33 results on '"Alexander G. Khandoga"'
Search Results
2. Chemokines and Hematopoietic Cell Trafficking
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Ulrich H. von Andrian, Antal Rot, Steffen Massberg, and Alexander G. Khandoga
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Chemokine ,Hematopoietic cell ,biology.protein ,Biology ,Cell biology - Published
- 2018
3. Contributors
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Omar Abdel-Wahab, Janet L. Abrahm, Sharon Adams, Adeboye H. Adewoye, Carl Allen, Richard F. Ambinder, Claudio Anasetti, John Anastasi, Julia A. Anderson, Joseph H. Antin, Aśok C. Antony, David J. Araten, Philippe Armand, Gillian Armstrong, Scott A. Armstrong, Donald M. Arnold, Andrew S. Artz, Farrukh T. Awan, Trevor P. Baglin, Don M. Benson, Edward J. Benz, Nancy Berliner, Govind Bhagat, Nina Bhardwaj, Ravi Bhatia, Smita Bhatia, Mihir D. Bhatt, Vijaya Raj Bhatt, Menachem Bitan, Craig D. Blinderman, Catherine M. Bollard, Benjamin S. Braun, Malcolm K. Brenner, Gary M. Brittenham, Robert A. Brodsky, Myles Brown, Hal E. Broxmeyer, Kathleen Brummel-Ziedins, Andrew M. Brunner, Francis K. Buadi, Birgit Burkhardt, Melissa Burns, John C. Byrd, Paolo F. Caimi, Michael A. Caligiuri, Michelle Canavan, Alan B. Cantor, Manuel Carcao, Michael C. Carroll, Shannon A. Carty, Jorge J. Castillo, Anthony K.C. Chan, John Chapin, April Chiu, John P. Chute, David B. Clark, Thomas D. Coates, Christopher R. Cogle, Nathan T. Connell, Elizabeth Cooke, Sarah Cooley, Paolo Corradini, Mark A. Creager, Richard J. Creger, Caroline Cromwell, Mark A. Crowther, Melissa M. Cushing, Corey Cutler, Chi V. Dang, Nika N. Danial, Sandeep S. Dave, James A. DeCaprio, Mary C. Dinauer, Shira Dinner, Reyhan Diz-Küçükkaya, Roger Y. Dodd, Michele L. Donato, Kenneth Dorshkind, Gianpietro Dotti, Yigal Dror, Kieron Dunleavy, Christopher C. Dvorak, Benjamin L. Ebert, Michael J. Eck, John W. Eikelboom, Narendranath Epperla, William B. Ershler, William E. Evans, Stefan Faderl, James L.M. Ferrara, Alexandra Hult Filipovich, Martin Fischer, James C. Fredenburgh, Kenneth D. Friedman, Ephraim Fuchs, Stephen J. Fuller, David Gailani, Jacques Galipeau, Patrick G. Gallagher, Karthik A. Ganapathi, Lawrence B. Gardner, Adrian P. Gee, Stanton L. Gerson, Morie A. Gertz, Patricia J. Giardina, Christopher J. Gibson, Karin Golan, Todd R. Golub, Matthew J. Gonzales, Jason Gotlib, Stephen Gottschalk, Marianne A. Grant, Timothy A. Graubert, Xylina T. Gregg, John G. Gribben, Dawn M. Gross, Tanja A. Gruber, Joan Guitart, Sandeep Gurbuxani, Shiri Gur-Cohen, Alejandro Gutierrez, Mehdi Hamadani, Parameswaran N. Hari, John H. Hartwig, Suzanne R. Hayman, Catherine P.M. Hayward, Robert P. Hebbel, Helen E. Heslop, Christopher Hillis, Christopher D. Hillyer, Karin Ho, David M. Hockenbery, Ronald Hoffman, Kerstin E. Hogg, Shernan G. Holtan, Hans-Peter Horny, Yen-Michael S. Hsu, Zachary R. Hunter, James A. Huntington, Camelia Iancu-Rubin, Ali Iqbal, David E. Isenman, Sara J. Israels, Joseph E. Italiano, Elaine S. Jaffe, Iqbal H. Jaffer, Sundar Jagannath, Ulrich Jäger, Nitin Jain, Paula James, Sima Jeha, Michael B. Jordan, Cassandra D. Josephson, Moonjung Jung, Leo Kager, Taku Kambayashi, Jennifer A. Kanakry, Hagop M. Kantarjian, Jason Kaplan, Matthew S. Karafin, Aly Karsan, Randal J. Kaufman, Richard M. Kaufman, Frank G. Keller, Kara M. Kelly, Craig M. Kessler, Nigel S. Key, Alla Keyzner, Alexander G. Khandoga, Arati Khanna-Gupta, Eman Khatib-Massalha, Harvey G. Klein, Birgit Knoechel, Orit Kollet, Barbara A. Konkle, Dimitrios P. Kontoyiannis, John Koreth, Gary A. Koretzky, Dipak Kotecha, Marina Kremyanskaya, Anju Kumari, Timothy M. Kuzel, Ralf Küppers, Martha Q. Lacy, Elana Ladas, Wendy Landier, Kfir Lapid, Tsvee Lapidot, Peter J. Larson, Marcel Levi, Russell E. Lewis, Howard A. Liebman, David Lillicrap, Wendy Lim, Judith C. Lin, Robert Lindblad, Gregory Y.H. Lip, Jane A. Little, Jens G. Lohr, José A. López, Francis W. Luscinskas, Jaroslaw P. Maciejewski, Navneet S. Majhail, Olivier Manches, Robert J. Mandle, Kenneth G. Mann, Catherine S. Manno, Andrea N. Marcogliese, Guglielmo Mariani, Francesco M. Marincola, John Mascarenhas, Steffen Massberg, Rodger P. McEver, Emer McGrath, Matthew S. McKinney, Rohtesh S. Mehta, William C. Mentzer, Giampaolo Merlini, Reid Merryman, Marc Michel, Anna Rita Migliaccio, Jeffrey S. Miller, Martha P. Mims, Traci Heath Mondoro, Paul Moorehead, Luciana R. Muniz, Nikhil C. Munshi, Vesna Najfeld, Lalitha Nayak, Ishac Nazy, Anne T. Neff, Paul M. Ness, Luigi D. Notarangelo, Sarah H. O'Brien, Owen A. O'Connor, Martin O'Donnell, Amanda Olson, Stuart H. Orkin, Menaka Pai, Sung-Yun Pai, Michael Paidas, Sandhya R. Panch, Reena L. Pande, Thalia Papayannopoulou, Rahul Parikh, Effie W. Petersdorf, Shane E. Peterson, Stefania Pittaluga, Doris M. Ponce, Laura Popolo, Josef T. Prchal, Ching-Hon Pui, Pere Puigserver, Janusz Rak, Carlos A. Ramos, Jacob H. Rand, Margaret L. Rand, Dinesh S. Rao, Farhad Ravandi, David J. Rawlings, Pavan Reddy, Mark T. Reding, Andreas Reiter, Lawrence Rice, Matthew J. Riese, Arthur Kim Ritchey, David J. Roberts, Elizabeth Roman, Cliona M. Rooney, Steven T. Rosen, David S. Rosenthal, Marlies P. Rossmann, Antal Rot, Scott D. Rowley, Jeffrey E. Rubnitz, Natalia Rydz, Mohamed E. Salama, Steven Sauk, Yogen Saunthararajah, William Savage, David Scadden, Kristen G. Schaefer, Fred Schiffman, Robert Schneidewend, Stanley L. Schrier, Edward H. Schuchman, Bridget Fowler Scullion, Kathy J. Selvaggi, Keitaro Senoo, Montaser Shaheen, Beth H. Shaz, Samuel A. Shelburne, Elizabeth J. Shpall, Susan B. Shurin, Deborah Siegal, Leslie E. Silberstein, Lev Silberstein, Roy L. Silverstein, Steven R. Sloan, Franklin O. Smith, James W. Smith, Katy Smith, David P. Steensma, Martin H. Steinberg, Wendy Stock, Jill R. Storry, Susan L. Stramer, Ronald G. Strauss, David F. Stroncek, Justin Taylor, Swapna Thota, Steven P. Treon, Anil Tulpule, Roberto Ferro Valdes, Peter Valent, Suresh Vedantham, Gregory M. Vercellotti, Michael R. Verneris, Elliott P. Vichinsky, Ulrich H. von Andrian, Julie M. Vose, Andrew J. Wagner, Ena Wang, Jia-huai Wang, Theodore E. Warkentin, Melissa P. Wasserstein, Ann Webster, Daniel J. Weisdorf, Jeffrey I. Weitz, Connie M. Westhoff, Allison P. Wheeler, Page Widick, James S. Wiley, Basem M. William, David A. Williams, Wyndham H. Wilson, Joanne Wolfe, Lucia R. Wolgast, Deborah Wood, Jennifer Wu, Joachim Yahalom, Donald L. Yee, Anas Younes, Neal S. Young, and Michelle P. Zeller
- Published
- 2018
4. Predictors of cerebrovascular events at mid-term after transcatheter aortic valve implantation - Results from EVERY-TAVI registry
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Maximilian Pichlmaier, Tobias Mir Sadry, Ingrid Ricard, Christian Hagl, Sebastian Sadoni, Magda Zadrozny, Hans D. Theiss, Steffen Massberg, Alexander G. Khandoga, Julinda Mehilli, Joerg Hausleiter, Florian Schwarz, David Jochheim, Axel Bauer, and Moritz Baquet
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Male ,medicine.medical_specialty ,Transcatheter aortic ,030204 cardiovascular system & hematology ,Balloon ,Transcatheter Aortic Valve Replacement ,03 medical and health sciences ,0302 clinical medicine ,Postoperative Complications ,Predictive Value of Tests ,medicine ,Humans ,030212 general & internal medicine ,Registries ,Stroke ,Aged ,Aged, 80 and over ,business.industry ,Incidence (epidemiology) ,Hazard ratio ,Aortic Valve Stenosis ,medicine.disease ,Surgery ,Cerebrovascular Disorders ,Predictive value of tests ,Aortic valve stenosis ,Female ,Cardiology and Cardiovascular Medicine ,business ,Complication ,Follow-Up Studies - Abstract
Background Clinical relevant cerebrovascular events (CVE) following transcatheter aortic valve implantation (TAVI) still remain a devastating complication associated with mortality and severe impairments. Therefore, identification of particularly modifiable predictors of this complication is clinically relevant and an important step for planning preventive strategies. Methods A total of 985 patients who underwent trans-femoral TAVI for aortic valve stenosis in our institution from February 2008 to January 2015 were considered. The influence of demographics, clinical and procedural data on the occurrence of CVE was assessed with a competing risk model with death as competing event. Clinical events were defined according to VARC-2 criteria. Results At a median follow-up of 838days, 95% CI 807–892, 59 patients experienced any CVE (5.9%) and the overall cumulative mortality rate was 46.1%. CVEs mainly occur later than 30days after TAVI (47.5%), 88.1% of them were of ischemic origin and 52.5% were disabling events. Independent predictors of CVEs were age (hazard ratio 1.05; 95% CI 1.01 to 1.09), history of CVE (hazard ratio 2.54; 95% CI 1.39 to 4.63) and use of balloon post-dilation (hazard ratio 1.85; 95% CI 1.08 to 3.18). Conclusion In patients undergoing TAVI incidence of clinically relevant CVEs is frequent with half of the events occurring after the first 30days post-TAVI. Identification of balloon post-dilation as the only modifiable predictor of CVE risk at mid-term, urges its cautious performance after prosthesis implantation. ClinicalTrials.gov identifier NCT02289339.
