuzzocrea S: Anti-inflammatory effects of adrenomedullin on acute lung injury induced by carrageenan in mice. Mediators Inflamm 2012, 2012: 177851.

Zhou M, Maitra SR, Wang P: Adrenomedullin and adrenomedullin binding protein-1 protect endothelium-dependent vascular relaxation in sepsis. Mol Med 2007, 13: 488–494.

Zhou M, Simms HH, Wang P: Adrenomedullin and adrenomedullin binding protein-1 attenuate vascular endothelial cell apoptosis in sepsis. Ann Surg 2004, 240: 321–330. 10.1097/01.sla.0000133253.45591.5b

Zudaire E, Portal-Núñez S, Cuttitta F: The central role of adrenomedullin in host defense. J Leukoc Biol 2006, 80: 237–244. 10.1189/jlb.0206123

Fowler DE, Wang P: The cardiovascular response in sepsis: proposed mechanisms of the beneficial effect of adrenomedullin and its binding protein (review). Int J Mol Med 2002, 9: 443–449.

Roch A: Increased levels of pro-AVP and pro-ADM in septic shock patients: what could it mean? Intensive Care Med 2009, 35: 1827–1829. 10.1007/s00134-009-1613-2

Westphal M, Stubbe H, Bone HG, Daudel F, Vocke S, Van Aken H, Booke M: Hemodynamic effects of exogenous adrenomedullin in healthy and endotoxemic sheep. Biochem Biophys Res Commun 2002, 296: 134–138. 10.1016/S0006-291X(02)00821-5

Gupta A, Berg DT, Gerlitz B, Richardson MA, Galbreath E, Syed S, Shrama AC, Lowry SF, Grinnell BW: Activated protein c suppresses adrenomedullin and ameliorates lipopolysaccharide-induced hypotension. Shock 2007, 28: 468–476. 10.1097/SHK.0b013e3180487f09

Nishio K, Akai Y, Murao Y, Doi N, Udea S, Tabuse H, Miyamoto S, Dohi K, Minamino N, Shoji H, Kitamura K, Kangawa K, Matsuo H: Increased plasma concentrations of adrenomedullin correlate with relaxation of vascular tone in patients with septic shock. Crit Care Med 1997, 25: 953–957. 10.1097/00003246-199706000-00010

Hirata Y, Mitaka C, Sato K, Nagura T, Tsunoda Y, Amaha K, Marumo F: Increased circulating adrenomedullin, a novel vasodilatory peptide, in sepsis. J Clin Endocrinol Metab 1996, 81: 1449–1453. 10.1210/jc.81.4.1449

Ueda S, Nishio K, Minamino N, Kubo A, Akai Y, Kangawa K, Matsuo H, Fujimura Y, Yoshioka A, Masui K, Doi N, Murao Y, Miyamoto S: Increased plasma levels of adrenomedullin in patients with systemic inflammatory response syndrome. Am J Respir Crit Care Med 1999, 160: 132–136. 10.1164/ajrccm.160.1.9810006

Christ-Crain M, Morgenthaler NG, Struck J, Harbarth S, Bergmann A, Müller B: Mid-regional pro-adrenomedullin as a prognostic marker in sepsis: an observational study. Crit Care 2005, 9: R816-R824. 10.1186/cc3885

Christ-Crain M, Morgenthaler NG, Stolz D, Müller C, Bingisser R, Harbarth S, Tamm M, Struck J, Bergmann A, Müller B: Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia. Crit Care 2006, 10: R96. 10.1186/cc4955

Guignant C, Voirin N, Venet F, Poitevin F, Malcus C, Bohé J, Lepape A, Monneret G: Assessment of pro-vasopressin and pro-adrenomedullin as predictors of 28-day mortality in septic shock patients. Intensive Care Med 2009, 35: 1859–1867. 10.1007/s00134-009-1610-5

Guignant C, Voirin N, Venet F, Lepape A, Monneret G: Persistent high level of circulating midregional-proadrenomedullin and increased risk of nosocomial infections after septic shock. J Trauma 2012, 72: 293–296.

Hattori Y, Nakanishi N, Gross SS, Kasai K: Adrenomedullin augments nitric oxide and tetrahydrobioptein synthesis in cytokine-stimulated vascular smooth muscle cells. Cardiovasc Res 1999, 44: 207–214. 10.1016/S0008-6363(99)00193-5

Mazzocchi G, Albertin G, Nussdorfer GG: Adrenomedullin (ADM), acting through ADM(22–52)-sensitive receptors, is involved in the endotoxin-induced hypotension in rats. Life Sci 2000, 66: 1445–1450. 10.1016/S0024-3205(00)00455-0

Hyvelin JM, Shan Q, Bourreau JP: Adrenomedullin: a cardiac depressant factor in septic shock. J Card Surg 2002, 17: 328–335.

