Research Area D: Matrix Regulation and Fibrosis
| Research Area Leaders | |
|---|---|
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Institute of Pharmacology & Toxicology Goethe University Frankfurt Theodor-Stern-Kai 7 60590 Frankfurt/Main |
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Director DPLD Program: Dept. of Internal Medicine Justus-Liebig-University Giessen Medical Chair Lung Center Waldhof Elgershausen Klinikstrasse 33 35392 Giessen |
| Faculty involved | ||||
|---|---|---|---|---|
| S. Bellusci | T. Braun | W. Eberhardt | J. Eble | F. Engel |
| I. Fleming | H.A. Ghofrani | V. Grau | F. Grimminger | A. Günther |
| H. Hackstein | C.W. Hamm | R. Henschler | W. Kummer | J. Lohmeyer |
| P. Markart | R.E. Morty | U. Müller-Ladner | J. Pfeilschifter | K.T. Preissner |
| S.S. Pullamsetti | C. Ruppert | L. Schäfer | W. Seeger | R.T. Schermuly |
| K.D. Schlüter | M. Schmidt | R. Voswinckel | M. Wygrecka | |
Summary
Area D focuses on the pathogenic processes underlying diffuse parenchymal lung disease (DPDL); with idiopathic lung fibrosis (IPF) as the prototypic entity, as well as heart and renal fibrosis. A unifying concept was developed based on the findings of the preceding funding period, where we hypothesised that the loss of parenchymal cells (e.g. alveolar epithelial type II cells in IPF) represents a key trigger event, that is then amplified by secondary processes, thus provoking adaptive, regenerative and maladaptive cellular responses and the recruitment of circulating mesenchymal cells. This finally results in the initiation of fibrosis by various profibrotic signalling pathways. Following this concept we will now
- investigate endoplasmic reticulum and lysosomal stress as key triggers of epithelial apoptosis and fibrosis,
- assess the interplay between lung infection and fibrosis as amplifying process, and
- study FGF- and Notch-related signalling with regard to incomplete epithelial regeneration and lipofibroblast-myofibroblast transition. With regard to cell-matrix interactions, we will focus on integrins, DMBT1, SMOC1 (and its regulation by miR-223) and biglycan. Synovial fibroblasts and bone marrow-derived fibrocytes as well as epithelial-to- mesenchymal transition (EMT) will be analysed with respect to local (myo)fibroblast enrichment. With regard to pro- and anti-fibrotic signalling pathways, we will
- focus on the DDAH–iNOS-ROS and the sGC-cGMP-PDE axes, and the role of LRP-1. Ultimately, we will harness exogenous stem/progenitor cells for novel regenerative treatment strategies in IPF/DPDL, and clinical trials will encompass the inhalative administration of heparin, urokinase and KGF and the further promotion of the recombinant surfactant-protein-B-urokinase hybrid molecule.
Most relevant publications of the Research Area D
1. Ikeda F, Deribe YL, Skånland SS, Stieglitz B, Grabbe C, Franz-Wachtel M, van Wijk S, Goswami P, Nagy V, Terzic J, Tokunaga F, Androulidaki A, Nakagawa T, Pasparakis M, Iwai K, Sundberg JP, Schaefer L, Rittinger K, Macek B, Dikic I. SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis. Nature 471: 637-41, 2011
2. Pullamsetti SS, Savai R, Dumitrascu R, Dahal BK, Wilhelm J, Konigshoff M, Zakrzewicz D, Ghofrani HA, Weissmann N, Eickelberg O, Guenther A, Leiper J, Seeger W, Grimminger F, Schermuly RT. The role of dimethylarginine dimethylaminohydrolase in idiopathic pulmonary fibrosis. Sci Transl Med 3:87ra53, 2011
3. 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
4. Wygrecka M, Kwapiszewska G, Jablonska E, von Gerlach S, Henneke I, Zakrzewicz D, Guenther A, Preissner KT, Markart P. Role of Protease-Activated Receptor-2 in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 183:1703-14, 2011
5. Henneke I, Korfei M, Greschus S, Markart P, Schermuly RT, Wygrecka M, Stürzebecher J, Seeger W, Guenther A, Ruppert C. Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model. Am J Respir Crit Care Med 181:611-9, 2010
6. Mahavadi P, Korfei M, Henneke I, Liebisch G, Schmitz G, Gochuico BR, Markart P, Bellusci S, Seeger W, Ruppert C, Guenther A. Epithelial stress and apoptosis underlie Hermansky-Pudlak syndrome-associated interstitial pneumonia. Am J Respir Crit Care Med 182:207-19, 2010
7. 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
8. 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
9. Puneet P, Yap CT, Wong L, Yulin L, Koh DR, Moochhala S, Pfeilschifter J, Huwiler A, Melendez AJ. SphK1 regulates proinflammatory responses associated with endotoxin and polymicrobial sepsis. Science 328: 1290-4, 2010
10. Randriamboavonjy V, Isaak J, Frömel T, Viollet B, Fisslthaler B, Preissner KT, Fleming I. The AMP-activated protein kinase (AMPK) a2 subunit is involved in platelet signaling, clot retraction and thrombus stability. Blood 116:2134-40, 2010
