@article{RadbruchPischonOstrowskietal.2017, author = {Radbruch, Moritz and Pischon, Hannah and Ostrowski, Anja and Volz, Pierre and Brodwolf, Robert and Neumann, Falko and Unbehauen, Michael and Kleuser, Burkhard and Haag, Rainer and Ma, Nan and Alexiev, Ulrike and Mundhenk, Lars and Gruber, Achim D.}, title = {Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin}, series = {Nanoscale Research Letters}, volume = {12}, journal = {Nanoscale Research Letters}, number = {64}, publisher = {Springer}, address = {New York}, issn = {1556-276X}, doi = {10.1186/s11671-017-1835-0}, pages = {12}, year = {2017}, abstract = {Dendritic hPG-amid-C18-mPEG core-multishell nanocarriers (CMS) represent a novel class of unimolecular micelles that hold great potential as drug transporters, e. g., to facilitate topical therapy in skin diseases. Atopic dermatitis is among the most common inflammatory skin disorders with complex barrier alterations which may affect the efficacy of topical treatment. Here, we tested the penetration behavior and identified target structures of unloaded CMS after topical administration in healthy mice and in mice with oxazolone-induced atopic dermatitis. We further examined whole body distribution and possible systemic side effects after simulating high dosage dermal penetration by subcutaneous injection. Following topical administration, CMS accumulated in the stratum corneum without penetration into deeper viable epidermal layers. The same was observed in atopic dermatitis mice, indicating that barrier alterations in atopic dermatitis had no influence on the penetration of CMS. Following subcutaneous injection, CMS were deposited in the regional lymph nodes as well as in liver, spleen, lung, and kidney. However, in vitro toxicity tests, clinical data, and morphometry-assisted histopathological analyses yielded no evidence of any toxic or otherwise adverse local or systemic effects of CMS, nor did they affect the severity or course of atopic dermatitis. Taken together, CMS accumulate in the stratum corneum in both healthy and inflammatory skin and appear to be highly biocompatible in the mouse even under conditions of atopic dermatitis and thus could potentially serve to create a depot for anti-inflammatory drugs in the skin.}, language = {en} } @article{EdlichVolzBrodwolfetal.2018, author = {Edlich, Alexander and Volz, Pierre and Brodwolf, Robert and Unbehauen, Michael and Mundhenk, Lars and Gruber, Achim D. and Hedtrich, Sarah and Haag, Rainer and Alexiev, Ulrike and Kleuser, Burkhard}, title = {Crosstalk between core-multishell nanocarriers for cutaneous drug delivery and antigen-presenting cells of the skin}, series = {Biomaterials : biomaterials reviews online}, volume = {162}, journal = {Biomaterials : biomaterials reviews online}, publisher = {Elsevier}, address = {Oxford}, issn = {0142-9612}, doi = {10.1016/j.biomaterials.2018.01.058}, pages = {60 -- 70}, year = {2018}, abstract = {Owing their unique chemical and physical properties core-multishell (CMS) nanocarriers are thought to underlie their exploitable biomedical use for a topical treatment of skin diseases. This highlights the need to consider not only the efficacy of CMS nanocarriers but also the potentially unpredictable and adverse consequences of their exposure thereto. As CMS nanocarriers are able to penetrate into viable layers of normal and stripped human skin ex vivo as well as in in vitro skin disease models the understanding of nanoparticle crosstalk with components of the immune system requires thorough investigation. Our studies highlight the biocompatible properties of CMS nanocarriers on Langerhans cells of the skin as they did neither induce cytotoxicity and genotoxicity nor cause reactive oxygen species (ROS) or an immunological response. Nevertheless, CMS nanocarriers were efficiently taken up by Langerhans cells via divergent endocytic pathways. Bioimaging of CMS nanocarriers by fluorescence lifetime imaging microscopy (FLIM) and flow cytometry indicated not only a localization within the lysosomes but also an energy-dependent exocytosis of unmodified CMS nanocarriers into the extracellular environment. (C) 2018 Elsevier Ltd. All rights reserved.