Molecular Basis of Organ Failure and Regeneration

Organ failure is a common consequence of trauma-induced shock and inflammation. In the intensive care unit, failure of vital organs is one of the most frequent causes of death. Organ failure arises for example due to tissue damage after inflammatory reactions or due to insufficient oxygen supply that is caused as a result of circulation disturbances and shock.

The group of Andrey Kozlov researches the underlying molecular mechanisms of trauma-, shock- and inflammation-induced organ failure. The focus is put on the dysfunction of different subcellular structures such as mitochondria, the endoplasmatic reticulum or the nucleus. Furthermore, pathological intracellular signaling cascades are examined that rely for example on gaseous messengers (nitric oxides, carbon monoxide, hydrogen sulphide) or intracellular redox reactions. Other research focuses on:

  • Impact of mitochondrial reactive oxygen species (ROS) on systemic inflammatory response system (SIRS)- or Sepsis-induced organ failure
  • Nitric oxide-mediated mechanisms of neuronal dysfunction induced through traumatic brain injuries
  • Impact of stress on the endoplasmatic reticulum during the development of shock- or sepsis-induced organ failure
  • Pathophysiological role of free redox active iron in hypoxic tissues during the development of organ failure
  • Pathophysiological role of STAT- and AIF-mediated processes during the development of inflammation reactions and cancer

The aim is to develop new diagnostic methods that facilitate the treatment of organ failure. Focus is put on the therapeutic relevance of reactive oxygen and nitrogen species (RONS) in organs or on the impacts of activating and inhibiting haem oxygenase and nitric oxide synthase.

Selected Publications

Kozlov AV, Grillari J (2022) Pathogenesis of Multiple Organ Failure: The Impact of Systemic Damage to Plasma Membranes. Front Med (Lausanne). 2022 Mar 15;9:806462.
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Weidinger A, Birgisdóttir L, Schäffer J, Meszaros AT, Zavadskis S, Müllebner A, Hecker M, Duvigneau JC, Sommer N, Kozlov AV (2022) Systemic Effects of mitoTEMPO upon Lipopolysaccharide Challenge Are Due to Its Antioxidant Part, While Local Effects in the Lung Are Due to Triphenylphosphonium. Antioxidants. 2022 Feb 6;11 (2): 323.
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Hosmann A, Milivojev N, Dumitrescu S, Reinprecht A, Weidinger A, Kozlov AV (2021) Cerebral nitric oxide and mitochondrial function in patients suffering aneurysmal subarachnoid hemorrhage-a translational approach. Acta Neurochir (Wien) 2021 Jan;163(1):139-149. 
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Zavadskis S, Weidinger A, Hanetseder D, Banerjee A, Schneider C, Wolbank S, Marolt Presen D, Kozlov AV (2020) Effect of Diphenyleneiodonium Chloride on Intracellular Reactive Oxygen Species Metabolism with Emphasis on NADPH Oxidase and Mitochondria in Two Therapeutically Relevant Human Cell Types. Pharmaceutics 2020 Dec 23;13(1):10
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Luís A, Hackl M, Jafarmadar M, Keibl C, Jilge JM, Grillari J, Bahrami S, Kozlov AV (2020) Circulating miRNAs Associated With ER Stress and Organ Damage in a Preclinical Model of Trauma Hemorrhagic Shock. Front Med (Lausanne) 2020 Sep 24;7:568096.
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Herminghaus A, Papenbrock H, Eberhardt R, Vollmer C, Truse R, Schulz J, Bauer I, Weidinger A, Kozlov AV, Stiban J, Picker O. (2019). Time-related changes in hepatic and colonic mitochondrial oxygen consumption after abdominal infection in rats. Intensive Care Med Exp. 2019 Jan 8;7(1):4.
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Cronin SJF, Seehus C, Weidinger A, Talbot S, Reissig S, Seifert M, Pierson Y, McNeill E, Longhi MS, Turnes BL, Kreslavsky T, Kogler M, Hoffmann D, Ticevic M, da Luz Scheffer D, Tortola L, Cikes D, Jais A, Rangachari M, Rao S, Paolino M, Novatchkova M, Aichinger M, Barrett L, Latremoliere A, Wirnsberger G, Lametschwandtner G, Busslinger M, Zicha S, Latini A, Robson SC, Waisman A, Andrews N, Costigan M, Channon KM, Weiss G, Kozlov AV, Tebbe M, Johnsson K, Woolf CJ, Penninger JM (2018). The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature. Nov;563(7732):564-568.
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Mkrtchyan GV, Üçal M, Müllebner A, Dumitrescu S, Kames M, Moldzio R, Molcanyi M, Schaefer S, Weidinger A, Schaefer U, Hescheler J, Duvigneau JC, Redl H, Bunik VI, Kozlov AV (2018). Thiamine preserves mitochondrial function in a rat model of traumatic brain injury, preventing inactivation of the 2-oxoglutarate dehydrogenase complex. Biochim Biophys Acta Bioenerg., Sep;1859(9):925-931

Kozlov AV, Lancaster JR Jr, Meszaros AT, Weidinger A (2017). Mitochondria-meditated pathways of organ failure upon inflammation. Redox Biol,13:170-181
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Kozlov AV, Bahrami S, Redl H & Szabo C (2017). Alterations in nitric oxide homeostasis during traumatic brain injury. Biochim Biophys Acta, S0925-4439(17):30004-2.

Üçal M, Kraitsy K, Weidinger A, Paier-Pourani J, Patz S, Fink B, Molcanyi M & Schäfer U (2016). Comprehensive Profiling of Modulation of Nitric Oxide Levels and Mitochondrial Activity in the Injured Brain: An Experimental Study Based on the Fluid Percussion Injury Model in Rats. J Neurotrauma, 34(2):475-486.

