Research Area F: Barrier integrity during inflammation and repair
| Research Area Leaders | |
|---|---|
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Dept. Internal Medicine, Medical Clinic II Klinikstrasse 33 35392 Giessen |
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MPI for Heart and Lung Research Parkstrasse 1 61231 Bad Nauheim |
| Faculty involved | |||
|---|---|---|---|
| T. Acker | T. Chakraborty | V. Grau | F. Grimminger |
| A. Günther | H. Hackstein | S. Herold | S. Kanse |
| M. Kracht | W. Kummer | J. Lohmeyer | P. Markart |
| K. Mayer | R.E. Morty | J. Pfeilschifter | S. Offermanns |
| A. Pingoud | K.T. Preissner | S. Santoso | L. Schäfer |
| L. Schmitz | W. Seeger | I. Vadasz | K. Zacharowski |
Summary
Survival in severe respiratory infection critically depends on prevention and/or repair of endothelial and epithelial barrier failure. We have identified key regulators of endothelial/epithelial barrier function, including novel pathogen/host mediators and signalling pathways directing barrier integrity. We will extend these studies to clarify mechanisms that underlie barrier failure and repair in pneumonia, ARDS and sepsis; and will exploit these pathways for novel treatment strategies. Studies will be performed in cell culture, mouse models of acute respiratory failure (bacterial/viral pneumonia; endotoxin-, acid-, and ventilator-induced lung injury) and lavage/blood samples from patient cohorts.
- We will dissect the role of specific sensor systems for foreign and endogenous “danger” signals (TLR, NLR, RLH) in lung injury and repair including the downstream signalling pathways.
- We aim to promote host defence capacity while maintaining barrier integrity, and will explore molecular pathways involved in leukocyte trafficking, neutrophil extracellular trap formation, endothelial Gq/11-mediated signalling, the role of prolyl hydroxylases in inflammation-hypoxia crosstalk, and epithelial overexpression of CCL-2, IL-22 and GM-CSF for therapeutic purposes.
- We will also evaluate resolvins, JNK-dependent pathways, anti-apoptotic strategies (e.g. anti- TRAIL and downstream signalling), inhaled peptides (Bβ15-42, intermedin), ion channel (ENaC) and ion pump (Na/K-ATPase) manipulation for resolution of inflammation and non-scarring tissue regeneration. The stimulation of lung-resident stem/progenitor cells and exogenous mesenchymal stem cells will also be evaluated.
- In clinical studies we will identify inflammatory versus regenerative signatures in lavage samples from pneumonia/ARDS lungs and evaluate the therapeutic impact of precursor lipids of resolvins, Bβ15-42 and mesenchymal stem cells.
Most relevant publications of the Research Area F
1. Wygrecka M, Wilhelm J, Jablonska E, Zakrzewicz D, Preissner KT, Seeger W, Guenther A, Markart P. Shedding of Low Density Lipoprotein Receptor-related Protein-1 in Acute Respiratory Distress Syndrome. Am J Respir Crit Care Med. Mar 11. [Epub ahead of print ]
2. Clauss M*, Voswinckel R*, Rajashekhar G, Sigua NL, Fehrenbach H, Rush NI, et al. Lung endothelial monocyte-activating protein 2 is a mediator of cigarette smoke-induced emphysema in mice. J Clin Invest 121:2470-9, 2011 *contribtued equally
