Funcionamiento del ciclo de krebs durante la sepsis y el choque séptico. Una mirada al metabolismo intermediario durante condiciones de hipoxia

The krebs cycle during sepsis and septic shock: a look at intermediate metabolism in hypoxia

Contenido principal del artículo

Juan Daniel Caicedo
Juan José Diaztagle
Alejandro Navarrete Gutiérrez
Cesar Andrés Lamilla
Martín Ocampo Posada
Sergio Ivan Latorre Alfonso
Jorge Iván Alvarado
Luis Eduardo Cruz Martínez

Resumen

El choque séptico es una patología que involucra alteraciones hemodinámicas y compromiso de la microvasculatura que derivan en una disfunción celular que conlleva a la falla orgánica múltiple propia de esta enfermedad. Los protocolos de manejo actuales se centran en la normalización de variables macrohemodinámicas y biomarcadores relacionados con la hipoxia tisular, convirtiéndose en un desafío clínico que requiere el reconocimiento temprano, el control de la infección y la optimización del estado hemodinámico del paciente. En los últimos años se ha identificado que la disfunción multiorgánica que se observa en el choque séptico se encuentra relacionada con el desarrollo de disfunción mitocondrial. Se han planteado dos posibilidades para explicar el surgimiento de esta disfunción mitocondrial, que son el convectivo e inmunometabólico. Dentro del contexto metabólico se observa que el ciclo de Krebs puede funcionar en un entorno de hipoxia mediante la fragmentación y reorientación de sus reacciones enzimáticas, permitiendo la adaptación al metabolismo intermediario a la noxa séptica.

Palabras clave:

Descargas

Los datos de descargas todavía no están disponibles.

Detalles del artículo

Referencias

Hotchkiss RS, Moldawer LL, Opal SM, Reinhart K, Turnbull IR, Vincent JL. Sepsis and septic shock. Nat Rev Dis Primers. 2016;2:16045. doi: 10.1038/nrdp.2016.45

Robin ED. Special report: dysoxia. Abnormal tissue oxygen utilization. Arch Intern Med. 1977;137(7):905-10. doi: 10.1001/archinte.137.7.905

Creery D, Fraser DD. Tissue dysoxia in sepsis: getting to know the mitochondrion. Crit Care Med. 2002;30(2):483-4. doi: 10.1097/00003246-200202000-00036

Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Med. 2017;43(3):304-77. doi: 10.1007/s00134-017-4683-6.

Hernandez G, Teboul JL. Is the macrocirculation really dissociated from the microcirculation in septic shock?. Intensive Care Med. 2016;42(10):1621-4. doi: 10.1007/s00134-016-4416-2.

Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care. 2015;19 Suppl 3:S8. doi: 10.1186/cc14726

Hotchkiss RS, Rust RS, Dence CS, Wasserman TH, Song SK, Hwang DR, et al. Evaluation of the role of cellular hypoxia in sepsis by the hypoxic marker [18F]fluoromisonidazole. Am J Physiol. 1991;261(4 Pt 2):R965-72. doi:

1152/ajpregu.1991.261.4.R965

Groeneveld AB, van Lambalgen AA, van den Bos GC, Bronsveld W, Nauta JJ, Thijs LG. Maldistribution of heterogeneous coronary blood flow during canine endotoxin shock. Cardiovasc Res. 1991;25(1):80-8. doi:

1093/cvr/25.1.80

Abraham E, Singer M. Mechanisms of sepsis-induced organ dysfunction. Crit Care Med. 2007;35(10):2408-16. doi: 10.1097/01.ccm.0000282072.56245.91

Ospina-Tascon G, Neves AP, Occhipinti G, Donadello K, Buchele G, Simion D, et al. Effects of fluids on microvascular perfusion in patients with severe sepsis. Intensive Care Med. 2010;36(6):949-55. doi: 10.1007/s00134-010-1843-3.

Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, et al. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990;113(3):227-42. doi: 10.7326/0003-4819-113-3-227

MacKenzie IM. The haemodynamics of human septic shock. Anaesthesia. 2001;56(2):130-44. doi: 10.1046/j.1365-2044.2001.01866.x

Court O, Kumar A, Parrillo JE. Clinical review: Myocardial depression in sepsis and septic shock. Crit Care. 2002;6(6):500-8.

Terborg C, Schummer W, Albrecht M, Reinhart K, Weiller C, Rother J. Dysfunction of vasomotor reactivity in severe sepsis and septic shock. Intensive Care Med. 2001;27(7):1231-4. doi: 10.1007/s001340101005

Aird WC. Endothelium and haemostasis. Hamostaseologie. 2015;35(1):11-6. doi: 10.5482/HAMO-14-11-0075.

Davis MJ. Perspective: physiological role(s) of the vascular myogenic response. Microcirculation.

;19(2):99-114. doi: 10.1111/j.1549-8719.2011.00131.x.

Trzeciak S, Cinel I, Phillip Dellinger R, Shapiro NI, Arnold RC, Parrillo JE, et al. Resuscitating the microcirculation

in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med. 2008;15(5):399-413. doi: 10.1111/j.1553-2712.2008.00109.x.