Weidinger A, Müllebner A, Paier-Pourani J, Banerjee A, Miller I, Lauterböck L, Duvigneau JC, Skulachev VP, Redl H & Kozlov AV (2015). Vicious inducible nitric oxide synthase-mitochondrial reactive oxygen species cycle accelerates inflammatory response and causes liver injury in rats. Antioxid Redox Signal, 22(7):572-586.

Dungel P, Perlinger M, Weidinger A, Redl H & Kozlov AV (2015). The cytoprotective effect of nitrite is based on the formation of dinitrosyl iron complexes. Free Radical Biology and Medicine, 89:300-310.

Weidinger A & Kozlov AV (2015). Biological activities of reactive oxygen and nitrogen species: oxidative stress versus signal transduction. Biomolecules, 5(2):472-484.
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Jais A, Einwallner E, Sharif O, Gossens K, Lu TT, Soyal SM, Medgyesi D, Neureiter D, Paier-Pourani J, Dalgaard K, Duvigneau JC, Lindroos-Christensen J, Zapf TC, Amann S, Saluzzo S, Jantscher F, Stiedl P, Todoric J, Martins R, Oberkofler H, Müller S, Hauser-Kronberger C, Kenner L, Casanova E, Sutterlüty-Fall H, Bilban M, Miller K, Kozlov AV, Krempler F, Knapp S, Lumeng CN, Patsch W, Wagner O, Pospisilik JA & Esterbauer H (2014). Heme oxygenase-1 drives metaflammation and insulin resistance in mouse and man. Cell, 158(1):25-40.
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Friedbichler K, Themanns M, Mueller KM, Schlederer M, Kornfeld JW, Terracciano LM, Kozlov AV, Haindl S, Kenner L, Kolbe T, Mueller M, Snibson KJ, Heim MH & Moriggl R (2012). Growth‐hormone–induced signal transducer and activator of transcription 5 signaling causes gigantism, inflammation, and premature death but protects mice from aggressive liver cancer. Hepatology, 55(3):941-952.

Kozlov AV1, Bahrami S, Calzia E, Dungel P, Gille L, Kuznetsov A & Troppmair J (2011). Mitochondrial dysfunction and biogenesis: do ICU patients die from mitochondrial failure? Ann Intensive Care, 1(1):41.
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Kuznetsov AV, Kehrer I, Kozlov AV, Haller M, Redl H, Hermann M, Grimm M & Troppmair J (2011). Mitochondrial ROS production under cellular stress: comparison of different detection methods. Anal Bioanal Chem, 400(8):2383-2390.

Duvigneau JC, Kozlov AV, Zifko C, Postl A, Hartl RT, Miller I, Gille L, Staniek K, Moldzio R, Gregor W, Haindl S, Behling T, Redl & Bahrami S (2010). Reperfusion does not induce oxidative stress but sustained endoplasmic reticulum stress in livers of rats subjected to traumatic-hemorrhagic shock. Shock, 33(3):289-298.

Kozlov AV, Duvigneau JC, Hyatt TC, Raju R, Behling T, Hartl RT, Staniek K, Miller I, Gregor W, Redl H & Chaudry IH (2010). Effect of estrogen on mitochondrial function and intracellular stress markers in rat liver and kidney following trauma-hemorrhagic shock and prolonged hypotension. Molecular Medicine, 16(7-8):254-261.
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Kozlov AV, Duvigneau JC, Miller I, Nürnberger S, Gesslbauer B, Kungl A, Ohlinger W, Hartl RT, Gille L, Staniek K, Gregor W, Haindl S & Redl H (2009). Endotoxin causes functional endoplasmic reticulum failure, possibly mediated by mitochondria. Biochim Biophys Acta, 1792(6):521-530.
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Lundberg JO, Gladwin MT, Ahluwalia A, Benjamin N, Bryan NS, Butler A, Cabrales P, Fago A, Feelisch M, Ford PC, Freeman BA, Frenneaux M, Friedman J, Kelm M, Kevil CG, Kim-Shapiro DB, Kozlov AV, Lancaster JR Jr, Lefer DJ, McColl K, McCurry K, Patel RP, Petersson J, Rassaf T, Reutov VP, Richter-Addo GB, Schechter A, Shiva S, Tsuchiya K, van Faassen EE, Webb AJ, Zuckerbraun BS, Zweier JL & Weitzberg E (2009). Nitrate and nitrite in biology, nutrition and therapeutics. Nature chemical biology, 5(12):865-869.
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Pospisilik JA, Knauf C, Joza N, Benit P, Orthofer M, Cani PD, Ebersberger I, Nakashima T, Sarao R, Neely G, Esterbauer H, Kozlov A, Kahn CR, Kroemer G, Rustin P, Burcelin R & Penninger JM (2007). Targeted deletion of AIF decreases mitochondrial oxidative phosphorylation and protects from obesity and diabetes. Cell, 131(3):476-491.
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Kozlov AV, Staniek K, Haindl S, Piskernik C, Ohlinger W, Gille L, Nohl H, Bahrami S & Redl H (2006). Different effects of endotoxic shock on the respiratory function of liver and heart mitochondria in rats. American Journal of Physiology-Gastrointestinal and Liver Physiology 290 (3). Am J Physiol Gastrointest Liver Physiol, 290(3):G543-549.

Kozlov AV, Costantino G, Sobhian B, Szalay L, Umar F, Nohl H, Bahrami S & Redl H (2005). Mechanisms of vasodilatation induced by nitrite instillation in intestinal lumen: possible role of hemoglobin. Antioxid Redox Signal, 7(3-4):515-21.