- Published
- 2017
5. Predictors for long-term survival after transcatheter edge-to-edge mitral valve repair
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Carolin Sonne, Axel Bauer, Simon Deseive, Julinda Mehilli, Mathias Orban, Michael Nabauer, Christian Hagl, Peter Boekstegers, Steffen Massberg, Ilka Ott, Jörg Hausleiter, Adnan Kastrati, Lisa Hutterer, Alexander G. Khandoga, Christian Grebmer, Heribert Schunkert, Jürgen Pache, Hasema Lesevic, Martin Orban, and Daniel Braun
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Male ,medicine.medical_specialty ,Cardiac Catheterization ,medicine.medical_treatment ,Long Term Adverse Effects ,030204 cardiovascular system & hematology ,Severity of Illness Index ,Ventricular Function, Left ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,Mitral valve ,Germany ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,030212 general & internal medicine ,Aged ,Proportional Hazards Models ,Heart Valve Prosthesis Implantation ,Mitral valve repair ,Mitral regurgitation ,Ejection fraction ,business.industry ,MitraClip ,Mortality rate ,Hazard ratio ,Mitral Valve Insufficiency ,Middle Aged ,medicine.disease ,Surgery ,medicine.anatomical_structure ,Treatment Outcome ,Cardiology ,Mitral Valve ,Female ,Risk Adjustment ,Cardiology and Cardiovascular Medicine ,Mitral valve regurgitation ,business - Abstract
Objectives: To determine predictors for long-term outcome in high-risk patients undergoing transcatheter edge-to-edge mitral valve repair (TMVR) for severe mitral regurgitation (MR). Background: There is no data on predictors of long-term outcome in high-risk real-world patients. Methods: From August 2009 to April 2011, 126 high-risk patients deemed inoperable were treated with TMVR in two high-volume university centers. Results: MR could be successfully reduced to grade
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- 2016
6. Coronin 1A, a novel player in integrin biology, controls neutrophil trafficking in innate immunity
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Doris Brechtefeld, Ralph T. Böttcher, Sarah Thome, Thomas J. Stocker, Melanie Salvermoser, Eloi Montanez, Daniela Begandt, Ludwig T. Weckbach, Ute Harrison, Ignasi Forné, Barbara Walzog, Raffaele Coletti, Robert Pick, Markus Sperandio, Steffen Massberg, Axel Imhof, Alexander G. Khandoga, and Rainer Haas
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0301 basic medicine ,Neutrophils ,Immunology ,Integrin ,Coronin ,Macrophage-1 Antigen ,Inflammation ,CD18 ,CD11a ,Biochemistry ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,4-Butyrolactone ,Cell Movement ,medicine ,Cell Adhesion ,Animals ,Calcium Signaling ,Cell adhesion ,Innate immune system ,biology ,Helicobacter pylori ,hemic and immune systems ,Cell Biology ,Hematology ,Actins ,Immunity, Innate ,Lymphocyte Function-Associated Antigen-1 ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Integrin alpha M ,CD18 Antigens ,Gastritis ,biology.protein ,medicine.symptom ,Rheology - Abstract
Trafficking of polymorphonuclear neutrophils (PMNs) during inflammation critically depends on the β2 integrins lymphocyte function-associated antigen 1 (LFA-1) (CD11a/CD18) and macrophage-1 antigen (CD11b/CD18). Here, we identify coronin 1A (Coro1A) as a novel regulator of β2 integrins that interacts with the cytoplasmic tail of CD18 and is crucial for induction of PMN adhesion and postadhesion events, including adhesion strengthening, spreading, and migration under flow conditions. Transition of PMN rolling to firm adhesion critically depends on Coro1A by regulating the accumulation of high-affinity LFA-1 in focal zones of adherent cells. Defective integrin affinity regulation in the genetic absence of Coro1A impairs leukocyte adhesion and extravasation in inflamed cremaster muscle venules in comparison with control animals. In a Helicobacter pylori mouse infection model, PMN infiltration into the gastric mucosa is dramatically reduced in Coro1A-/- mice, resulting in an attenuated gastric inflammation. Thus, Coro1A represents an important novel player in integrin biology, with key functions in PMN trafficking during innate immunity.
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- 2016
7. Capillary and arteriolar pericytes attract innate leukocytes exiting through venules and 'instruct' them with pattern-recognition and motility programs
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Barbara Walzog, Konstantin Stark, Kyle R. Legate, Ingrid Hepper, Selgai Haidari, Marie-Luise von Brühl, Florian Gärtner, Steffen Massberg, Alexander G. Khandoga, Robert Pless, Kirsten Lauber, Anca Tirniceriu, Michael Lorenz, and Annekathrin Eckart
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Leukocyte migration ,Immunology ,Motility ,Cell Communication ,Biology ,Neutrophil Activation ,03 medical and health sciences ,0302 clinical medicine ,Venules ,Cell Movement ,Leukocytes ,Humans ,Immunology and Allergy ,Antibodies, Blocking ,Macrophage Migration-Inhibitory Factors ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Intercellular Adhesion Molecule-1 ,Immunity, Innate ,Capillaries ,Up-Regulation ,3. Good health ,Cell biology ,Intramolecular Oxidoreductases ,Arterioles ,nervous system ,Receptors, Pattern Recognition ,Pattern recognition (psychology) ,Myeloid cells ,Inflammation Mediators ,Pericytes ,030217 neurology & neurosurgery - Abstract
Coordinated navigation within tissues is essential for cells of the innate immune system to reach the sites of inflammatory processes, but the signals involved are incompletely understood. Here we demonstrate that NG2(+) pericytes controlled the pattern and efficacy of the interstitial migration of leukocytes in vivo. In response to inflammatory mediators, pericytes upregulated expression of the adhesion molecule ICAM-1 and released the chemoattractant MIF. Arteriolar and capillary pericytes attracted and interacted with myeloid leukocytes after extravasating from postcapillary venules, 'instructing' them with pattern-recognition and motility programs. Inhibition of MIF neutralized the migratory cues provided to myeloid leukocytes by NG2(+) pericytes. Hence, our results identify a previously unknown role for NG2(+) pericytes as an active component of innate immune responses, which supports the immunosurveillance and effector function of extravasated neutrophils and macrophages.