}, language = {en} } @article{SzymanskiToenniesBecheretal.2012, author = {Szymanski, Kolja V. and T{\"o}nnies, Mario and Becher, Anne and Fatykhova, Diana and N'Guessan, Philippe D. and Gutbier, Birgitt and Klauschen, Frederick and Neusch{\"a}fer-Rube, Frank and Schneider, Paul and R{\"u}ckert, Jens and Neudecker, Jens and Bauer, Torsten T. and Dalhoff, Klaus and Droemann, Daniel and Gruber, Achim D. and Kershaw, Olivia and Temmesfeld-Wollbrueck, Bettina and Suttorp, Norbert and Hippenstiel, Stefan and Hocke, Andreas C.}, title = {Streptococcus pneumoniae-induced regulation of cyclooxygenase-2 in human lung tissue}, series = {The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology}, volume = {40}, journal = {The European respiratory journal : official journal of the European Society for Clinical Respiratory Physiology}, number = {6}, publisher = {European Respiratory Society}, address = {Sheffield}, issn = {0903-1936}, doi = {10.1183/09031936.00186911}, pages = {1458 -- 1467}, year = {2012}, abstract = {The majority of cases of community-acquired pneumonia are caused by Streptococcus pneumoniae and most studies on pneumococcal host interaction are based on cell culture or animal experiments. Thus, little is known about infections in human lung tissue. Cyclooxygenase-2 and its metabolites play an important regulatory role in lung inflammation. Therefore, we established a pneumococcal infection model on human lung tissue demonstrating mitogen-activated protein kinase (MAPK)-dependent induction of cyclooxygenase-2 and its related metabolites. In addition to alveolar macrophages and the vascular endothelium, cyclooxygenase-2 was upregulated in alveolar type II but not type I epithelial cells, which was confirmed in lungs of patients suffering from acute pneumonia. Moreover, we demonstrated the expression profile of all four E prostanoid receptors at the mRNA level and showed functionality of the E prostanoid(4) receptor by cyclic adenosine monophosphate production. Additionally, in comparison to previous studies, cyclooxygenase-2/prostaglandin E-2 related pro- and anti-inflammatory mediator regulation was partly confirmed in human lung tissue after pneumococcal infection. Overall, cell type-specific and MAPK-dependent cyclooxygenase-2 expression and prostaglandin E-2 formation in human lung tissue may play an important role in the early phase of pneumococcal infections.}, language = {en} } @misc{RadbruchPischonOstrowskietal.2017, author = {Radbruch, Moritz and Pischon, Hannah and Ostrowski, Anja and Volz, Pierre and Brodwolf, Robert and Neumann, Falko and Unbehauen, Michael and Kleuser, Burkhard and Haag, Rainer and Ma, Nan and Alexiev, Ulrike and Mundhenk, Lars and Gruber, Achim D.}, title = {Dendritic core-multishell nanocarriers in murine models of healthy and atopic skin}, series = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe}, journal = {Postprints der Universit{\"a}t Potsdam Mathematisch-Naturwissenschaftliche Reihe}, number = {724}, issn = {1866-8372}, doi = {10.25932/publishup-43013}, url = {http://nbn-resolving.de/urn:nbn:de:kobv:517-opus4-430136}, pages = {12}, year = {2017}, abstract = {Dendritic hPG-amid-C18-mPEG core-multishell nanocarriers (CMS) represent a novel class of unimolecular micelles that hold great potential as drug transporters, e. g., to facilitate topical therapy in skin diseases. Atopic dermatitis is among the most common inflammatory skin disorders with complex barrier alterations which may affect the efficacy of topical treatment. Here, we tested the penetration behavior and identified target structures of unloaded CMS after topical administration in healthy mice and in mice with oxazolone-induced atopic dermatitis. We further examined whole body distribution and possible systemic side effects after simulating high dosage dermal penetration by subcutaneous injection. Following topical administration, CMS accumulated in the stratum corneum without penetration into deeper viable epidermal layers. The same was observed in atopic dermatitis mice, indicating that barrier alterations in atopic dermatitis had no influence on the penetration of CMS. Following subcutaneous injection, CMS were deposited in the regional lymph nodes as well as in liver, spleen, lung, and kidney. However, in vitro toxicity tests, clinical data, and morphometry-assisted histopathological analyses yielded no evidence of any toxic or otherwise adverse local or systemic effects of CMS, nor did they affect the severity or course of atopic dermatitis. Taken together, CMS accumulate in the stratum corneum in both healthy and inflammatory skin and appear to be highly biocompatible in the mouse even under conditions of atopic dermatitis and thus could potentially serve to create a depot for anti-inflammatory drugs in the skin.