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AG Prof. Thome

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Physiology of Lung Epithelia

Hauptaugenmerk der Arbeitsgruppe ist das Atemnotsyndrom bei Frühgeborenen: Weltweit kommen rund 10 Prozent aller Neugeborenen als Frühgeborene zur Welt. Dies gilt auch für Industrienationen wie Deutschland. Überlebensentscheidend für ein Frühgeborenes ist das Ausmaß der Lungenreife, da sich die Lunge erst relativ spät in der Embryonalentwicklung vollständig ausbildet. An diesem Punkt setzt der Forschungsschwerpunkt der Arbeitsgruppe mit verschiedenen Projekten an. Neben der Grundlagenforschung auf biochemischer und elektrophysiologischer Ebene, ist es ebenfalls Ziel der Arbeitsgruppe, erworbene Erkenntnisse kliniknah zum Einsatz zu bringen.


​Alveolar fluid clearance from the distal airspaces is mainly driven by vectorial sodium transport, where sodium enters the alveolar epithelial cells through apically located sodium channels (ENaC) and is extruded by basolaterally operating Na,K-ATPases. Hence sodium transport plays a crucial role in the immediate postnatal fluid clearance and the reabsorption of pulmonary edema. Our group aims to analyze new strategies to enhance epithelial sodium transport and thereby improve the morbidity and mortality of pulmonary complications associated with a reduced alveolar fluid clearance.


Projects:

Development of a lung organoid model to study fetal ​lung maturation

Hormonal regulation of pulmonary chloride secretion​

Sex-related differences in alveolar sodium transport​

Stem cell-based stimulation of lung maturation

Single channel characterization in fetal and adult lung slices

Mechanical properties of the premature lung

Impact of the epithelial-mesenchymal relationship ​

Ureaplasma-driven Neonatal Inflammation

​Klinische Studien legen nahe, dass eine Ureaplasmen-Exposition unmittelbar vor oder nach der Geburt mit einem erhöhten Risiko für Entzündungsreaktionen und Folgeerkrankungen insbesondere bei Frühgeborenen einhergeht. Ziel dieses Projektes ist die Charakterisierung zugrundeliegender Mechanismen. Unter Verwendung von Nabelschnurblut-Monozyten wird die Interaktion von Ureaplasmen mit Schlüsselproteinen der Signaltransduktion untersucht. In Zusammenarbeit mit der Universitätskinderklinik Würzburg erfolgen Analysen zur proinflammatorischen und immunmodulatorischen Kapazität von Ureaplasmen in komplexen in vitro-Modellen mit neonatalen Monozyten, pulmonale Endothel- und Epithelzellen sowie Hirnendothelzellen. Die Arbeiten werden durch Studien im Schafmodell ergänzt, die in Kooperation mit der Abteilung für Experimentelle Perinatologie des Universitätsklinikums Maastricht, Niederlande, durchführt werden. Die dargestellten Arbeiten sollen die Entwicklung gezielter antiinfektiöser und antiinflammatorischer Therapie-Strategien ermöglichen.


​Substantial evi​dence exists that prenatal, perinatal, and postnatal Ureaplasma exposure confers an increased risk for adverse inflammation and short-term and long-term morbidity, especially in preterm infants. The current project aims at characterizing underlying mechanisms. Using primary neonatal monocytes, the interaction of Ureaplasma spp. with pattern recognition receptors and key signaling proteins is analyzed in vitro. In collaboration with the University Children's Hospital Würzburg pro-inflammatory and immunomodulatory capacities of Ureaplasma spp. are investigated by means of complex in vitro models co-cultivating neonatal monocytes and human endothelial and epithelial cells. Analyses in an ovine model of perinatal Ureaplasma exposure performed at and in cooperation with the Department of Experimental Perinatology at the Maastricht University Medical Centre addds to this work. The given experiments may allow the development of specific anti-inflammatory and anti-infective strategies.