Hollenberg SM, Broussard M, Osman J, Parrillo JE: Increased microvascular reactivity and improved mortality in septic mice lacking inducible nitric oxide synthase. Circ Res 2000, 86: 774–778. 10.1161/01.RES.86.7.774

Wagner F, Wagner K, Weber S, Stahl B, Knöferl MW, Huber-Lang M, Seitz DH, Asfar P, Calzia E, Senftleben U, Gebhard F, Georgieff M, Radermacher P, Hysa V: Inflammatory effects of hypothermia and inhaled H 2 S during resuscitated, hyperdynamic murine septic shock. Shock 2011, 35: 396–402. 10.1097/SHK.0b013e3181ffff0e

Wagner F, Scheuerle A, Weber S, Stahl B, McCook O, Knöferl MW, Huber-Lang M, Thomas J, Asfar P, Szabó C, Möller P, Gebhard F, Georgieff M, Calzia E, Radermacher P, Wagner K: Cardiopulmonary, histologic, and inflammatory effects of intravenous Na 2 S after blunt chest trauma-induced lung contusion in mice. J Trauma 2011, 71: 1659–1667. 10.1097/TA.0b013e318228842e

Barth E, Radermacher P, Thiemermann C, Weber S, Georgieff M, Albuszies G: Role of iNOS in the reduced responsiveness of the myocardium to catecholamines in a hyperdynamic, murine model of septic shock. Crit Care Med 2006, 34: 307–313. 10.1097/01.CCM.0000199070.46812.21

Baumgart K, Wagner F, Gröger M, Weber S, Barth E, Vogt JA, Wachter U, Huber-Lang M, Knöferl MW, Albuszies G, Georgieff M, Asfar P, Szabó C, Calzia E, Radermacher P, Simkova S: Cardiac and metabolic effects of hypothermia and inhaled H 2 S in anesthetized and ventilated mice. Crit Care Med 2010, 38: 588–595. 10.1097/CCM.0b013e3181b9ed2e

Isaac J, Tögel FE, Westenfelder C: Extent of glomerular tubularization is an indicator of the severity of experimental acute kidney injury in mice. Nephron Exp Nephrol 2007, 105: e33-e40. 10.1159/000097017

Loi YH, Kane KA, McPhaden AR, Wainwright CL: Adrenomedullin acts via nitric oxide and peroxynitrite to protect against myocardial ischaemia-induced arrhythmias in anaesthetized rats. Br J Pharmacol 2006, 148: 599–609. 10.1038/sj.bjp.0706771

Groesdonk HV, Wagner F, Hoffarth B, Georgieff M, Senftleben U: Enhancement of NF-κB activation in lymphocytes prevents T cell apoptosis and improves survival in murine sepsis. J Immunol 2007, 179: 8083–8089.

Lawrence T, Bebien M, Liu GY, Nizet V, Karin M: IKKα limits macrophage NF-κB activation and contributes to the resolution of inflammation. Nature 2005, 434: 1138–1142. 10.1038/nature03491

Wu F, Wilson JX, Tyml K: Ascorbate inhibits iNOS expression and preserves vasoconstrictor responsiveness in skeletal muscle of septic mice. Am J Physiol Regul Integr Comp Physiol 2003, 285: R50-R56.

Wang Z, Holthoff JH, Seely KA, Pathak E, Spencer HJ, Gokden N, Mayeux PR: Development of oxidative stress in the peritubular capillary microenvironment mediates sepsis-induced renal microcirculatory failure and kidney injury. Am J Pathol 2012, 180: 505–516. 10.1016/j.ajpath.2011.10.011

Kaufmann S, Andrew P, Sultanian R, Deng Y: Adrenomedullin increases fluid extravasation from the splenic circulation of the rat. J Physiol 2001, 534: 527–533. 10.1111/j.1469-7793.2001.00527.x

Kuwabara T, Mori K, Mukoyama M, Kasahara M, Yokoi H, Saito Y, Yoshioka T, Ogawa Y, Imamaki H, Kusakabe T, Ebihara K, Omata M, Satoh N, Sugawara A, Barasch J, Nakao K: Urinary neutrophil gelatinase-associated lipocalin levels reflect damage to glomeruli, proximal tubules, and distal nephrons. Kidney Int 2009, 75: 285–294. 10.1038/ki.2008.499

Wu L, Gokden N, Mayeux PR: Evidence for the role of reactive nitrogen species in polymicrobial sepsis-induced renal peritubular capillary dysfunction and tubular injury. J Am Soc Nephrol 2007, 18: 1807–1815. 10.1681/ASN.2006121402

Soriano FG, Lorigados CB, Pacher P, Szabó C: Effects of a potent peroxynitrite decomposition catalyst in murine models of endotoxemia and sepsis. Shock 2011, 35: 560–566. 10.1097/SHK.0b013e31820fe5d5

Wang Z, Herzog C, Kaushal GP, Gokden N, Mayeux PR: Actinonin, a meprin A inhibitor, protects the renal microcirculation during sepsis. Shock 2011, 35: 141–147. 10.1097/SHK.0b013e3181ec39cc

Albuszies G, Vogt J, Wachter U, Thiemermann C, Leverve XM, Weber S, Georgieff M, Radermacher P, Barth E: The effect of iNOS deletion on hepatic gluconeogenesis in hyperdynamic murine septic shock. Intensive Care Med 2007, 33: 1094–1101. 10.1007/s00134-007-0638-7

Korvald C, Elvenes OP, Myrmel T: Myocardial substrate metabolism influences left ventricular energetics in vivo . Am J Physiol Heart Circ Physiol 2000, 278: H1345-H1351.

Leverve XM: Mitochondrial function and substrate availability. Crit Care Med 2007,35(suppl):S454-S460. 10.1097/01.CCM.0000278044.19217.73

Thông tin
Thông tin xuất bản

Intensive Care Medicine Experimental

Thông tin tác giả