3. Herold S, Shafiei Tabar T, Janßen H, Högner, K, Cabanski M, Lewe-Schlosser P, Albrecht J, Driever F, Vadasz I, Seeger W, Steinmüller M, Lohmeyer J. Exudate macrophages attenuate epithelial injury by the release of IL-1 receptor antagonist in gram-negative pneumonia. Am J Respir Crit Care Med 183:1380-90, 2011
4. Krasteva G, Canning BJ, Hartmann P, Veres TZ, Papadakis T, Mühlfeld C, Schliecker K, Tallini YN, Braun A, Hackstein H, Baal N, Weihe E, Schütz B, Kotlikoff M, Ibanez-Tallon I, Kummer W Cholinergic chemosensory cells in the trachea regulate breathing. Proc Natl Acad Sci USA 108:9478-83, 2011
5. Sachs UJ, Wasel W, Bayat B, Bohle RM, Hattar K, Berghöfer H, Reil A, Bux J, Bein G, Santoso S, Weissmann N. Mechanism of transfusion-related acute lung injury induced by HLA class II antibodies. Blood 117:669-77, 2011
6. Spragg R, Taut F, Lewis J, Schenk P, Ruppert C, Dean N, Krell K, Karabinis A, Guenther A. Recombinant Surfactant Protein C Based Surfactant for Patients with Severe Direct Lung Injury. Am J Respir Crit Care Med 183:1055-61, 2011
7. Gottschald OR, Malec V, Krasteva G, Hasan D, Kamlah F, Herold S, Rose F, Seeger W, Hänze J. TIAR and TIA-1 mRNA-binding proteins coaggregate under conditions of rapid oxygen decline and extreme hypoxia and suppress the HIF-1α pathway. J Mol Cell Biol 2:345-56, 2010
8. Hecker M, Zaslona Z, Kwapiszewska G, Niess G, Zakrzewicz A, Hergenreider E, Wilhelm J, Marsh LM, Sedding D, Klepetko W, Lohmeyer J, Dimmeler S, Seeger W, Weissmann N, Schermuly RT, Kneidinger N, Eickelberg O, Morty RE. Dysregulation of the IL-13 receptor system: a novel pathomechanism in pulmonary arterial hypertension. Am J Respir Crit Care Med 182:805-18, 2010
9. Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, Brinkmann V, Lorenz M, Bidzhekov K, Khandagale A, Konrad I, Kennerknecht E, Reges K, Holdenrieder S, Braun S, Reinhardt C, Spannagl M, Preissner KT, Engelmann B. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16:887-96, 2010
10. Moreth K, Brodbeck R, Babelova A, Gretz N, Spieker T, Zeng-Brouwers J, Pfeilschifter J, Young M, Schaefer RM, Schaefer L. The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis. J Clin Invest 120:4251-72, 2010
11. Ritterhoff S, Farah CM, Grabitzki J, Lochnit G, Skurat AV, Schmitz ML. The WD40 repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions. EMBO J 29:3747-49, 2010
12. Cakarova L, Marsh LM, Wilhelm J, Mayer K, Grimminger F, Seeger W, Lohmeyer J, Herold S. Macrophage TNF-a induces epithelial expression of GM-CSF: Impact on alveolar epithelial repair. Am J Respir Crit Care Med 180:521-32, 2009
13. Gaestel M, Kotlyarov A, Kracht M. Targeting innate immunity protein kinase signaling in inflammation. Nat Rev Drug Discov 8:480-99, 2009
14. Korhonen H, Fisslthaler B, Moers A, Wirth A, Habermehl D, Wieland T, Schütz G, Wettschureck N, Fleming I, Offermanns S. Anaphylactic shock depends on endothelial Gq/G11. J Exp Med 206: 411-20, 2009
15. Mayer K, Kiessling A, Ott J, Schaefer MB, Hecker M, Henneke I, Schulz R, Günther A, Wang J, Wu L, Roth J, Seeger W, Kang JX. Acute lung injury is reduced in fat-1 mice endogenously synthesizing n-3 fatty acids. Am J Resp Crit Care Med 179: 474-83, 2009
16. Shibamiya A, Hersemeyer K, Schmidt-Wöll T, Sedding D, Daniel JM, Bauer S, Koyama T, Preissner KT, Kanse SM. Key role of double-stranded RNA and toll-like receptor-3 in disrupting the haemostasis balance on endothelial cells. Blood 113:714-22, 2009
