Molekulare Mechanismen der Funktion von neutrophilen Granulozyten im Rahmen des akuten Lungenversagens

• Antragsteller: Professor Dr. Alexander Zarbock
• Fachliche Zuordnung: Anästhesiologie ; Public Health, Gesundheitsbezogene Versorgungsforschung, Sozial- und Arbeitsmedizin
• Förderung: Förderung von 2012 bis 2017
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 223566930

• Erstellungsjahr: 2018

Zusammenfassung der Projektergebnisse

Acute lung injury (ALI) is a common disease with an incidence of 79 per 100,000 person years in the United States. Despite the use of state-of-the-art treatment, this disease is associated with high mortality of up to 38%. Sepsis, trauma, and massive transfusion are all extrapulmonary causes of ALI, whereas pneumonia and acid aspiration are typical causes of intrapulmonary ALI. Recruitment of neutrophils into the lung is a key event in the development of ALI. Neutrophils can interact with adherent platelets and leukocytes in a process called secondary capture, which is often followed by neutrophil-endothelial interactions. These interactions lead to neutrophil activation by a process of outside-in-signaling through integrins in addition to the presentation of chemokines and lipid mediators by platelets to neutrophils. One important lipid mediator is thromboxane A2 (TxA2). Small GTPases such as Rac and Cdc42 play a key role in the directed migration of neutrophils to sites of inflammation. p21-activated kinases (PAK) 1, 2, and 3 constitute a family of serine/threonine kinases activated by Rac and Cdc42. In neutrophils, PAK is activated by chemoattractants such as fMLP and CXCL1, a ligand for CXCR2. PAK is implicated in the directional movement of neutrophils towards a chemotactic gradient in vitro. PAK has been shown to be activated by CXCL1, CXCL8 (interleukin-8) and CCL5 (RANTES). These chemokines are known to be of critical importance in acute lung injury. In addition to CXCR2 chemokines and LFA-1, lipid mediators also play a role in pulmonary inflammation. Lipoxygenases incorporate molecular oxygen into unsaturated fatty acids and are named according to the position of the carbon double bonds they oxidize. However, the exact contribution of TxA2 production triggered by platelet-neutrophil interactions, the contribution of GTPases and PAK signaling as well as lipoxygenases, e.g. 12/15-lipoxygenases remained unknown and were subject to research and investigation in the scope of this project.

Projektbezogene Publikationen (Auswahl)

• Regulation of PTEN activity by p38δ-PKD1 signaling in neutrophils confers inflammatory responses in the lung. J Exp Med. 2012 Nov 19;209(12):2229-46
  Ittner A, Block H, Reichel CA, Varjosalo M, Gehart H, Sumara G, Gstaiger M, Krombach F, Zarbock A, Ricci R
  
• GDF-15 prevents platelet integrin activation and thrombus formation. J Thromb Haemost. 2013 Feb;11(2):335-44
  Rossaint J, Vestweber D, Zarbock A
  
• Tissue-specific neutrophil recruitment into the lung, liver, and kidney. J Innate Immun. 2013;5(4):348-57
  Rossaint J, Zarbock A
  
• Neutrophils scan for activated platelets to initiate inflammation. Science. 2014 Dec 5;346(6214):1234-8
  Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, Nácher M, Pitaval C, Radovanovic I, Fukui Y, McEver RP, Filippi MD, Lizasoain I, Ruiz-Cabello J, Zarbock A, Moro MA, Hidalgo A
  
• Platelets in inflammation and immunity. J Thromb Haemost. 2014 Nov;12(11):1764-75
  Herter JM, Rossaint J, Zarbock A
  
• Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood. 2014 Apr 17;123(16):2573-84
  Rossaint J, Herter JM, Van Aken H, Napirei M, Döring Y, Weber C, Soehnlein O, Zarbock A
  
• GDF-15 prevents ventilator-induced lung injury by inhibiting the formation of platelet-neutrophil aggregates. Thromb Haemost. 2015 Aug;114(2):434-7
  Herter JM, Kraft F, Van Aken H, Meersch M, Zarbock A, Rossaint J
  
• Hydroxyethyl starch 130/0.4 decreases inflammation, neutrophil recruitment, and neutrophil extracellular trap formation. Br J Anaesth. 2015 Mar;114(3):509-19
  Rossaint J, Berger C, Kraft F, Van Aken H, Giesbrecht N, Zarbock A
  
• Platelets in leucocyte recruitment and function. Cardiovasc Res. 2015 Aug 1;107(3):386-95
  Rossaint J, Zarbock A
  
• Directed transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response. Nat Commun. 2016 Nov 15;7:13464
  Rossaint J, Kühne K, Skupski J, Van Aken H, Looney MR, Hidalgo A, Zarbock A
  
• Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease. J Exp Med. 2017 Jul 3;214(7):2121-2138
  Uderhardt S, Ackermann JA, Fillep T, Hammond VJ, Willeit J, Santer P, Mayr M, Biburger M, Miller M, Zellner KR, Stark K, Zarbock A, Rossaint J, Schubert I, Mielenz D, Dietel B, Raaz-Schrauder D, Ay C, Gremmel T, Thaler J, Heim C, Herrmann M, Collins PW, Schabbauer G, Mackman N, Voehringer D, Nadler JL, Lee JJ, Massberg S, Rauh M, Kiechl S, Schett G, O'Donnell VB, Krönke G
  
• Perioperative Inflammation and Its Modulation by Anesthetics. Anesth Analg. 2018 Mar;126(3):1058-1067
  Rossaint J, Zarbock A