Advances in Clinical and Experimental Medicine
2019, vol. 28, nr 3, March, p. 291–297
Publication type: original article
Early propranolol treatment ameliorates endothelial dysfunction in experimental septic lung
1 Department of Chest Diseases, Faculty of Medicine, Çukurova University, Balcalı, Turkey
2 Department of Pharmacology, Faculty of Pharmacy, Çukurova University, Balcalı, Turkey
3 Department of Pathology, Faculty of Medicine, Çukurova University, Balcalı, Turkey
4 Department of Histology and Embryology, Faculty of Medicine, Çukurova University, Balcalı, Turkey
5 Department of Biochemistry, Faculty of Medicine, Çukurova University, Balcalı, Turkey
6 Department of General Surgery, Faculty of Medicine, Çukurova University, Balcalı, Turkey
7 Department of Microbiology, Faculty of Medicine, Çukurova University, Balcalı, Turkey
8 Department of Biostatistics, Faculty of Medicine, Çukurova University, Balcalı, Turkey
Background. Recent reports have indicated an improved prognosis in sepsis with β-blocker agents; however, the underlying action mechanism is still under debate.
Objectives. The aim of this study was to investigate the potential effect of propranolol on endothelial dysfunction in septic rats.
Material and Methods. The cecal ligation and puncture model (CLP) was used to generate sepsis. Adult male Wistar-Albino rats were divided into 4 groups: group 1 was a sham group, group 2 received sterile saline, group 3 received 10 mg/kg of propranolol 3 days before the intervention, and group 4 received 10 mg/kg of propranolol 30 min after CLP. Six rats from each group were sacrificed 24 h postoperatively. The remaining rats were followed for survival. We have also evaluated the effects on systemic inflammation, coagulation and the lung tissue with immunohistochemical and electron microscopic evaluation.
Results. Serum tumor necrosis factor alpha (TNF-α) and plasminogen activator inhibitor-1 (PAI-1) levels, as well as tissue TNF-α scores were elevated in septic rats. Electron microscopic examination of the lung tissue showed endothelial dysfunction in the sepsis group. Pretreatment significantly improved survival. Moreover, pre-treatment altered serum vascular endothelial growth factor receptor-1 (VEGFR-1) levels and post-treatment reduced serum PAI-1 and VEGFR-1 levels. In both the preand post-treatment groups, electron microscopic examination revealed improvement of the destroyed lung endothelium and showed only mild alterations in the cytoplasmic organelles, especially in the mitochondria of the endothelial cells.
Conclusion. These results suggest that the improved outcome with β-blockers in sepsis may be due to the ameliorated endothelial dysfunction. Further studies focusing on the potential effect of β-blockers on the endothelium may lead to a better understanding of sepsis.
sepsis, endothelial dysfunction, experimental, β-blockers
- Gohil SK, Cao C, Phelan M, et al. Impact of policies on the rise in sepsis incidence, 2000–2010. Clin Infect Dis. 2016;62(6):695–703.
- Ince C, Mayeux PR, Nguyen T, et al; ADQI XIV Workgroup. The endothelium in sepsis. Shock. 2016;45(3):259–270.
- de Montmollin E, Aboab J, Mansart A, Annane D. Bench-to-bedside review: Beta-adrenergic modulation in sepsis. Crit Care. 2009;13(5):230.
- Deng J, Muthu K, Gamelli R, Shankar R, Jones SB. Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis. Am J Physiol Cell Physiol. 2004;287(3):C730–736.
- Muthu K, Deng J, Romano F, et al. Thermal injury and sepsis modulates beta-adrenergic receptors and cAMP responses in monocyte-committed bone marrow cells. J Neuroimmunol. 2005;165(1–2):129–138.
- Cohen MJ, Shankar R, Stevenson J, Fernandez R, Gamelli RL, Jones SB. Bone marrow norepinephrine mediates development of functionally different macrophages after thermal injury and sepsis. Ann Surg. 2004;240(1):132–141.
- Heilbrunn SM, Shah P, Bristow MR, Valantine HA, Ginsburg R, Fowler MB. Increased beta-receptor density and improved hemodynamic response to catecholamine stimulation during long-term metoprolol therapy in heart failure from dilated cardiomyopathy. Circulation. 1989;79(3):483–490.
- Prass K, Meisel C, Hoeflich C, et al. Stroke induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke T helper cell type 1-like immunostimulation. J Exp Med. 2003;198(5):725–736.
- Boomer JS, To K, Chang KC, et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 2011;306(23):2594–2605.
- Mori K, Morisaki H, Yajima S, et al. Beta-1 blocker improves survival of septic rats through preservation of gut barrier function. Intensive Care Med. 2011;37(11):1849–1856.
- Rittirsch D, Huber-Lang MS, Flierl MA, Ward PA. Immunodesign of experimental sepsis by cecal ligation and puncture. Nat Protoc. 2009; 4(1):31–36.