​Projects:​

  • Underlying mechanisms of Ureaplasma-induced immune responses in neonatal monocytes
  • Ureaplasma-driven immunomodulation in neonatal monocytes and endothelial- and epithelial cells.   
  • Mechanisms of Ureaplasma-induced neuroinflammation ​​
  • Pathomechanisms of the Ureaplasma-induced pulmonary inflammation

Neonatal Inflammation and Short- and Long-term Morbidity

​Neu- und insbesondere Frühgeborene zeigen ein hohes Risiko für schwere Infektionen und unreifeassoziierte Folgeerkrankungen, wie die Bronchopulmonale Dysplasie (BPD) oder die Nekrotisierende Enterokolitis (NEC). Überschießende Entzündungsreaktionen haben einen wesentlichen Anteil an deren Genese. Ziel dieses Projektes ist es zu untersuchen, inwieweit Reife-abhängige Funktionen der Signalvermittlung oder der Einfluss des Stimulus die neonatale Immunantwort beeinflussen. Vor dem Hintergrund der Entwicklung neuer Primärzellmodelle, sog. Organoide, stellt die Etablierung einer Biobank an Dünndarm-Organoiden von Frühgeborenen mit und ohne NEC und Neugeborener einen weiteren Schwerpunkt dar. Dieses Kooperations-Projekt mit der Klinik und Poliklinik für Kinderchirurgie des Universitätsklinikums Leipzig sowie der Universitäts-Kinderklinik Würzburg, der Chirurgischen Klinik I des Uniklinikums Würzburg und dem Zentrum für Infektionsforschung (ZINF) der Universität Würzburg untersucht die immunologischen und physikalischen Barrierefunktionen des neonatalen Epithels und  Signalwege in der Entstehung von Darmentzündungen bei Frühgeborenen.

 

Term, and especially preterm infants are at high risk of severe infections and immaturity-related morbities, such as bronchopulmonary dysplasia (BPD) or necrotizing enterocolitis (NEC). Exaggerated and perpetuated inflammation is a principle contributing mechanism. This project aims at characterizing innate immune responses in preterm and term neonatal monocytes - according to gestational age and stimulus exposure. Given the recent advent of the organoid technology, another field of research focuses on the generation of organoids derived from preterm infants with and without NEC and term neonates, to characterize immune and physical barrier properties systematically, and to investigate NEC-associated adverse signaling. This project is a collaboration between the Division of Neonatology, Leipzig, the University Children's Hospital Würzburg, the Departments of Pediatric Surgery in Leipzig and Würzburg and the Research Center for Infectious Diseases (ZINF) at the University of Würzburg.

 

Projects:

Characterization of stimulus-induced immune responses in preterm and term neonatal monocytes

​Characterization of the neonatal intestinal immune response and barrier function in human intestinal organoids - a new model to study necrotizing enterocolitis (NEC)​