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- 2012
8. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo
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Alexander Brill, Axel Walch, Robert A. Byrne, Nigel Mackman, Selgai Haidari, Iina Laitinen, Susanne Pfeiler, Alexander Steinhart, Michael Lorenz, Raffaele Coletti, Katrin Echtler, Martina Rudelius, Ildiko Konrad, Anca Tirniceriu, Marie-Luise von Brühl, Bernd Engelmann, Maria Köllnberger, Klaus T. Preissner, Steffen Massberg, Volker Brinkmann, Alexander G. Khandoga, Jerry Ware, Siegmund Braun, Christian Schulz, Julia Riegger, Philipp S. Lange, Markus Schwaiger, Denisa D. Wagner, Annekathrin Eckart, Davit Manukyan, Konstantin Stark, and Sue Chandraratne
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Blood Platelets ,Myeloid ,P-selectin ,Neutrophils ,Immunology ,Cell Communication ,030204 cardiovascular system & hematology ,Monocytes ,Article ,Fibrin ,Thromboplastin ,Mice ,03 medical and health sciences ,Tissue factor ,0302 clinical medicine ,medicine ,Animals ,Immunology and Allergy ,Platelet ,cardiovascular diseases ,030304 developmental biology ,Venous Thrombosis ,0303 health sciences ,Factor XII ,biology ,business.industry ,Neutrophil extracellular traps ,3. Good health ,Mice, Inbred C57BL ,P-Selectin ,medicine.anatomical_structure ,cardiovascular system ,biology.protein ,business - Abstract
Deep vein thrombosis initiation is mediated by cross talk between monocytes, neutrophils, and platelets., Deep vein thrombosis (DVT) is a major cause of cardiovascular death. The sequence of events that promote DVT remains obscure, largely as a result of the lack of an appropriate rodent model. We describe a novel mouse model of DVT which reproduces a frequent trigger and resembles the time course, histological features, and clinical presentation of DVT in humans. We demonstrate by intravital two-photon and epifluorescence microscopy that blood monocytes and neutrophils crawling along and adhering to the venous endothelium provide the initiating stimulus for DVT development. Using conditional mutants and bone marrow chimeras, we show that intravascular activation of the extrinsic pathway of coagulation via tissue factor (TF) derived from myeloid leukocytes causes the extensive intraluminal fibrin formation characteristic of DVT. We demonstrate that thrombus-resident neutrophils are indispensable for subsequent DVT propagation by binding factor XII (FXII) and by supporting its activation through the release of neutrophil extracellular traps (NETs). Correspondingly, neutropenia, genetic ablation of FXII, or disintegration of NETs each confers protection against DVT amplification. Platelets associate with innate immune cells via glycoprotein Ibα and contribute to DVT progression by promoting leukocyte recruitment and stimulating neutrophil-dependent coagulation. Hence, we identified a cross talk between monocytes, neutrophils, and platelets responsible for the initiation and amplification of DVT and for inducing its unique clinical features.
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- 2012
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9. Stabilizing the VE-cadherin-catenin complex blocks leukocyte extravasation and vascular permeability
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Hang Li, Olena Kamenyeva, Steffen Massberg, Alexander G. Khandoga, Dörte Schulte, Verena Küppers, Dietmar Vestweber, Nina Dartsch, Friedemann Kiefer, Andre Broermann, and Alexander Zarbock
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General Immunology and Microbiology ,General Neuroscience ,Vascular permeability ,Biology ,Actin cytoskeleton ,Leukocyte extravasation ,General Biochemistry, Genetics and Molecular Biology ,Extravasation ,Cell biology ,Endothelial stem cell ,Immunology ,Catenin complex ,VE-cadherin ,Lymphocyte homing receptor ,Molecular Biology - Abstract
To determine whether leukocytes need to open endothelial cell contacts during extravasation, we decided to generate mice with strongly stabilized endothelial junctions. To this end, we replaced VE-cadherin genetically by a VE-cadherin–α-catenin fusion construct. Such mice were completely resistant to the induction of vascular leaks by VEGF or histamine. Neutrophil or lymphocyte recruitment into inflamed cremaster, lung and skin were strongly inhibited in these mice, documenting the importance of the junctional route in vivo. Surprisingly, lymphocyte homing into lymph nodes was not inhibited. VE-cadherin–α-catenin associated more intensely with the actin cytoskeleton as demonstrated by its membrane mobility and detergent extractability. Our results establish the junctional route as the main pathway for extravasating leukocytes in several, although not in all tissues. Furthermore, in these tissues, plasticity of the VE-cadherin–catenin complex is central for the leukocyte diapedesis mechanism.
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- 2011
10. von Willebrand factor promotes leukocyte extravasation
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Dietmar Vestweber, Tobias Goerge, Fritz Krombach, Björn Petri, Stefan W. Schneider, Alexander G. Khandoga, Bernhard Nieswandt, Andre Broermann, Claire Jones, Martin K. Wild, Alexander Zarbock, and Hang Li
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Blood Platelets ,congenital, hereditary, and neonatal diseases and abnormalities ,Neutrophils ,Immunology ,Leukocyte Rolling ,Vascular permeability ,Peritonitis ,Granulocyte ,Biochemistry ,Antibodies ,Capillary Permeability ,Mice ,Von Willebrand factor ,Cell Movement ,hemic and lymphatic diseases ,von Willebrand Factor ,Leukocytes ,medicine ,Animals ,Neutrophil extravasation ,biology ,Chemistry ,Cell Biology ,Hematology ,Leukocyte extravasation ,Extravasation ,Mice, Inbred C57BL ,P-Selectin ,medicine.anatomical_structure ,Platelet Glycoprotein GPIb-IX Complex ,Glycoprotein Ib ,cardiovascular system ,biology.protein ,Peritoneum ,circulatory and respiratory physiology - Abstract
von Willebrand factor (VWF) is an important player in hemostasis but has also been suggested to promote inflammatory processes. Gene ablation of VWF causes a simultaneous defect in P-selectin expression making it difficult to identify VWF-specific functions. Therefore, we analyzed whether blocking antibodies against VWF would be able to interfere with neutrophil extravasation. We found that these antibodies inhibited neutrophil recruitment into thioglycollate-inflamed peritoneum and KC-stimulated cremaster by approximately 50%. Whereas platelet-VWF was not involved, the contribution of VWF to granulocyte recruitment was strictly dependent on the presence of platelets and the accessibility of their VWF-receptor glycoprotein Ib. Surprisingly, platelet P-selectin was largely dispensable for leukocyte extravasation, in agreement with our observation that anti-VWF antibodies did not affect leukocyte rolling and adhesion. Searching for possible effects downstream of leukocyte capture, we found that anti-VWF antibodies significantly inhibited thioglycollate-induced vascular permeability. The increase of permeability was independent of circulating granulocytes, showing that it was not a side effect of neutrophil diapedesis. Collectively, our results demonstrate that VWF-associated platelets strongly support neutrophil extravasation at a step downstream of leukocyte docking to the vessel wall. This step could be related to leukocyte diapedesis facilitated by destabilization of the endothelial barrier.
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- 2010
11. Leukocyte transmigration in inflamed liver: A role for endothelial cell-selective adhesion molecule
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Stefan Butz, Alexander G. Khandoga, Hang Li, Stefanie Huettinger, Dietmar Vestweber, Fritz Krombach, Andrej Khandoga, and Karl-Walter Jauch
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Male ,Leukocyte migration ,Pathology ,medicine.medical_specialty ,Naphthol AS D Esterase ,Endothelium ,Leukocyte Count ,Mice ,medicine ,Animals ,Platelet ,Receptor ,Crosses, Genetic ,Inflammation ,Mice, Knockout ,Hepatology ,Tight junction ,Cell adhesion molecule ,Chemistry ,Liver Diseases ,Microcirculation ,Molecular biology ,Mice, Inbred C57BL ,Endothelial stem cell ,medicine.anatomical_structure ,Liver ,Leukocyte Common Antigens ,Female ,Endothelium, Vascular ,Cell Adhesion Molecules ,Intravital microscopy ,Granulocytes ,Liver Circulation - Abstract
Background/Aims This study was designed to investigate the role of endothelial cell-selective adhesion molecule (ESAM), a recently discovered receptor expressed in endothelial tight junctions and platelets, for leukocyte migration in inflamed liver. Methods The role of ESAM for leukocyte migration in the liver was analyzed using ESAM-deficient mice in a model of warm hepatic ischemia-reperfusion (90min/30–360min). Results As shown by immunostaining, ESAM is expressed in sinusoids as well as in venules and is not upregulated upon I/R. Emigrated leukocytes were quantified in tissue sections. Postischemic neutrophil transmigration was significantly attenuated in ESAM−/− mice after 2h of reperfusion, whereas it was completely restored after 6h. In contrast, T-cell migration did not differ between ESAM+/+ and ESAM−/− mice. Using intravital microscopy, we demonstrate that ESAM deficiency attenuates I/R-induced vascular leakage after 30min of reperfusion. The I/R-induced elevation in AST/ALT activity, the sinusoidal perfusion failure, and the number of TUNEL-positive hepatocytes were comparable between ESAM+/+ and ESAM−/− mice. Conclusions ESAM is expressed in the postischemic liver and mediates neutrophil but not T-cell transmigration during early reperfusion. ESAM deficiency attenuates I/R-induced vascular leakage and does not affect leukocyte adherence. Despite the effect on neutrophil migration, ESAM-deficiency does not protect from I/R-induced injury.