}, language = {en} } @article{WallmeyerDietertSochorovaetal.2017, author = {Wallmeyer, Leonie and Dietert, Kristina and Sochorova, Michaela and Gruber, Achim D. and Kleuser, Burkhard and Vavrova, Katerina and Hedtrich, Sarah}, title = {TSLP is a direct trigger for T cell migration in filaggrin-deficient skin equivalents}, series = {Scientific reports}, volume = {7}, journal = {Scientific reports}, publisher = {Nature Publ. Group}, address = {London}, issn = {2045-2322}, doi = {10.1038/s41598-017-00670-2}, pages = {12}, year = {2017}, abstract = {Mutations in the gene encoding for filaggrin (FLG) are major predisposing factors for atopic dermatitis (AD). Besides genetic predisposition, immunological dysregulations considerably contribute to its pathophysiology. For example, thymic stromal lymphopoietin (TSLP) is highly expressed in lesional atopic skin and significantly contributes to the pathogenesis of AD by activating dendritic cells that then initiate downstream effects on, for example, T cells. However, little is known about the direct interplay between TSLP, filaggrin-deficient skin and other immune cells such as T lymphocytes. In the present study, FLG knockdown skin equivalents, characterised by intrinsically high TSLP levels, were exposed to activated CD4(+) T cells. T cell exposure resulted in an inflammatory phenotype of the skin equivalents. Furthermore, a distinct shift from a Th1/Th17 to a Th2/Th22 profile was observed following exposure of T cells to filaggrin-deficient skin equivalents. Interestingly, TSLP directly stimulated T cell migration exclusively in filaggrin-deficient skin equivalents even in the absence of dendritic cells, indicating a hitherto unknown role of TSLP in the pathogenesis of AD.}, language = {en} } @article{WienholdMacriNouaillesetal.2018, author = {Wienhold, Sandra-Maria and Macri, Mario and Nouailles, Geraldine and Dietert, Kristina and Gurtner, Corinne and Gruber, Achim D. and Heimesaat, Markus M. and Lienau, Jasmin and Schumacher, Fabian and Kleuser, Burkhard and Opitz, Bastian and Suttorp, Norbert and Witzenrath, Martin and M{\"u}ller-Redetzky, Holger C.}, title = {Ventilator-induced lung injury is aggravated by antibiotic mediated microbiota depletion in mice}, series = {Critical Care}, volume = {22}, journal = {Critical Care}, number = {282}, publisher = {BMC}, address = {London}, issn = {1466-609X}, doi = {10.1186/s13054-018-2213-8}, pages = {12}, year = {2018}, abstract = {BackgroundAntibiotic exposure alters the microbiota, which can impact the inflammatory immune responses. Critically ill patients frequently receive antibiotic treatment and are often subjected to mechanical ventilation, which may induce local and systemic inflammatory responses and development of ventilator-induced lung injury (VILI). The aim of this study was to investigate whether disruption of the microbiota by antibiotic therapy prior to mechanical ventilation affects pulmonary inflammatory responses and thereby the development of VILI.MethodsMice underwent 6-8weeks of enteral antibiotic combination treatment until absence of cultivable bacteria in fecal samples was confirmed. Control mice were housed equally throughout this period. VILI was induced 3 days after completing the antibiotic treatment protocol, by high tidal volume (HTV) ventilation (34ml/kg; positive end-expiratory pressure=2 cmH(2)O) for 4h. Differences in lung function, oxygenation index, pulmonary vascular leakage, macroscopic assessment of lung injury, and leukocyte and lymphocyte differentiation were assessed. Control groups of mice ventilated with low tidal volume and non-ventilated mice were analyzed accordingly.ResultsAntibiotic-induced microbiota depletion prior to HTV ventilation led to aggravation of VILI, as shown by increased pulmonary permeability, increased oxygenation index, decreased pulmonary compliance, enhanced macroscopic lung injury, and increased cytokine/chemokine levels in lung homogenates.ConclusionsDepletion of the microbiota by broad-spectrum antibiotics prior to HTV ventilation renders mice more susceptible to developing VILI, which could be clinically relevant for critically ill patients frequently receiving broad-spectrum antibiotics.