Publications

  • Laube M, Thome UH (2022): Albumin stimulates epithelial Na+ transport and barrier integrity by activating the PI3K/AKT/SGK1 pathway. Int J Mol Sci 23(15), 8823. doi: 10.3390/ijms23158823 .
  • Laube M, Thome UH. (2022): Y It Matters-Sex Differences in Fetal Lung Development. Biomolecules 12 (3). doi: 10.3390/biom12030437 .
  • Laube M, Riedel D, Wenzel F, Thome UH (2021): Epidermal growth factor strongly affects epithelial Na+ transport and barrier function in fetal alveolar cells, with minor sex-specific effects. Sci Rep 11, 15951. doi: 10.1038/s41598-021-95410-y .
  • Laube M, Pietsch S, Pannicke T, Thome UH, Fabian C (2021): Development and Functional Characterization of Fetal Lung Organoids. Front Med 8. doi: 10.3389/fmed.2021.678438 .
  • Obendorf J, Fabian C, Thome UH, Laube M (2020). Paracrine stimulation of perinatal lung functional and structural maturation by mesenchymal stem cells. Stem Cell Res Ther 11(1):525. doi: 10.1186/s13287-020-02028-4 .
  • Lazrak A; Yu Z; Doran S; Jian MY; Creighton J; Laube M et al. (2020): Upregulation of airway smooth muscle calcium-sensing receptor by low-molecular-weight hyaluronan. Am J Physiol Lung Cell Mol Physiol 318 (3), L459-L471. doi: 10.1152/ajplung.00429.2019 .
  • Laube M, Riedel D, Ackermann B, Haase M, Thome UH (2019): Glucocorticoids Equally Stimulate Epithelial Na+ Transport in Male and Female Fetal Alveolar Cells. Int J Mol Sci 21(1): pii: E57. doi: 10.3390/ijms21010057 .
  • Bossmann M, Ackermann BW, Thome UH, Laube M (2017): Signaling Cascade Involved in Rapid Stimulation of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) by Dexamethasone. Int J Mol Sci 18(8). doi: 10.3390/ijms18081807
  • Haase M, Laube M, Thome UH (2017): Sex-specific effects of sex steroids on alveolar epithelial Na+ transport. Am J Physiol Lung Cell Mol Physiol 312(3):L405-L414. doi: 10.1152/ajplung.00275.2016
  • Laube M, Amann E, Uhlig U, Yang Y, Fuchs HW, Zemlin M, Mercier JC, Maier RF, Hummler HD, Uhlig S, Thome UH (2017): Inflammatory mediators in tracheal aspirates of preterm infants participating in a randomized trial of inhaled nitric oxide. PLoS One 12(1):e0169352. doi: 10.1371/journal.pone.0169352
  • Gentner S, Laube M, Uhlig U, Yang Y, Fuchs HW, Dreyhaupt J, Hummler HD, Uhlig S, Thome UH (2017): Inflammatory Mediators in Tracheal Aspirates of Preterm Infants Participating in a Randomized Trial of Permissive Hypercapnia. Front Pediatr. 5:246. doi: 10.3389/fped.2017.00246 .
  • Laube M, Stolzing A, Thome UH, Fabian C (2016): Therapeutic potential of mesenchymal stem cells for pulmonary complications associated with preterm birth. Int J Biochem Cell Biol 74:19-32. doi: 10.1016/j.biocel.2016.02.023 .
  • Kaltofen T, Haase M, Thome UH, Laube M (2015): Male Sex is associated with a reduced Alveolar Epithelial Sodium Transport. PLoS One 10(8):e0136178. doi: 10.1371/journal.pone.0136178
  • Laube M, Bossmann M, Thome UH (2015): Glucocorticoids distinctively modulate the CFTR channel with possible implications in lung development and transition into extrauterine life. PLoS One 10(4):e0124833. doi: 10.1371/journal.pone.0124833 .
  • Schmidt C, Klammt J, Thome UH, Laube M (2014): The interaction of glucocorticoids and progesterone distinctively affects epithelial sodium transport. Lung 192(6):935-46. doi: 10.1007/s00408-014-9640-3 .
  • Mattes C, Laube M, Thome UH (2014): Rapid elevation of sodium transport through insulin is mediated by AKT in alveolar cells. Physiol Rep 2(3) e00269. doi: 10.1002/phy2.269
  • Laube M, Kimpel SU, Dietl P, Thome UH, Wittekindt OH (2013): Benzimidazolones enhance the function of epithelial Na+ transport.  Br J Pharmacol 168:1329-1340. doi: 10.1111/bph.12027 .
  • Laube M, Küppers E, Thome UH (2011): Modulation of sodium transport in alveolar epithelial cells by estradiol and progesterone. Pediatr Res 69(3):200-205. doi:  10.1203/PDR.0b013e3182070ec8 .​