- Published
- 2009
12. Transseptal Transcatheter Implantation of a Third-Generation Balloon-Expandable Valve in Degenerated Mitral Bioprosthesis
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David Jochheim, Hans D. Theiss, Joerg Hausleiter, Moritz Baquet, Axel Bauer, Julinda Mehilli, Steffen Massberg, Alexander G. Khandoga, and Jan Schenzle
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mitral valve ,Reoperation ,medicine.medical_specialty ,valve-in-valve ,Cardiac Catheterization ,medicine.medical_treatment ,macromolecular substances ,Mitral valve stenosis ,Mitral valve ,medicine ,Heart Septum ,Humans ,Mitral Valve Stenosis ,Cardiac catheterization ,Fibrillation ,Aged, 80 and over ,Bioprosthesis ,Heart Valve Prosthesis Implantation ,business.industry ,Mitral valve replacement ,Mitral Valve Insufficiency ,Sapien 3 ,medicine.disease ,Pulmonary hypertension ,Heart septum ,Surgery ,Prosthesis Failure ,medicine.anatomical_structure ,Heart failure ,Heart Valve Prosthesis ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Tomography, X-Ray Computed ,Echocardiography, Transesophageal - Abstract
A 84-year-old woman with known hepatic cancer, severe pulmonary hypertension, and atrial fibrillation on phenprocoumon was admitted for recurrent congestive heart failure in our institution. Nine years earlier, she underwent mitral valve replacement with a 25-mm Perimount Magna (Edwards
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- 2015
13. Matrix metalloproteinases modulate ameboid-like migration of neutrophils through inflamed interstitial tissue
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Fritz Krombach, Bernd Uhl, Markus Rehberg, Annekathrin Eckart, Marc Praetner, Steffen Massberg, Christoph A. Reichel, Alexander G. Khandoga, Konstantin Stark, Daniel Puhr-Westerheide, Meike Miller, Kirsten Lauber, Gabriele Zuchtriegel, and Max Lerchenberger
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Male ,Leukocyte migration ,Proteases ,Immunology ,Motility ,Mice, Transgenic ,Matrix metalloproteinase ,Peritonitis ,Biochemistry ,Phagocytes, Granulocytes, and Myelopoiesis ,Mice ,Aprotinin ,Transcellular Cell Migration ,In vivo ,Animals ,Actin ,Aminocaproates ,Inflammation ,Neutrophil extravasation ,Chemistry ,Cell Biology ,Hematology ,610 Medical sciences ,Medicine ,Matrix Metalloproteinases ,Cell biology ,Mice, Inbred C57BL ,Chemotaxis, Leukocyte ,Immune System Diseases ,Neutrophil Infiltration ,Tranexamic Acid ,ddc: 610 ,Leukocyte Disorders ,Chemotaxis assay - Abstract
Introduction: Recruitment of leukocytes to the site of inflammation is a crucial step in the development of inflammatory processes. The single steps of the leukocyte recruitment process, described as rolling, firm adherence and transendothelial migration have been studied in detail in the past decades,[for full text, please go to the a.m. URL], 132. Kongress der Deutschen Gesellschaft für Chirurgie
- Published
- 2015
14. TCT-682 Predictors and Impact of Cerebrovascular Events 4 Years after Transcatheter Aortic Valve Implantation
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Florian Schwarz, Julinda Mehilli, Philipp Lange, Moritz Baquet, Axel Bauer, Steffen Massberg, Hans D. Theiss, Jörg Hausleiter, Tobias Mir Sadry, Alexander G. Khandoga, David Jochheim, and Magda Zadrozny
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medicine.medical_specialty ,Transcatheter aortic ,business.industry ,Internal medicine ,Cardiology ,Medicine ,Cardiology and Cardiovascular Medicine ,business - Published
- 2016
15. Flavopiridol protects against inflammation by attenuating leukocyte-endothelial interaction via inhibition of cyclin-dependent kinase 9
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Jos Joore, Nina Berberich, Frank Totzke, Robert Fürst, Gabriele Sass, Gisa Tiegs, Bettina A. Mayer, Alexander G. Khandoga, Fritz Krombach, Stefan Zahler, Ulrike K. Schmerwitz, and Angelika M. Vollmar
- Subjects
Male ,Vascular Cell Adhesion Molecule-1 ,Cell Communication ,Mice ,Piperidines ,Cyclin-dependent kinase ,Cell Movement ,Cell Adhesion ,Concanavalin A ,Leukocytes ,Animals ,Humans ,Cell adhesion ,Protein kinase A ,Protein Kinase Inhibitors ,Cells, Cultured ,Flavonoids ,Inflammation ,biology ,Kinase ,Cell adhesion molecule ,NF-kappa B ,adhesion molecules ,endothelium ,leukocytes ,pharmacology ,signal transduction ,cyclin-dependent kinase ,inflammation ,leukocyte extravasation ,leukocyte-endothelial cell interaction ,Intercellular Adhesion Molecule-1 ,Cyclin-Dependent Kinase 9 ,Mice, Inbred C57BL ,Disease Models, Animal ,Biochemistry ,biology.protein ,Cancer research ,Cyclin-dependent kinase 9 ,Cyclin-dependent kinase 6 ,Endothelium, Vascular ,Casein kinase 2 ,Chemical and Drug Induced Liver Injury ,Cardiology and Cardiovascular Medicine ,E-Selectin - Abstract
Objective— The cyclin-dependent kinase (CDK) inhibitor flavopiridol is currently being tested in clinical trials as anticancer drug. Beyond its cell death–inducing action, we hypothesized that flavopiridol affects inflammatory processes. Therefore, we elucidated the action of flavopiridol on leukocyte–endothelial cell interaction and endothelial activation in vivo and in vitro and studied the underlying molecular mechanisms. Methods and Results— Flavopiridol suppressed concanavalin A–induced hepatitis and neutrophil infiltration into liver tissue. Flavopiridol also inhibited tumor necrosis factor-α–induced leukocyte–endothelial cell interaction in the mouse cremaster muscle. Endothelial cells were found to be the major target of flavopiridol, which blocked the expression of endothelial cell adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin), as well as NF-κB-dependent transcription. Flavopiridol did not affect inhibitor of κB (IκB) kinase, the degradation and phosphorylation of IκBα, nuclear translocation of p65, or nuclear factor-κB (NF-κB) DNA-binding activity. By performing a cellular kinome array and a kinase activity panel, we found LIM domain kinase-1 (LIMK1), casein kinase 2, c-Jun N-terminal kinase (JNK), protein kinase Cθ (PKCθ), CDK4, CDK6, CDK8, and CDK9 to be influenced by flavopiridol. Using specific inhibitors, as well as RNA interference (RNAi), we revealed that only CDK9 is responsible for the action of flavopiridol. Conclusion— Our study highlights flavopiridol as a promising antiinflammatory compound and inhibition of CDK9 as a novel approach for the treatment of inflammation-associated diseases.
- Published
- 2010
16. CD99 and CD99L2 act at the same site as, but independently of, PECAM-1 during leukocyte diapedesis
- Author
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Alexander Zarbock, Karen Wolburg-Buchholz, Stefan Butz, Dietmar Vestweber, Dagmar Zeuschner, Fritz Krombach, Hartwig Wolburg, M. Gabriele Bixel, Sigrid Maerz, Hang Li, Andrej Khandoga, Bjoern Petri, Lydia Sorokin, and Alexander G. Khandoga
- Subjects
Neutrophils ,Immunology ,Fluorescent Antibody Technique ,Biology ,12E7 Antigen ,Biochemistry ,Basement Membrane ,Mice ,Peritoneum ,In vivo ,Antigens, CD ,Cell Movement ,Fluorescence microscope ,medicine ,Cell Adhesion ,Leukocytes ,Animals ,Humans ,Cells, Cultured ,Basement membrane ,Inflammation ,Mice, Knockout ,Cell adhesion molecule ,Cell Biology ,Hematology ,Leukocyte extravasation ,Cell biology ,Endothelial stem cell ,Mice, Inbred C57BL ,Platelet Endothelial Cell Adhesion Molecule-1 ,medicine.anatomical_structure ,embryonic structures ,cardiovascular system ,Tumor necrosis factor alpha ,Endothelium, Vascular - Abstract
Leukocyte extravasation depends on various adhesion receptors at endothelial cell contacts. Here we have analyzed how mouse CD99 and CD99L2 cooperate with PECAM-1. We found that antibodies against mouse CD99 and PECAM-1 trap neutrophils between endothelial cells in in vitro transmigration assays. A sequential function, as has been suggested for human PECAM-1 and CD99, could not be demonstrated. In contrast to these in vitro results, blocking CD99 or CD99L2 or gene disruption of PECAM-1 trapped neutrophils in vivo between endothelial cells and the underlying basement membrane as revealed by electron microscopy and by 3-dimensional confocal fluorescence microscopy in the inflamed cremaster tissue. Leukocyte extravasation was inhibited in interleukin-1β-inflamed peritoneum and in the cremaster by PECAM-1 gene disruption and was further attenuated by blocking antibodies against CD99 and CD99L2. In addition, CD99 and CD99L2 were required for leukocyte extravasation in the cremaster after stimulation with tumor necrosis factor-α, where the need for PECAM-1 is known to be bypassed. We conclude that CD99 and CD99L2 act independently of PECAM-1 in leukocyte extravasation and cooperate in an independent way to help neutrophils overcome the endothelial basement membrane.