}, language = {en} } @article{GutbierSchoenrockEhrleretal.2018, author = {Gutbier, Birgitt and Sch{\"o}nrock, Stefanie M. and Ehrler, Carolin and Haberberger, Rainer and Dietert, Kristina and Gruber, Achim D. and Kummer, Wolfgang and Michalick, Laura and Kuebler, Wolfgang M. and Hocke, Andreas C. and Szymanski, Kolja and Letsiou, Eleftheria and L{\"u}th, Anja and Schumacher, Fabian and Kleuser, Burkhard and Mitchell, Timothy J. and Bertrams, Wilhelm and Schmeck, Bernd and Treue, Denise and Klauschen, Frederick and Bauer, Torsten T. and T{\"o}nnies, Mario and Weissmann, Norbert and Hippenstiel, Stefan and Suttorp, Norbert and Witzenrath, Martin}, title = {Sphingosine Kinase 1 Regulates Inflammation and Contributes to Acute Lung Injury in Pneumococcal Pneumonia via the Sphingosine-1-Phosphate Receptor 2}, series = {Critical care medicine}, volume = {46}, journal = {Critical care medicine}, number = {3}, publisher = {Lippincott Williams \& Wilkins}, address = {Philadelphia}, organization = {CAPNETZ Study Grp}, issn = {0090-3493}, doi = {10.1097/CCM.0000000000002916}, pages = {e258 -- e267}, year = {2018}, abstract = {Objectives: Severe pneumonia may evoke acute lung injury, and sphingosine-1-phosphate is involved in the regulation of vascular permeability and immune responses. However, the role of sphingosine-1-phosphate and the sphingosine-1-phosphate producing sphingosine kinase 1 in pneumonia remains elusive. We examined the role of the sphingosine-1-phosphate system in regulating pulmonary vascular barrier function in bacterial pneumonia. Design: Controlled, in vitro, ex vivo, and in vivo laboratory study. Subjects: Female wild-type and SphK1-deficient mice, 8-10 weeks old. Human postmortem lung tissue, human blood-derived macrophages, and pulmonary microvascular endothelial cells. Interventions: Wild-type and SphK1-deficient mice were infected with Streptococcus pneumoniae. Pulmonary sphingosine-1-phosphate levels, messenger RNA expression, and permeability as well as lung morphology were analyzed. Human blood-derived macrophages and human pulmonary microvascular endothelial cells were infected with S. pneumoniae. Transcellular electrical resistance of human pulmonary microvascular endothelial cell monolayers was examined. Further, permeability of murine isolated perfused lungs was determined following exposition to sphingosine-1-phosphate and pneumolysin. Measurements and Main Results: Following S. pneumoniae infection, murine pulmonary sphingosine-1-phosphate levels and sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 expression were increased. Pneumonia-induced lung hyperpermeability was reduced in SphK1(-/-) mice compared with wild-type mice. Expression of sphingosine kinase 1 in macrophages recruited to inflamed lung areas in pneumonia was observed in murine and human lungs. S. pneumoniae induced the sphingosine kinase 1/sphingosine-1-phosphate system in blood-derived macrophages and enhanced sphingosine-1-phosphate receptor 2 expression in human pulmonary microvascular endothelial cell in vitro. In isolated mouse lungs, pneumolysin-induced hyperpermeability was dose dependently and synergistically increased by sphingosine-1-phosphate. This sphingosine-1-phosphate-induced increase was reduced by inhibition of sphingosine-1-phosphate receptor 2 or its downstream effector Rho-kinase. Conclusions: Our data suggest that targeting the sphingosine kinase 1-/sphingosine-1-phosphate-/sphingosine-1-phosphate receptor 2-signaling pathway in the lung may provide a novel therapeutic perspective in pneumococcal pneumonia for prevention of acute lung injury.}, language = {en} } @misc{PischonRadbruchOstrowskietal.2017, author = {Pischon, Hannah and Radbruch, Moritz and Ostrowski, Anja and Schumacher, Fabian and Hoenzke, Stefan and Kleuser, Burkhard and Hedtrich, Sarah and Fluhr, Joachim W. and Gruber, Achim D. and Mundhenk, Lars}, title = {How Effective Is Tacrolimus in the Imiquimod}, series = {The journal of investigative dermatology}, volume = {138}, journal = {The journal of investigative dermatology}, number = {2}, publisher = {Elsevier}, address = {New York}, issn = {0022-202X}, doi = {10.1016/j.jid.2017.09.019}, pages = {455 -- 458}, year = {2017}, language = {en} }