  • Marissen J, Gomez de Agüero M, Chandorkar P, Reichert L, Glaser K, Speer CP, Härtel C. The Delicate Skin of Preterm Infants: Barrier Function, Immune-Microbiome Interaction, and Clinical Implications. Neonatology. 2023 Mar 17:1-13. doi: 10.1159/000529026  . Epub ahead of print. PMID: 36934717  .
  • Glaser K, Kern D, Speer CP, Schlegel N, Schwab M, Thome UH, Härtel C, Wright CJ. Imbalanced Inflammatory Responses in Preterm and Term Cord Blood Monocytes and Expansion of the CD14+CD16+ Subset upon Toll-like Receptor Stimulation. Int J Mol Sci. 2023 Mar 3;24(5):4919. doi: 10.3390/ijms24054919 . PMID: 36902350 ; PMCID: PMC10002861.
  • Coggins SA, Glaser K. Updates in Late-Onset Sepsis: Risk Assessment, Therapy, and Outcomes. Neoreviews. 2022 Nov 1;23(11):738-755. doi: 10.1542/neo.23-10-e738 . PMID: 36316254 ; PMCID: PMC9675597.
  • Silwedel C, Hütten MC, Speer CP, Härtel C, Haarmann A, Henrich B, Tijssen MPM, Alnakhli AA, Spiller OB, Schlegel N, Seidenspinner S, Kramer BW, Glaser K. Ureaplasma-Driven Neonatal Neuroinflammation: Novel Insights from an Ovine Model. Cell Mol Neurobiol. 2023 Mar;43(2):785-795. doi: 10.1007/s10571-022-01213-8 . Epub 2022 Mar 25. PMID: 35334011 ; PMCID: PMC9957905.
  • Twisselmann N, Pagel J, Künstner A, Weckmann M, Hartz A, Glaser K, Hilgendorff A, Busch H, Weinberg J and Härtel C. Hyperoxia /hypoxia exposure primes a sustained pro-inflammatory profile of preterm infant macrophages upon LPS stimulation. Front Immunol 2021; 18 November. doi: 10.3389/fimmu.2021.762789 ​
  • Silwedel C, Speer CP, Härtel C and Glaser K. Ureaplasma-driven neuroinflammation in neonates: assembling the puzzle pieces. Neonatology 2020;117(6):665-672. doi: 10.1159/0005 12019. 
  • Silwedel C, Speer CP, Haarmann A, Fehrholz M, Claus H, Schlegel N and Glaser K. Ureaplasma species modulate cytokine and chemokine responses in human brain microvascular endothelial cells. Int J Mol Sci, 2019 July 22;20(14). pii: E3583. doi: 10.3390/ijms20143583 .
  • Silwedel C, Fehrholz M, Speer CP, Ruf KC, Manig S and Glaser K. Differential modulation of pulmonary caspases: Is this the key to Ureaplasma-driven chronic inflammation? PLoS One, 2019;14(5): e0216569. Online 2019 May 8. doi: 10.1371/journal.pone.0216569
  • ​​Silwedel C, Speer CP, Haarmann A, Fehrholz M, Claus H, Schlegel N and Glaser K. Ureaplasma species modulate cell adhesion molecules and growth factors in human brain microvascular endothelial cells. Cytokine, 2019 May 31; 121:154737. doi: 10.1016/j.cyto.2019.154737
  • Silwedel C, Fehrholz M, Speer CP, Ruf KC, Mang S and Glaser K. Modulation of caspases by Ureaplasma species: is this the key to chronic infection? PLoS One, 2019 May 8;14(5):e0216569. doi: 10.1371/journal.pone.0216569 .
  • Glaser K, Gradzka-Luczewska A, Szymankiewicz-Breborowicz M, Kawczynska-Leda N, Henrich B, Waaga-Gasser AM and Speer CP. Perinatal Ureaplasma exposure is associated with increased risk of late onset sepsis and imbalanced inflammation in preterm infants and may add to lung injury. Front Cell Infect Microbiol, 2019 Apr 2; doi: 10.3389/fcimb.2019.00068 .
  • Silwedel C, Haarmann A, Fehrholz M, Claus H, Speer CP and Glaser K. More than just inflammation: Ureaplasma species induce apoptosis in human brain microvascular endothelial cells. J Neuroinflammation, 2019 Feb 14;16(1):38. doi: 10.1186/s12974-019-1413-8 .
  • Silwedel C, Speer CP, Haarmann A, Fehrholz M, Claus H, Buttmann M and Glaser K. Novel insights into neuroinflammation: bacterial lipopolysaccharide, tumor necrosis factor α, and Ureaplasma species differentially modulate atypical chemokine receptor 3 responses in human brain microvascular endothelial cells. J Neuroinflammation, 2018 May 23;15(1):156. doi: 10.1186/s12974-018-1170-0 .
  • Glaser K, Silwedel C, Fehrholz M, Henrich B, Waaga-Gasser AM, Henrich B, Claus H and Speer CP. Ureaplasma species differentially modulate growth factors and cell adhesion molecules in neonatal and adult monocytes. Cytokine, 2018 May;105:45-48. doi: 10.1016/j.cyto.2018.01.026 .​
  • ​Glaser K, Silwedel C, Fehrholz M, Henrich B, Waaga-Gasser AM, Claus H and Speer CP. Ureaplasma isolates induce pro-inflammatory CC chemokines and matrix metalloproteinase-9 in neonatal and adult monocytes. PLoS One, 2018 Mar 20;13(3):e0194514. doi:10.1371/journal.pone.0194514 .
  • Glaser K, Silwedel C, Fehrholz M, Waaga-Gasser AM, Henrich B, Claus H and Speer CP. Ureaplasma species differentially modulate pro- and anti-inflammatory cytokine responses in newborn and adult human monocytes pushing the state toward pro-inflammation. Front Cell Infect Microbiol, 2017 Nov 28, 7:484. doi.org/10.3389/fcimb.2017.00484 .
  • Silwedel C, Speer CP and Glaser K. Ureaplasma-associated prenatal, perinatal, and neonatal morbidities. Expert Rev Clin Immunol. 2017 Sep 23:1-15. doi: 10.1080/1744666X.2017.1381559 .
  • Glaser K, Fehrholz M, Henrich B, Claus H, Papsdorf M and Speer CP. Anti-inflammatory effects of the new generation synthetic surfactant CHF5633 on Ureaplasma-induced cytokine responses in human monocytes. Expert Rev Anti Infect Ther, 2017 Feb;15(2):181-89. doi:10.1080/14787210.2017.1259067 .
  • Glaser K and Speer CP. Neonatal CNS infection and inflammation caused by Ureaplasma species: rare or relevant? Expert Rev Anti Infect Ther. 2015 Feb; 13(2):233-48. doi:10.1586/14787210.2015.999670.
  • Glaser K and Speer CP. Toll-like receptor signaling in neonatal sepsis and inflammation: a matter of orchestration and conditioning. Expert Rev Clin Immunol. 2013 Dec;9(12):1239-52. doi:10.1586/1744666X.2013.857275.​