- Published
- 2010
17. Platelet adhesion and fibrinogen deposition in murine microvessels upon inhalation of nanosized carbon particles
- Author
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Erwin Karg, D. Ettehadieh, Janos Fent, Peter Bihari, Tobias Stoeger, Fritz Krombach, Alexander G. Khandoga, Andrej Khandoga, Holger Schulz, and Susan Lakatos
- Subjects
Pathology ,medicine.medical_specialty ,Fibrinogen ,Systemic inflammation ,Proinflammatory cytokine ,Microcirculation ,Mice ,Platelet Adhesiveness ,Administration, Inhalation ,medicine ,Animals ,Platelet ,Tissue Distribution ,Inflammation ,Lung ,medicine.diagnostic_test ,Inhalation ,Chemistry ,Biological Transport ,Thrombosis ,Hematology ,Carbon ,Mice, Inbred C57BL ,Bronchoalveolar lavage ,medicine.anatomical_structure ,Liver ,Nanoparticles ,medicine.symptom ,medicine.drug - Abstract
Summary. Background: The translocation of nanoparticles in the lung toward effector organs via the circulation is considered an important direct pathway for systemic effects of nanoparticles after inhalation. Recently, we have reported that a moderate dose of systemically administered nanosized carbon black particles exerted thrombogenic effects in hepatic microvessels of healthy mice. Objectives: This study addresses the questions of whether similar thrombogenic effects are also evoked upon inhalation of nanosized carbon particles (NCP) and whether NCP-induced hepatic platelet accumulation is associated with pulmonary or systemic inflammation. Methods: Two and 8 h after a 24-h exposure to either filtered air or to NCP, intravital fluorescence microscopy of the hepatic microcirculation was performed in C57Bl/6 mice. Parameters of pulmonary or systemic inflammatory response were determined in bronchoalveolar lavage and blood/plasma samples. Results: Inhalative exposure to NCP caused platelet accumulation in the hepatic microvasculature, whereas leukocyte recruitment and sinusoidal perfusion did not differ from controls. Fibrinogen deposition was detected by immunohistochemistry in both hepatic and cardiac microvessels from NCP-exposed mice. In contrast, inhalation of NCP affected neither the plasma levels of proinflammatory cytokines nor blood cell counts. Moreover, the bronchoalveolar lavage data indicate that no significant inflammatory response occurred in the lung. Conclusions: Thus, exposure to NCP exerts thrombogenic effects in the microcirculation of healthy mice independent of the route of administration (i.e. inhalation or systemic intra-arterial administration). The NCP-induced thrombogenic effects are not liver specific, are associated with neither a local nor a systemic inflammatory response, and seem to be independent of pulmonary inflammation.
- Published
- 2010
18. Identification of novel downstream targets of platelet glycoprotein VI activation by differential proteome analysis: implications for thrombus formation
- Author
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Alexander G. Khandoga, Christian Schulz, Thomas Fröhlich, Elisabeth Kremmer, Steffen Massberg, Mirjam Kessler, Michael Lorenz, Bernd Engelmann, Nina V. Leuschen, Georg J. Arnold, Christian A. Gleissner, Klaus Ley, and Susanne Pfeiler
- Subjects
Adult ,Blood Platelets ,Male ,Platelet Aggregation ,Proteome ,Immunology ,Blotting, Western ,Platelet Membrane Glycoproteins ,Aldose reductase inhibitor ,Actin-related protein ,Receptor gamma-chain ,Collagen receptor ,Disulfide-isomerase ,Gel-electrophoresis ,Endothelial-cells ,In-vivo ,Phosphorylation ,Aggregation ,Platelet membrane glycoprotein ,Biochemistry ,Tissue factor ,Young Adult ,Humans ,Platelet ,Electrophoresis, Gel, Two-Dimensional ,Platelet activation ,Blood Coagulation ,Chemistry ,Antibodies, Monoclonal ,Thrombosis ,Cell Biology ,Hematology ,Charged multivesicular body protein 3 ,Flow Cytometry ,Platelet Activation ,Coagulation ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Female ,Signal transduction ,GPVI ,Biomarkers ,Signal Transduction - Abstract
Platelets play a key role in hemostasis and various diseases including arterial thrombosis. Glycoprotein VI (GPVI) mediates adhesion to collagen structures exposed at sites of vascular injury and subsequent platelet activation. We determined the effects of specific activation of GPVI on the human platelet proteome. Isolated human platelets were stimulated with an activating monoclonal antibody specific for GPVI. Platelet proteins were analyzed by 2-dimensional difference gel electrophoresis (2D-DIGE) and mass spectrometry. We identified 8 differentially abundant proteins associated with cell signaling, metabolism, organization and rearrangement of the cytoskeleton, and membrane trafficking. Differentially abundant proteins included aldose reductase (AR), beta-centractin, charged multivesicular body protein 3, Src substrate cortactin, ERp57, and pleckstrin. Importantly, GPVI-modulated protein abundance was functionally relevant. Correspondingly, AR enzyme activity significantly increased upon GPVI activation and inhibition of AR resulted in reduced platelet aggregation. Furthermore, ERp57 was released upon ligation of platelet GPVI and increased the activity of tissue factor, a major initiator of blood coagulation. In summary, GPVI activation results in differential changes in abundance of platelet proteins, including AR and ERp57, which support platelet aggregation and platelet-dependent coagulation. These results provide further insight into the mechanisms that underlie platelet activation through the GPVI receptor and may help to identify novel pharmacologic targets.
- Published
- 2010
19. Resident dendritic cells prevent postischemic acute renal failure by help of single Ig IL-1 receptor-related protein
- Author
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Fritz Krombach, Cecilia Garlanda, Maciej Lech, Stephan Segerer, Ramanjaneyulu Allam, Alexander G. Khandoga, Hans-Joachim Anders, Alberto Mantovani, and Alejandro Avila-Ferrufino
- Subjects
Necrosis ,Neutrophils ,Immunology ,Cell Count ,Biology ,CCL2 ,Mice ,medicine ,Immunology and Allergy ,Animals ,Myeloid Cells ,Mice, Knockout ,Kidney ,Innate immune system ,Macrophages ,Microcirculation ,Acute kidney injury ,Receptors, Interleukin-1 ,Epithelial Cells ,Dendritic Cells ,Acute Kidney Injury ,medicine.disease ,TLR2 ,CXCL2 ,Chemotaxis, Leukocyte ,medicine.anatomical_structure ,Kidney Tubules ,Reperfusion Injury ,Cancer research ,TLR4 ,medicine.symptom - Abstract
Ischemia-reperfusion (IR) triggers tissue injury by activating innate immunity, for example, via TLR2 and TLR4. Surprisingly, TLR signaling in intrinsic renal cells predominates in comparison to intrarenal myeloid cells in the postischemic kidney. We hypothesized that immune cell activation is specifically suppressed in the postischemic kidney, for example, by single Ig IL-1-related receptor (SIGIRR). SIGIRR deficiency aggravated postischemic acute renal failure in association with increased renal CXCL2/MIP2, CCL2/MCP-1, and IL-6 mRNA expression 24 h after IR. Consistent with this finding interstitial neutrophil and macrophage counts were increased and tubular cell necrosis was aggravated in Sigirr-deficient vs wild-type IR kidneys. In vivo microscopy revealed increased leukocyte transmigration in the postischemic microvasculature of Sigirr-deficient mice. IL-6 and CXCL2/MIP2 release was much higher in Sigirr-deficient renal myeloid cells but not in Sigirr-deficient tubular epithelial cells after transient hypoxic culture conditions. Renal IR studies with chimeric mice confirmed this finding, as lack of SIGIRR in myeloid cells largely reproduced the phenotype of renal IR injury seen in Sigirr−/− mice. Additionally, clodronate depletion of dendritic cells prevented the aggravated renal failure in Sigirr−/− mice. Thus, loss of function mutations in the SIGIRR gene predispose to acute renal failure because SIGIRR prevents overshooting tissue injury by suppressing the postischemic activation of intrarenal myeloid cells.
- Published
- 2009
20. Ccl2 and Ccl3 mediate neutrophil recruitment via induction of protein synthesis and generation of lipid mediators
- Author
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Christoph A. Reichel, Peter Bihari, Alexander G. Khandoga, Nina Berberich, Fritz Krombach, Markus Rehberg, Stefan Zahler, and Max Lerchenberger
- Subjects
Male ,Chemokine ,Indoles ,Indomethacin ,CCL3 ,Biology ,Leukotriene B4 ,Sensitivity and Specificity ,chemistry.chemical_compound ,Mice ,Random Allocation ,Downregulation and upregulation ,medicine ,Benzoquinones ,Animals ,Lipoxygenase Inhibitors ,leukocyte ,migration ,chemokines ,permeability ,basement membrane ,Cells, Cultured ,Chemokine CCL2 ,Chemokine CCL3 ,Mice, Inbred BALB C ,Platelet-activating factor ,Monocyte ,Chemotaxis ,Lipid signaling ,respiratory system ,Molecular biology ,Chemotaxis, Leukocyte ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Integrin alpha M ,Neutrophil Infiltration ,Protein Biosynthesis ,Immunology ,1-Alkyl-2-acetylglycerophosphocholine Esterase ,biology.protein ,Dactinomycin ,Cardiology and Cardiovascular Medicine - Abstract
Objective—Although the chemokines monocyte chemoattractant protein-1 (Ccl2/JE/MCP-1) and macrophage inflammatory protein-1α (Ccl3/MIP-1α) have recently been implicated in neutrophil migration, the underlying mechanisms remain largely unclear.Methods and Results—Stimulation of the mouse cremaster muscle with Ccl2/JE/MCP-1 or Ccl3/MIP-1α induced a significant increase in numbers of firmly adherent and transmigrated leukocytes (>70% neutrophils) as observed by in vivo microscopy. This increase was significantly attenuated in mice receiving an inhibitor of RNA transcription (actinomycin D) or antagonists of platelet activating factor (PAF; BN 52021) and leukotrienes (MK-886; AA-861). In contrast, leukocyte responses elicited by PAF and leukotriene-B4(LTB4) themselves were not affected by actinomycin D, BN 52021, MK-886, or AA-861. Conversely, PAF and LTB4, but not Ccl2/JE/MCP-1 and Ccl3/MIP-1α, directly activated neutrophils as indicated by shedding of CD62L and marked upregulation of CD11b. Moreover, Ccl2/JE/MCP-1- and Ccl3/MIP-1α-elicited leakage of fluorescein isothiocyanate dextran as well as collagen IV remodeling within the venular basement membrane were completely absent in neutrophil-depleted mice.Conclusions—Ccl2/JE/MCP-1 and Ccl3/MIP-1α mediate firm adherence and (subsequent) transmigration of neutrophils via protein synthesis and secondary generation of leukotrienes and PAF, which in turn directly activate neutrophils. Thereby, neutrophils facilitate basement membrane remodeling and promote microvascular leakage.