Chelazzi C, Villa G, Mancinelli P, De Gaudio AR, Adembri C. Glycocalyx and sepsis-induced alterations in vascular permeability. Crit Care. 2015;19:26. doi: 10.1186/s13054-015-0741-z

Price SA, Spain DA, Wilson MA, Harris PD, Garrison RN. Subacute sepsis impairs vascular smooth muscle contractile machinery and alters vasoconstrictor and dilator mechanisms. J Surg Res. 1999;83(1):75-80. doi: 10.1006/jsre.1998.5568

Marechal X, Favory R, Joulin O, Montaigne D, Hassoun S, Decoster B, et al. Endothelial glycocalyx damage during endotoxemia coincides with microcirculatory dysfunction and vascular oxidative stress. Shock. 2008;29(5):572-6. doi: 10.1097/SHK.0b013e318157e926.

Eichelbronner O, Sielenkamper A, Cepinskas G, Sibbald WJ, Chin-Yee IH. Endotoxin promotes adhesion of human erythrocytes to human vascular endothelial cells under conditions of flow. Crit Care Med.

;28(6):1865-70. doi: 10.1097/00003246-200006000-00030

Fink MP. Cytopathic hypoxia and sepsis: is mitochondrial dysfunction pathophysiologically important or just an epiphenomenon. Pediatr Crit Care Med 2015; 16: 89-91. doi: 10.1097/PCC.0000000000000299

Fink MP. Bench-to-bedside review: Cytopathic hypoxia. Crit Care. 2002;6(6):491-9.

Fink MP. Cytopathic Hypoxia Mitochondrial Dysfunction as Mechanism Contributing to Organ Dysfunction in Sepsis. Crit Care Clin 2001; 17(1): 219-237.

Levy RJ. Mit chondrial dysfunction, bioenergetic impairment, and metabolic down-regulation in sepsis. Shock. 2007;28(1):24-8. doi: 10.1097/01.shk.0000235089.30550.2d

Carré, J.E. & Singer, M. Cellular energetic metabolism in sepsis: the need for a systems approach. Biochim Biophys Acta 2008; 1777(7-8):763–771. doi: 10.1016/j.bbabio.2008.04.024

Levy B, Desebbe O, Montemont C, Gibot S. Increased aerobic glycolysis through beta2 stimulation is a common mechanism involved in lactate formation during shock states. Shock. 2008;30(4):417-21. doi:

1097/SHK.0b013e318167378f

Crouser ED, Julian MW, Blaho DV, Pfeiffer DR. Endotoxin-induced mitochondrial damage correlates with impaired respiratory activity. Crit Care Med. 2002;30(2):276-84. doi: 10.1097/00003246-200202000-00002

Eyenga P, Roussel D, Morel J, Rey B, Romestaing C, Teulier L, et al. Early septic shock induces loss of oxidative phosphorylation yield plasticity in liver mitochondria. J Physiol Biochem. 2014;70(2):285-96. doi: 10.1007/s13105-013-0280-5

Robergs RA, Ghiasvand F, Parker D. Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Regul Integr Comp Physiol. 2004;287(3):502-16. doi: 10.1152/ajpregu.00114.2004

Taylor DE, Ghio AJ, Piantadosi CA. Reactive oxygen species produced by liver mitochondria of rats in sepsis. Arch Biochem Biophys. 1995;316(1):70-6. doi: 10.1006/abbi.1995.1011

Galley HF. Oxidative stress and mitochondrial dysfunction in sepsis. Br J Anaesth. 2011;107(1):57-64. doi: 10.1093/bja/aer093

Frayn KN, et al. Metabolic regulation. A human perspective. 3rd edn. 2010. Oxford: Willey Blackwell, 2010.

Connett RJ, Honig CR, Gayeski TE, Brooks GA. Defining hypoxia: a systems view of VO2, glycolysis, energetics, and intracellular PO2. J Appl Physiol (1985). 1990;68(3):833-42. doi: 10.1152/jappl.1990.68.3.833

Duke T. Dysoxia and lactate. Arch Dis Child. 1999;81(4):343-50. doi: 10.1136/adc.81.4.343

Hochachka PW. Oxygen, homeostasis, and metabolic regulation. Adv Exp Med Biol. 2000;475:311-35. doi: 10.1007/0-306-46825-5_30

Viollet B, Athea Y, Mounier R, Guigas B, Zarrinpashneh E, Horman S, et al. AMPK: Lessons from transgenic and knockout animals. Front Biosci (Landmark Ed). 2009;14:19-44.

Gomez H, Kellum JA, Ronco C. Metabolic reprogramming and tolerance during sepsis-induced AKI. Nat Rev Nephrol. 2017;13(3):143-51. doi: 10.1038/nrneph.2016.186.

Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447-54. doi: 10.1128/mcb.12.12.5447

Chandel NS, Maltepe E, Goldwasser E, Mathieu CE, Simon MC, Schumacker PT. Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A. 1998;95(20):11715-20. doi: 10.1073/pnas.95.20.11715

Poyton RO, Ball KA, Castello PR. Mitochondrial generation of free radicals and hypoxic signaling. Trends Endocrinol Metab. 2009;20(7):332-40. doi: 10.1016/j.tem.2009.04.001

Srivastava A, Mannam P. Warburg revisited: lessons for innate immunity and sepsis. Front Physiol 2015; 6: 70. doi: 10.3389/fphys.2015.00070

Senyilmaz D, Teleman AA. Chicken or the egg: Warburg effect and mitochondrial dysfunction. F1000Prime Rep. 2015;7:41. doi: 10.12703/P7-41

Solaini G, Baracca A, Lenaz G, Sgarbi G. Hypoxia and mitochondrial oxidative metabolism. Biochim Biophys Acta. 2010;1797(6-7):1171-7. doi: 10.1016/j.bbabio.2010.02.011

Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177-85. doi: 10.1016/j.cmet.2006.02.002

Nuzzo E, Berg KM, Andersen LW, Balkema J, Montissol S, Cocchi MN, et al. Pyruvate Dehydrogenase Activity Is Decreased in the Peripheral Blood Mononuclear Cells of Patients with Sepsis. A Prospective Observational Trial. Ann Am Thorac Soc. 2015;12(11):1662-6. doi: 10.1513/AnnalsATS.201505-267BC

Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem. 2002;277(34):30409-12. doi: 10.1074/jbc.R200006200

Randall HM, Jr., Cohen JJ. Anaerobic CO2 production by dog kidney in vitro. Am J Physiol. 1966;211(2):493-505. doi: 10.1152/ajplegacy.1966.211.2.493

Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, et al. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature. 2011;481(7381):385-8. doi: 10.1038/nature10642

Chinopoulos C. Which way does the citric acid cycle turn during hypoxia? The critical role of alpha-ketoglutarate dehydrogenase complex. J Neurosci Res. 2013;91(8):1030-43. doi: 10.1002/jnr.23196

Pisarenko O, Studneva I, Khlopkov V, Solomatina E, Ruuge E. An assessment of anaerobic metabolism during ischemia and reperfusion in isolated guinea pig heart. Biochim Biophys Acta. 1988;934(1):55-63. doi: 10.1016/0005-2728(88)90119-3

Randle PJ, England PJ, Denton RM. Control of the tricarboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart. Biochem J. 1970;117(4):677-95. doi: 10.1042/bj1170677

Weinberg JM, Venkatachalam MA, Roeser NF, Saikumar P, Dong Z, Senter RA, et al. Anaerobic and aerobic pathways for salvage of proximal tubules from hypoxia-induced mitochondrial injury. Am J Physiol Renal Physiol. 2000;279(5):F927-43. doi: 10.1152/ajprenal.2000.279.5.F927

Brekke E, Walls AB, Norfeldt L, Schousboe A, Waagepetersen HS, Sonnewald U. Direct measurement of backflux between oxaloacetate and fumarate following pyruvate carboxylation. Glia. 2012; 60(1): 147–158. doi: 10.1002/glia.21265

Hochachka PW, Dressendorfer RH. Succinate accumulation in man during exercise. Eur J Appl Physiol Occup Physiol. 1976;35(4):235-42. doi: 10.1007/bf00423282

Sanborn T, Gavin W, Berkowitz S, Perille T, Lesch M. Augmented conversion of aspartate and glutamate to succinate during anoxia in rabbit heart. Am J Physiol. 1979;237(5):H535-41. doi: 10.1152/ajpheart.1979.237.5.H535

Cerra FB, Siegel JH, Border JR, Peters DM, McMenamy RR. Correlations between metabolic and cardiopulmonary measurements in patients after trauma, general surgery, and sepsis. J Trauma. 1979;19(8):621-9. doi: 10.1097/00005373-197908000-00010

Whelan SP, Carchman EH, Kautza B, Nassour I, Mollen K, Escobar D, et al. Polymicrobial sepsis is associated with decreased hepatic oxidative phosphorylation and an altered metabolic profile. J Surg Res. 2014;186(1):297-303. doi: 10.1016/j.jss.2013.08.007

D’Alessandro A, Slaughter AL, Peltz ED, et al. Trauma/hemorrhagic shock instigates aberrant metabolic flux through glycolytic pathways, as revealed by preliminary 13C-glucose labeling metabolomics. J Transl Med 2015; 13: 253-265. doi: 10.1186/s12967-015-0612-z

Infantino V, Convertini P, Cucci L, Panaro MA, Di Noia MA, Calvello R, et al. The mitochondrial citrate carrier: a new player in inflammation. Biochem J. 2011;438(3):433-6. doi: 10.1042/BJ20111275

Selak MA, Armour SM, MacKenzie ED, Boulahbel H, Watson DG, Mansfield KD, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7(1):77-85. doi:: 10.1016/j.ccr.2004.11.022

Rubic T, Lametschwandtner G, Jost S, Hinteregger S, Kund J, Carballido-Perrig N, et al. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol. 2008;9(11):1261-9. doi: 10.1038/ni.1657

Mills E, O'Neill LA. Succinate: a metabolic signal in inflammation. Trends Cell Biol. 2014;24(5):313-20. doi: 10.1016/j.tcb.2013.11.008

Contadores