- Wilson J, Higgins D, Hutting H, et al. Early propranolol treatment induces lung hemeoxygenase-1, attenuates metabolic dysfunction, and improves survival following experimental sepsis. Crit Care. 2013;17(5):R195.
- Berk JL, Hagen JF, Beyer WH, Gerber MJ, Dochat GR. The treatment of endotoxin shock by beta adrenergic blockade. Ann Surg. 1969;169 (1):74–81.
- Ackland GL, Yao ST, Rudiger A, et al. Cardioprotection, attenuated systemic inﬂammation, and survival beneﬁt of 1-adrenoceptor blockade in severe sepsis in rats. Crit Care Med. 2010;38(2):388–394.
- Ibrahim-Zada I, Rhee P, Gomez CT, Weller J, Friese RS. Inhibition of sepsis-induced inflammatory response by beta1-adrenergic antagonists. J Trauma Acute Care Surg. 2014;76(2):320–327.
- Sanfilippo F, Santonocito C, Morelli A, Foex P. Beta-blocker use in severe sepsis and septic shock: A systematic review. Curr Med Res Opin. 2015;31(10):1817–1825.
- Rudiger A. Beta-block the septic heart. Crit Care Med. 2010;38(Suppl 10):608–612.
- Macchia A, Romero M, Comignani PD, et al. Previous prescription of β-blockers is associated with reduced mortality among patients hospitalized in intensive care units for sepsis. Crit Care Med. 2012;40 (10):2768–2772.
- Morelli A, Ertmer C, Westphal M, et al. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: A randomized clinical trial. JAMA. 2013;310(16):1683–1691.
- Berk JL, Hagen JF, Maly G, Koo R. The treatment of shock with beta adrenergic blockade. Arch Surg. 1972;104(1):46–51.
- Johansson PI, Haase N, Perner A, Ostrowski SR. Association between sympathoadrenal activation, fibrinolysis, and endothelial damage in septic patients: A prospective study. J Crit Care. 2014;29(3):327–333.
- Hamzaoui O, Teboul JL. The role of beta-blockers in septic patients. Minerva Anestesiol. 2015;81(3):312–319.
- Oberbeck R. Catecholamines: Physiological immunomodulators during health and illness. Curr Med Chem. 2006;13(17):1979–1989.
- Takahashi H, Kobayashi M, Tsuda Y, Herndon DN, Suzuki F. Contribution of the sympathetic nervous system on the burn-associated impairment of CCL3 production. Cytokine. 2005;29(5):208–214.
- Jawa A, Nachimuthu S, Pendergrass M, Asnani S, Fonseca V. Beta-blockers have a beneficial effect upon endothelial function and microalbuminuria in African-American subjects with diabetes and hypertension. J Diabetes Complications. 2008;22(5):303–308.
- Lin ZP, Dong M, Liu J. Bisoprolol improved endothelial function and myocardium survival of hypertension with stable angina: A randomized double-blinded trial. Eur Rev Med Pharmacol Sci. 2013;17(6):794–801.
- Pasini AF, Garbin U, Stranieri C, et al. Nebivolol treatment reduces serum levels of asymmetric dimethylarginine and improves endothelial dysfunction in essential hypertensive patients. Am J Hypertens. 2008;21(11):1251–1257.
- Nerla R, Di Franco A, Milo M, et al. Differential effects of heart rate reduction by atenolol or ivabradine on peripheral endothelial function in type 2 diabetic patients. Heart. 2012;98(24):1812–1816.
- Joseph EK, Levine JD. Role of endothelial cells in antihyperalgesia induced by a triptan and β-blocker. Neuroscience. 2013;232:83–89.
- Perros F, Ranchoux B, Izikki M, et al. Nebivolol for improving endothelial dysfunction, pulmonary vascular remodeling, and right heart function in pulmonary hypertension. J Am Coll Cardiol. 2015;65(7):668–680.
- Ji Y, Chen S, Xu C, Li L, Xiang B. The use of propranolol in the treatment of infantile hemangiomas: An update on potential mechanisms of action. Br J Dermatol. 2015;172(1):24–32.
- Peller M, Ozierański K, Balsam P, Grabowski M, Filipiak KJ, Opolski G. Influence of beta-blockers on endothelial function: A meta-analysis of randomized controlled trials. Cardiol J. 2015;22(6):708–716.
- Jacquet-Lagrèze M, Allaouchiche B, Restagno D, et al. Gut and sublingual microvascular effect of esmolol during septic shock in a porcine model. Crit Care. 2015;19:241.
- Morelli A, Donati A, Ertmer C, et al. Microvascular effects of heart rate control with esmolol in patients with septic shock: A pilot study. Crit Care Med. 2013;41(9):2162–2168.