- Published
- 2009
21. The role of Endothelial Cell-Selective Adhesion Molecule (ESAM) for leukocyte migration and vascular permeability during hepatic ischemia-reperfusion
- Author
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Fritz Krombach, Andrej Khandoga, K. W. Jauch, S. Hüttinger, Alexander G. Khandoga, Dietmar Vestweber, and Stefan Butz
- Subjects
Leukocyte migration ,Downregulation and upregulation ,Tight junction ,Chemistry ,Platelet ,Receptor ,Perfusion ,Molecular biology ,Intravital microscopy ,Immunostaining - Abstract
Background: The endothelial receptors that control leukocyte transmigration in the postischemic liver are not identified. This study was designed to investigate the role of endothelial cell selective adhesion molecule (ESAM), a recently discovered receptor expressed in endothelial tight junctions and platelets, for leukocyte migration in inflamed liver. Methods and Results: The role of ESAM for leukocyte migration in the liver was analyzed using ESAM-deficient mice in a model of warm hepatic ischemia-reperfusion (90 min/30–360 min). As shown by immunostaining, ESAM is expressed in sinusoids as well as in venules and is not upregulated upon I/R. Emigrated leukocytes were quantified in tissue sections. The postischemic neutrophil transmigration was significantly attenuated in ESAM−/− mice after 2 h of reperfusion, whereas it was completely restored after 6 h. In contrast, T-cell migration did not differ between ESAM+/+ and ESAM−/− mice. Using intravital microscopy, we demonstrate that ESAM deficiency attenuates I/R-induced vascular leakage after 30 min of reperfusion. The I/R-induced elevation in AST/ALT activity, the sinusoidal perfusion failure, and the number of TUNEL-positive hepatocytes were comparable between ESAM+/+ and ESAM−/− mice. Conclusions: ESAM is expressed in the postischemic liver and mediates neutrophil but not T-cell transmigration during early reperfusion. ESAM deficiency attenuates I/R-induced vascular leakage and does not affect leukocyte adherence. Despite the effect on neutrophil migration, ESAM-deficiency does not protect from I/R-induced injury.
- Published
- 2009
22. Postischemic vascular permeability requires both TLR-2 and TLR-4, but only TLR-2 mediates the transendothelial migration of leukocytes
- Author
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Andrej Khandoga, Alexander G. Khandoga, Fritz Krombach, and Hans-Joachim Anders
- Subjects
Leukocyte migration ,Motility ,Vascular permeability ,Critical Care and Intensive Care Medicine ,Capillary Permeability ,chemistry.chemical_compound ,Leukocyte Count ,Mice ,Cell Movement ,Cell Adhesion ,Leukocytes ,Animals ,Fluorescein ,Receptor ,Innate immune system ,Transendothelial migration ,Mice, Mutant Strains ,Toll-Like Receptor 2 ,Cell biology ,Mice, Inbred C57BL ,Toll-Like Receptor 4 ,chemistry ,Microscopy, Fluorescence ,Reperfusion Injury ,Cremaster muscle ,Emergency Medicine - Abstract
Ischemia-reperfusion (I/R) activates innate immunity involving Toll-like receptor (TLR) 2 and TLR-4 signaling. Leukocyte migration and vascular permeability contribute to postischemic tissue damage. We hypothesized that TLR-2 and TLR-4 directly mediate leukocyte migration and vascular permeability during I/R. We used in vivo microscopy on postischemic murine cremaster muscle to quantify leukocyte adhesion as well as transendothelial and interstitial migration in sham-operated wild-type mice and in wild-type, TLR-2(-/-), and TLR-4-mutant mice 30 and 120 min after I/R. Alterations in fluorescein isothiocyanate-dextran leakage across cremasteric venules were determined as a measure of endothelial permeability. I/R-induced leukocyte adhesion in TLR-2(-/-) and TLR-4-mutant mice was comparable to that in wild-type mice. The number of transmigrated leukocytes was increased upon I/R in wild-type mice as compared with the sham-operated group. In contrast, leukocyte transmigration was significantly attenuated in TLR-2(-/-) but not in TLR-4-mutant mice. Motility and polarization of interstitially migrating leukocytes did not significantly differ in TLR-2(-/-) and TLR-4-mutant mice from wild-type mice. Postischemic vascular leakage was significantly lower in both TLR-2(-/-) and TLR-4-mutant than in wild-type mice. We conclude that both TLR-2 signaling and TLR-4 signaling enhance postischemic vascular permeability and that TLR-2 has additional effects on the transendothelial migration of leukocytes at the postischemic vascular wall.
- Published
- 2008
23. Atrial natriuretic peptide protects against histamine-induced endothelial barrier dysfunction in vivo
- Author
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Martin F. Bubik, Bettina A. Mayer, Angelika M. Vollmar, Fritz Krombach, Peter Bihari, Robert Fürst, Alexander G. Khandoga, Florian Hoffmann, Markus Rehberg, and Stefan Zahler
- Subjects
Male ,medicine.medical_specialty ,Umbilical Veins ,medicine.drug_class ,Vascular permeability ,Biology ,Adherens junction ,Capillary Permeability ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Mice ,Atrial natriuretic peptide ,In vivo ,Internal medicine ,medicine ,Natriuretic peptide ,Electric Impedance ,Animals ,Humans ,Fluorescein isothiocyanate ,Cells, Cultured ,Fluorescent Dyes ,Pharmacology ,Endothelial Cells ,Immunohistochemistry ,Extravasation ,Rats ,Mice, Inbred C57BL ,Endocrinology ,chemistry ,Hematocrit ,Molecular Medicine ,Endothelium, Vascular ,Histamine ,Atrial Natriuretic Factor ,Fluorescein-5-isothiocyanate - Abstract
Endothelial barrier dysfunction is a hallmark of many severe pathologies, including sepsis or atherosclerosis. The cardiovascular hormone atrial natriuretic peptide (ANP) has increasingly been suggested to counteract endothelial leakage. Surprisingly, the precise in vivo relevance of these observations has never been evaluated. Thus, we aimed to clarify this issue and, moreover, to identify the permeability-controlling subcellular systems that are targeted by ANP. Histamine was used as important pro-inflammatory, permeability-increasing stimulus. Measurements of fluorescein isothiocyanate (FITC)-dextran extravasation from venules of the mouse cremaster muscle and rat hematocrit values were performed to judge changes of endothelial permeability in vivo. It is noteworthy that ANP strongly reduced the histamine-evoked endothelial barrier dysfunction in vivo. In vitro, ANP blocked the breakdown of transendothelial electrical resistance (TEER) induced by histamine. Moreover, as judged by immunocytochemistry and Western blot analysis, ANP inhibited changes of vascular endothelial (VE)-cadherin, beta-catenin, and p120(ctn) morphology; VE-cadherin and myosin light chain 2 (MLC2) phosphorylation; and F-actin stress fiber formation. These changes seem to be predominantly mediated by the natriuretic peptide receptor (NPR)-A, but not by NPR-C. In summary, we revealed ANP as a potent endothelial barrier protecting agent in vivo and identified adherens junctions and the contractile apparatus as subcellular systems targeted by ANP. Thus, our study highlights ANP as an interesting pharmacological compound opening new therapeutic options for preventing endothelial leakage.