17. Wygrecka M, Marsh L, Morty R, Henneke I, Lohmeyer J, Guenther A, Markart P, Preissner KT. Enolase-1 promotes plasminogen-mediated recruitment of monocytes to the acutely inflamed lung. Blood 113:5588-98, 2009
18. Yoshikawa Y, Ogawa M, Hain T, Yoshida M, Fukumatsu M, Kim M, Mimuro H, Nakagawa I, Yanagawa T, Ishii T, Kakizuka A, Sztul E, Chakraborty T, Sasakawa C. Listeria monocytogenes ActA-mediated escape from autophagic recognition. Nat Cell Biol 11:1233-40, 2009
19. Herold S, Steinmueller M, von Wulffen W, Cakarova L, Pinto R, Pleschka S, Mack M, Kuziel WA, Corazza N, Brunner T, Seeger W, Lohmeyer J. Lung epithelial apoptosis in influenza virus pneumonia: The role of macrophage expressed TNF-related apoptosis-inducing ligand. J Exp Med 205:3065-77, 2008
20. Choi EY*, Chavakis E*, Czabanka MA, Langer HF, Fraemohs L, Economopoulou M, Kundu RK, Orlandi A, Zheng YY, Prieto DA, Ballantyne CM, Constant SL, Aird WC, Papayannopoulou T, Gahmberg CG, Udey MC, Vajkoczy P, Quertermous T, Dimmeler S, Weber C, Chavakis T. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflame cell recruitment. Science 322: 1101-4, 2008 *contributed equally
21. Geng H, Wittwer T, Dittrich-Breiholz O, Kracht M, Schmitz, ML. Phosphorylation of NF-κB p65 at serine 468 controls its COMMD1-dependent ubiquitination and target gene specific proteasomal elimination. EMBO Rep 10:381-86, 2008
22. Liebner S, Corada M, Bangsow T, Babbage J, Taddei A, Czupalla CJ, Reis M, Felici A, Wolburg H, Fruttiger M, Taketo MM, von Melchner H, Plate KH, Gerhardt H, Dejana E. Wnt/beta catenin signaling controls development of the blood-brain barrier. J Cell Biol 183:409-17,2008
23. Mouton R, Finch D, Davies I, Binks A, Zarachowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: a retrospective observational study. Lancet 371:475-82, 2008
24. Vadász I, Dada LA, Briva A, Trejo HE, Welch LC, Chen J, Tóth PT, Lecuona E, Witters LA, Schumacker PT, Chandel NS, Seeger W, Sznajder JI. AMP-activated protein kinase regulates CO2-induced alveolar epithelial dysfunction in rats and human cells by promoting Na,KATPase endocytosis. J Clin Invest 118:752-62, 2008
25. Fischer S, Gerriets T, Wessels C, Walberer M, Kostin S, Stolz E, Zheleva K, Hocke A, Hippenstiel S, Preissner KT. Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor. Blood 110:2457-65, 2007
26. Pingoud A, Sivla GH. Precision genome surgery. Nat Biotechn 25:743-4, 2007
27. Horn C, Hansen J, Schnütgen F, Seisenberger C, Floss T, Irgang M, De-Zolt S, Wurst W, von Melchner H*, Noppinger PR* Splinkerette PCR for more efficient characterization of gene trap events. Nat Genet 39:933-34, 2007 (*contributed equally)
28. Fiedler U*, Reiss Y*, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG. Angiopoietin-2 sensitizes endothelial cells to TNF-α and has a crucial role in the induction of inflammation. Nat Med 12:235-39, 2006 *contributed equally
29. Orlova VV, Economopoulou M, Lupu F, Santoso S, Chavakis T. Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-Cadherin mediated cell-cell contacts. J Exp Med 203:2703-14, 2006
30. Zacharowski K, Zacharowski PA, Koch A, Baban A, Tran N, Berkels R, Papewalis C, Schulze-Osthoff K, Knuefermann P, Zähringer U, Schumann RR, Rettori V, McCann SM, Bornstein SR. Toll-like receptor 4 plays a crucial role in the immune-adrenal response to systemic inflammatory response syndrome. Proc Natl Acad Sci USA 103:6392-7, 2006