11. Carmona G, Göttig S, Orlandi A, Scheele J, Bäuerle T, Jugold M, Kiessling F, Henschler R. Zeiher AM, Dimmeler S, Chavakis E. Role of small GTPase Rap1 for integrin activity regulation in endothelial cells and angiogenesis. Blood 113:488-97, 2009
12. Dreieicher E, Beck KF, Lazaroski S, Boosen M, Tsalastra-Greul W, Beck M, Fleming I, Schaefer L, Pfeilschifter J. Nitric oxide inhibits glomerular TGF-beta signaling via SMOC-1. J Am Soc Nephrol 20:1963-74, 2009
13. Gupte VV, Ramasamy SK, Reddy R, Lee J, Weinreb PH, Violette SM, Guenther A, Warburton D, Driscoll B, Minoo P, Bellusci S. Overexpression of fibroblast growth factor-10 during both inflammatory and fibrotic phases attenuates bleomycin-induced pulmonary fibrosis in mice. Am J Respir Crit Care Med 180:424-36, 2009
14. Eble JA, Niland S, Bracht T, Mormann M, Peter-Katalinic J, Pohlentz G, Stetefeld J. The
alpha2beta1 integrin-specific antagonist rhodocetin is a cruciform, heterotetrameric molecule
FASEB J 23:2917-27, 2009 IF 6,515
15. Königshoff M, Wilhelm J, Jahn A, Amarie OV, Kramer M, Kitowska K, Wilhelm A, Bohle RM, Obert M, Traupe H, Seeger W, Rose F, Fink L, Schaefer L, Günther A, Eickelberg O. WISP1, a matricellular protein of the CCN family, is a novel mediator of pulmonary fibrosis. J Clin Invest 119:772-787,2009
16. Kumarasamy A, Schmitt I, Reiss I, van der Horst I, Dony E, Roberts JD, de Krijger RR, Tibboel D, Seeger W, Schermuly RT, Eickelberg O, Morty RE. Lysyl oxidase activity is dysregulated during impaired alveolarization of mouse and human lungs. Am J Respir Crit Care Med 180:1239-52, 2009
17. Lefevre S, Knedla A, Tennie C, Kampmann A, Wunrau C, Dinser R, Korb A, Schnaker EM, Tarner IH, Robbins PD, Evans CH, Sturz H, Steinmeyer J, Gay S, Schölmerich J, Pap T, Müller-Ladner U, Neumann E. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat Med 15: 1414-20, 2009
18. Schmidt MHH, Bicker F, Nikolic I, Meister J, Babuke T, Picuric S, Müller-Esterl W, Plate KH, Dikic I. Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal. Nat Cell Biol 11:873-80, 2009
19. Akool El-S, Doller A, Babelova A, Tsalastra W, Moreth K, Schaefer L, Pfeilschifter J, Eberhardt W. Molecular mechanisms of TGFb-receptor-triggered signaling in cascades rapidly incuced by the calcineurin inhibitors cyclosphorine and FK 506. J Immunol 181:2831-45, 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. Korfei M, Ruppert C, Mahavadi P, Henneke I, Markart P, Koch M, Lang G, Fink L, Bohle RM, Seeger W, Weaver TE, Günther A. Epithelial Endoplasmic Reticulum Stress and Apoptosis in Sporadic Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 178:838-46, 2008
22. Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ, Wassen FWJS, Crescenzi A, da-Silva WS, Harney J, Engel FB, Obregon MJ, Larsen PR, Bianco AC, Huang SA. Hypoxia-inducible factor induces local thyroid hormone inactivation in hypoxic-ischemic disease. J Clin Invest 118:975-83, 2008
23. Westermann D, Mersmann, J, Melchior A, Petrik C, Freudenberger T, Lettau O, Schaefer L, Lüllmann-Rauch R, Jacoby C, Schrader J, Brand-Herrman SM, Young MF, Levkau B, Babba H, Unger T, Zacharowski K, Tschöpe C, Fischer JW: Biglycan is required for adaptive remodelling after myocardial infarction. Circulation 117:1269-76, 2008
24. Kannemeier C, Shibamiya A, Nakazawa F, Trusheim H, Ruppert C, Markart P, Song Y, Tzima E, Kennerknecht E, Niepmann M, von Bruehl ML, Sedding D, Massberg S, Günther A, Engelmann B, Preissner KT. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 104:6388-93, 2007
25. Orlova VV, Choi EY, Xie C, Chavakis E, Bierhaus A, Ihanus E, Ballantyne CM, Gahmberg CG, Bianchi ME, Nawroth PP, Chavakis T. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin.EMBO J. 26:1129-39, 2007
26. Zakrzewicz A, Hecker M, Marsh LM, Kwapiszewska G, Nejman B, Long L, Seeger W, Schermuly RT, Morrell NW, Morty RE, Eickelberg O. Receptor for activated C-kinase 1, a novel interaction partner of type II bone morphogenetic protein receptor, regulates smooth muscle cell proliferation in pulmonary arterial hypertension. Circulation 12:2957-68, 2007
27. Dumitrascu R, Weissmann N, Ghofrani HA, Dony E, Beuerlein K, Schmidt H, Stasch JP, Gnoth MJ, Seeger W, Grimminger F, Schermuly RT. Activation of soluble guanylase reverses experimental pulmonary hypertension and vascular remodelling. Circulation113:286-95, 2006
28. Engel FB, Hsieh PCH, Lee RT, Keating MT. FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring and rescues function after myocardial infarction. Proc Natl Acad Sci USA 103:15546-51, 2006
29. Rüster B, Göttig S, Ludwig RJ, Bistrian R, Müller S, Seifried E, Gille J, Henschler R. Mesenchymal stem cells display coordinated rolling and adhesion behaviour on endothelial cells. Blood 108: 3938-44, 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