- Published
- 2008
24. Reziproke Aktivierung von CD4+ T-Zellen und Kupffer-Zellen bei hepatischer Ischämie-Reperfusion
- Author
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Alexander G. Khandoga, Marc Hanschen, and Fritz Krombach
- Subjects
chemistry.chemical_classification ,Reactive oxygen species ,medicine.diagnostic_test ,Cell adhesion molecule ,T cell ,Glutathione ,Molecular biology ,In vitro ,Flow cytometry ,Proinflammatory cytokine ,chemistry.chemical_compound ,medicine.anatomical_structure ,Downregulation and upregulation ,chemistry ,ddc: 610 ,medicine - Abstract
Mechanisms mediating CD4+ T cell activation during hepatic ischemia-reperfusion (I/R) remain not fully understood. In this study, we tested the hypothesis that CD4+ T cells and Kupffer cells (KCs) interact during I/R via proinflammatory mediators causing reciprocal activation. In mice, accumulation of fluorescence-labeled CD4+ T cells was analyzed using intravital fluorescence microscopy in a sham-operated group, a group after warm lobar hepatic I/R (90/30–120min), and an additional I/R-group after depletion of KCs with GdCl3 (n = 6 each group). The I/R-induced accumulation of CD4+ T cells in sinusoids was significantly attenuated in mice undergoing depletion of KCs. To investigate whether KCs activate CD4+ T cells by releasing reactive oxygen species (ROS) and IL-6 as well as TNF-alpha, accumulation of CD4+ T cells was quantified in mice treated with the ROS scavenger glutathione, in IL-6-/- mice, and in wild-type mice after infusion of TNF-receptor-1-/- CD4+ T cells. Reduction of ROS and IL-6 as well as TNF-R1 deficiency attenuated postischemic CD4+ T cell accumulation (p < 0.05). Using flow cytometry we show in vitro that TNF-alpha and IL-6 are able to directly activate isolated CD4+ T cells and upregulate the expression of adhesion molecules on sinusoidal endothelial cells. Finally, we assessed whether CD4+ T cells might, in turn, trigger KC activation. As shown by an intravital microscopic analysis of the clearance kinetics of fluorescence-labeled latex beads, phagocytic activity of KCs was significantly depressed after I/R and this effect was enhanced in CD4-/- mice. In conclusion, this study demonstrates that KCs support the intrasinusoidal recruitment of CD4+ T cells during I/R. This effect is mediated by release of ROS and the cytokines TNF-alpha and IL-6, which together trigger activation of both CD4+ T cells and sinusoidal endothelial cells. In addition, CD4+ T cells seem to enhance the activation of KCs in the postischemic liver.
- Published
- 2008
25. The Role of Interstitial Macrophages in Nephropathy of Type 2 Diabetic db/db Mice
- Author
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Alexander G. Khandoga, Laszlo Revesz, Volha Ninichuk, Detlef Schlöndorff, Roland Feifel, Pius Loetscher, Achim Schlapbach, Peter J. Nelson, Stephan Segerer, Andrej Khandoga, Hans-Joachim Anders, and Fritz Krombach
- Subjects
Male ,medicine.medical_specialty ,CCR2 ,Receptors, CCR2 ,Kidney Glomerulus ,Receptors, CCR1 ,Administration, Oral ,Gene Expression ,Mice, Obese ,CCL2 ,Kidney ,Pathology and Forensic Medicine ,Nephropathy ,Cell Line ,Diabetic nephropathy ,Transforming Growth Factor beta1 ,Mice ,Diabetic Neuropathies ,Fibrosis ,Internal medicine ,medicine ,Animals ,RNA, Messenger ,Cells, Cultured ,Proteinuria ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Macrophages ,medicine.disease ,Antigens, Differentiation ,Immunohistochemistry ,Mice, Inbred C57BL ,Endocrinology ,medicine.anatomical_structure ,Kidney Tubules ,Diabetes Mellitus, Type 2 ,Microscopy, Fluorescence ,Receptors, Chemokine ,medicine.symptom ,business ,Kidney disease ,Regular Articles - Abstract
Diabetic nephropathy is associated with interstitial macrophage infiltrates, but their contribution to disease progression is unclear. We addressed this question by blockade of chemokine receptor (CCR)1 because CCR1 mediates the macrophage recruitment to the renal interstitium. In fact, when CCR1 was blocked with BL5923, a novel orally available CCR1 antagonist, the interstitial recruitment of ex vivo labeled macrophages was markedly decreased in uninephrectomized male db/db mice with advanced diabetic nephropathy. Likewise, BL5923 (60 mg/kg, twice a day) orally administered from months 5 to 6 of life reduced the numbers of interstitial macrophages in uninephrectomized db/db mice. This was associated with reduced numbers of Ki-67 proliferating tubular epithelial and interstitial cells, tubular atrophy, and interstitial fibrosis in uninephrectomized db/db mice. Glomerular pathology and proteinuria were not affected by the CCR1 antagonist. BL5923 reduced renal mRNA expression of Ccl2, Ccr1, Ccr2, Ccr5, transforming growth factor-beta1, and collagen I-alpha1 when compared with untreated uninephrectomized male db/db mice of the same age. Thus, we identified a previously unrecognized role for interstitial macrophages for tubulointerstitial injury, loss of peritubular microvasculature, interstitial inflammation, and fibrosis in type 2 diabetic db/db mice. These data identify oral treatment with the CCR1 antagonist BL5923 as a potential therapy for late-stage diabetic nephropathy.
- Published
- 2007
26. A CD99-related antigen on endothelial cells mediates neutrophil but not lymphocyte extravasation in vivo
- Author
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Dietmar Vestweber, Andrej Khandoga, Hartwig Wolburg, Sigrid März, Karen Wolburg-Buchholz, M. Gabriele Bixel, Fritz Krombach, Alexander G. Khandoga, and Björn Petri
- Subjects
Neutrophils ,Lymphocyte ,Immunology ,Biology ,12E7 Antigen ,Biochemistry ,Mice ,Antigen ,Venules ,In vivo ,Antigens, CD ,Cell Movement ,medicine ,Cell Adhesion ,Animals ,Lymphocytes ,Cells, Cultured ,Basement membrane ,Inflammation ,Neutrophil extravasation ,Endothelial Cells ,Cell Biology ,Hematology ,Extravasation ,Cell aggregation ,Cell biology ,medicine.anatomical_structure ,biology.protein ,Endothelium, Vascular ,Antibody - Abstract
CD99 is a long-known leukocyte antigen that does not belong to any of the known protein families. It was recently found on endothelial cells, where it mediates transendothelial migration of human monocytes and lymphocyte recruitment into inflamed skin in the mouse. Here, we show that CD99L2, a recently cloned, widely expressed antigen of unknown function with moderate sequence homology to CD99, is expressed on mouse leukocytes and endothelial cells. Using antibodies, we found that CD99L2 and CD99 are involved in transendothelial migration of neutrophils in vitro and in the recruitment of neutrophils into inflamed peritoneum. Intravital and electron microscopy of cremaster venules revealed that blocking CD99L2 inhibited leukocyte transmigration through the vessel wall (diapedesis) at the level of the perivascular basement membrane. We were surprised to find that, in contrast to CD99, CD99L2 was not relevant for the extravasation of lymphocytes into inflamed tissue. Although each protein promoted cell aggregation of transfected cells, endothelial CD99 and CD99L2 participated in neutrophil extravasation independent of these proteins on neutrophils. Our results establish CD99L2 as a new endothelial surface protein involved in neutrophil extravasation. In addition, this is the first evidence for a role of CD99 and CD99L2 in the process of leukocyte diapedesis in vivo.
- Published
- 2007
27. ESAM supports neutrophil extravasation, activation of Rho, and VEGF-induced vascular permeability
- Author
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Ines Nasdala, Björn Petri, Andrej Khandoga, Alexander G. Khandoga, Dietmar Vestweber, Oliver Brandau, Frank Wegmann, Stefan Butz, Hang Li, Christian Moser, Fritz Krombach, Reinhard Fässler, and Stefan Volkery
- Subjects
Male ,Vascular Endothelial Growth Factor A ,rho GTP-Binding Proteins ,Neutrophils ,Immunology ,Vascular permeability ,Leukocyte Rolling ,Cell Communication ,Biology ,Capillary Permeability ,Mice ,Cell Movement ,Animals ,Immunology and Allergy ,Mice, Knockout ,Neutrophil extravasation ,Tight junction ,Brief Definitive Report ,Cell Biology ,Leukocyte extravasation ,Extravasation ,Cell biology ,Enzyme Activation ,Endothelial stem cell ,Vascular endothelial growth factor A ,Brief Definitive Reports ,Female ,Cell Adhesion Molecules - Abstract
Endothelial cell–selective adhesion molecule (ESAM) is specifically expressed at endothelial tight junctions and on platelets. To test whether ESAM is involved in leukocyte extravasation, we have generated mice carrying a disrupted ESAM gene and analyzed them in three different inflammation models. We found that recruitment of lymphocytes into inflamed skin was unaffected by the gene disruption. However, the migration of neutrophils into chemically inflamed peritoneum was inhibited by 70% at 2 h after stimulation, recovering at later time points. Analyzing neutrophil extravasation directly by intravital microscopy in the cremaster muscle revealed that leukocyte extravasation was reduced (50%) in ESAM−/− mice without affecting leukocyte rolling and adhesion. Depletion of >98% of circulating platelets did not abolish the ESAM deficiency–related inhibitory effect on neutrophil extravasation, indicating that it is only ESAM at endothelial tight junctions that is relevant for the extravasation process. Knocking down ESAM expression in endothelial cells resulted in reduced levels of activated Rho, a GTPase implicated in the destabilization of tight junctions. Indeed, vascular permeability stimulated by vascular endothelial growth factor was reduced in ESAM−/− mice. Collectively, ESAM at endothelial tight junctions participates in the migration of neutrophils through the vessel wall, possibly by influencing endothelial cell contacts.
- Published
- 2006
28. Matrix metalloproteinase-9 promotes neutrophil and T cell recruitment and migration in the postischemic liver
- Author
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Fritz Krombach, Dorothe Burggraf, Julia S. Kessler, Christoph A. Reichel, Alexander G. Khandoga, Andrej Khandoga, Gerhard F. Hamann, Georg Enders, and Marc Hanschen
- Subjects
CD4-Positive T-Lymphocytes ,Leukocyte migration ,Neutrophils ,T cell ,Immunology ,Motility ,Apoptosis ,Matrix metalloproteinase ,Biology ,Matrix Metalloproteinase Inhibitors ,Peptides, Cyclic ,Mice ,Venules ,Ischemia ,medicine ,Cell Adhesion ,Immunology and Allergy ,Animals ,Antigens, Ly ,Protease Inhibitors ,Aspartate Aminotransferases ,RNA, Messenger ,Muscle, Skeletal ,Hepatocyte Growth Factor ,Tumor Necrosis Factor-alpha ,Alanine Transaminase ,Cell Biology ,Dipeptides ,Molecular biology ,Enzyme Activation ,Mice, Inbred C57BL ,Chemotaxis, Leukocyte ,P-Selectin ,Protein Transport ,medicine.anatomical_structure ,Liver ,Matrix Metalloproteinase 9 ,Reperfusion Injury ,Cremaster muscle ,Leukocyte Common Antigens ,Matrix Metalloproteinase 2 ,Tumor necrosis factor alpha ,Female ,Endothelium, Vascular ,Intravital microscopy - Abstract
Matrix metalloproteinases-2 and -9 (MMP-2/9) are critically involved in degradation of extracellular matrix, and their inhibition is discussed as a promising strategy against hepatic ischemia-reperfusion (I/R) injury. Here, we analyzed the role of MMP-2 and -9 for leukocyte migration and tissue injury in sham-operated mice and in mice after I/R, treated with a MMP-2/9 inhibitor or vehicle. Using zymography, we show that the MMP-2/9 inhibitor abolished I/R-induced MMP-9 activation, whereas MMP-2 activity was not detectable in all groups. As demonstrated by intravital microscopy, MMP-9 inhibition attenuated postischemic rolling and adherence of total leukocytes in hepatic postsinusoidal venules, CD4+ T cell accumulation in sinusoids, and neutrophil transmigration. These effects were associated with reduction of plasma tumor necrosis factor α (TNF-α) levels and endothelial expression of CD62P. Motility of interstitially migrating leukocytes was assessed by near-infrared reflected light oblique transillumination microscopy in the postischemic cremaster muscle. Upon MMP-9 blockade, leukocyte migration velocity and curve-line and straight-line migration distances were reduced significantly as compared with the vehicle-treated I/R group. Postischemic sinusoidal perfusion failure, hepatocellular apoptosis, and alanine aminotransferase activity were only slightly reduced after MMP-9 inhibition, whereas aspartate aminotransferase activity and mortality were significantly lower. In conclusion, MMP-9 is involved in the early recruitment cascades of neutrophils and CD4+ T cells, promotes neutrophil and T cell transmigration during hepatic I/R, and is required for motility of interstitially migrating leukocytes. MMP-9 blockade is associated with an attenuation of TNF-α release and endothelial CD62P expression, weakly protects from early microvascular/hepatocellular I/R damage, but improves postischemic survival.
- Published
- 2006
29. T-Zell-Rekrutierung und Interaktionen mit Thrombozyten bei hepatischer Ischämie-Reperfusion in vivo
- Author
-
Julia S. Kessler, Marc Hanschen, Alexander G. Khandoga, and Fritz Krombach
- Subjects
Cell type ,medicine.anatomical_structure ,Endothelium ,Acinus ,In vivo ,Chemistry ,T cell ,medicine ,Platelet ,medicine.disease ,Molecular biology ,T cell deficiency ,CD8 - Abstract
T cells are suggested to be involved in the induction of antigen-independent hepatic ischemia-reper-fusion (I/R) injury. In the present study, we analyzed the recruitment of T cell subpopulations in the postischemic liver in vivo and investigated by which pathway T cells mediate tissue injury. In a murine model of warm hepatic I/R (I: 90min, R: 30, 120 min), the recruitment of freshly isolated (magnetic immunosorting) and CFDA-SE-labeled syngeneic CD4+ and CD8+ T cells was analyzed using intra-vital microscopy (n = 6 each group). Hepatic I/R induced accumulation of CD4+ T cells in sinusoids (4.4 ± 0.7 vs. 1.6 ± 0.2/acinus in the sham-operated group) as well as transmigration into the perivas-cular space. In contrast, postischemic recruitment of CD8+ T cells was very low and did not differ from controls. To investigate the role of CD4+ cells during hepatic I/R, we performed an in vivo analysis of sinusoidal colocalization of CD4+ cells with platelets (n = 6). After I/R (90/30 min), 27 ± 3% of adherent CD4+ cells were colocalized with platelets, a fact pointing to interactions between both types of blood cells. In a third set of experiments (n = 6), we tested the hypothesis that CD4+ T cells mediate microvascular I/R injury by enhancing platelet recruitment. Indeed, the postischemic increase in the number of accumulated platelets was significantly lower in sinusoids of CD4-/- mice than in those of wild-type controls. Moreover, the postischemically impaired sinusoidal perfusion was ameliorated in CD4-/- mice (WT 30 ± 1; CD4-/- 18 ± 2% non-perfused sinusoids). In summary, these in vivo data indicate that hepatic I/R induces accumulation as well as transmigration of CD4+but not CD8+ T cells in sinusoids during early reperfusion. CD4+ T cells are colocalized with platelets in sinusoids, suggesting a reciprocal activation of both cell types either due to direct interactions or through activation of hepatic endothelium. CD4+ T cell deficiency is associated with an attenuation of postischemic platelet recruitment as well as with an improvement of postischemic tissue perfusion. Supported by DFG (FOR440/2)
- Published
- 2005
30. Rekrutierung von T-Zellen bei Ischämie-Reperfusion der Leber in vivo
- Author
-
Marc Hanschen, Fritz Krombach, and Alexander G. Khandoga
- Subjects
Liver injury ,Chemistry ,T cell ,Kupffer cell ,Ischemia ,Cell sorting ,medicine.disease ,Molecular biology ,medicine.anatomical_structure ,ddc: 610 ,In vivo ,medicine ,CD8 ,Ex vivo - Abstract
T cells are suggested to participate in the manifestation of ischemia-reperfusion-induced inflammatory responses in the liver. The aim of this study was to investigate the recruitment of T cells in the postischemic hepatic microvasculature in vivo and to test the hypothesis that this recruitment is mediated by Kupffer cell activation. In C57B1/6 mice, ischemia of the left liver lobe was induced for 90 min. CD4+ and CD8+ T cells were isolated from spleens of syngenic mice by magnetic cell sorting and labeled ex vivo with CFDA-SE. After 30 min of reperfusion, either 1 × 107 CD4+ or 0.7 × 107CD8+ T cells were infused intraarterially (n = 5 each group). In control experiments, an identical number of either CD4+ or CD8+ T cells was infused into sham-operated animals. In an additional ischemia-reperfusion group, activation of Kupffer cells was blocked by gadolinium chloride (10 µg/kg, i.V., n = 5). The number of T cells accumulated in hepatic microvessels as well as of T cells transmigrated to the perivascular space was quantitatively analyzed by means of intravital video fluorescence microscopy. Hepatic ischemia-reperfusion induced an increase in the number of adherent CD4+ T cells in postsinusoidal venules and sinusoids after 30 min as well as 120 min of reperfusion as compared to the sham-operated group. The prolongation of reperfusion time from 30 min to 120 min significantly enhanced T cell transmigration. The blockade of Kupffer cells with gadolinium chloride completely attenuated both postischemic adherence and transmigration of CD4+ T cells. In contrast, the postischemic recruitment of CD8+ T cells was very low in all segments of the hepatic microvasculature and did not differ among experimental groups. Thus, normothermic hepatic I/R induces accumulation of CD4+, but not CD8+ T cells, in the hepatic microcirculation. This accumulation is triggered by Kupffer cells and occurs in sinusoids and to a lesser extent in postsinusoidal venules during early reperfusion. CD4+ T cell transmigration is enhanced as reperfusion time is prolonged up to 120 min. Accumulation of T cells in the postischemic liver may provide a potential mechanism underlying postischemic liver injury.
- Published
- 2004
31. ESAM deficiency impairs diapedesis and extravasation of neutrophils in vivo
- Author
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Reinhard Faessler, Frank Wegmann, Dietmar Vestweber, Fritz Krombach, Stefan Butz, Andrej Khandoga, Bjoern Petri, and Alexander G. Khandoga
- Subjects
Pharmacology ,Pathology ,medicine.medical_specialty ,Physiology ,In vivo ,business.industry ,medicine ,Molecular Medicine ,business ,Extravasation - Published
- 2006
32. BLOCKADE OF POLY(ADP-RIBOSE)POLYMERASE BY 5-AIQ: IMPACT ON CELL INJURY AND SURVIVAL AFTER HEPATIC ISCHEMIA-REPERFUSION
- Author
-
Alexander G. Khandoga, Fritz Krombach, and Georg Enders
- Subjects
Chemistry ,Poly ADP ribose polymerase ,Emergency Medicine ,Cell injury ,Critical Care and Intensive Care Medicine ,Molecular biology ,Hepatic ischemia ,Blockade - Published
- 2004
33. T-CELL RECRUITMENT DURING ISCHEMIA-REPERFUSION OF THE LIVER IN VIVO
- Author
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M. Hanschen, Alexander G. Khandoga, and Fritz Krombach
- Subjects
medicine.anatomical_structure ,In vivo ,business.industry ,T cell ,Emergency Medicine ,Ischemia ,medicine ,Pharmacology ,Critical Care and Intensive Care Medicine ,medicine.disease ,business - Published
- 2004
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