Funding

  • ​Roland Ernst Stiftung für Gesundheitswesen 2023/2025​
  • Deutsche Forschungsgemeinschaft 2022/2023​
  • Roland Ernst Stiftung für Gesundheitswesen 2022/2024​
  • Sächsische Aufbaubank 2018/2020​​
  • Roland Ernst Stiftung für Gesundheitswesen 2017/2018
  • Nachwuchsförderung der Medizinischen Fakultät 2013/2014​

Group members

​Current:

  • Prof. Dr. med. Ulrich H. Thome (PI)
  • Priv.-Doz.​ Dr. rer. nat. habil. Mandy Laube (Group Leader)
  • Priv.-Doz. Dr. med. Kirsten Glaser (Physician)
  • Emmi Schneider (Ph.D. Student)​
  • Daniela Ulrich (Medical Student)​
  • Tabea Peukert (Medical Student)​

Former:

  • ​Carolin Schmidt (Medical Student)
  • Charlott Mattes (Medical Student)
  • Juliane Lutze (Medical Student)
  • Till Kaltofen (Medical Student)
  • Miriam Bossmann (Medical Student)
  • Melanie Haase (Medical Student)
  • Fine Wenzel (Medical Student)
  • Dr. rer. nat. Diana Riedel (Research Scientist)
  • Janine Obendorf (Ph.D. Student)
  • Dr. rer. nat. Thomas Pannicke (Post-Doc)
  • Corinna Leibl (Medical Student)
  • Maxi Klemm (Medical Student)
  • Jule Marie Dittmer (Medical Student)
  • Carl-Bernd Rieger (Medical Student)​
  • Chiara Becattini (Research Technician)
  • Elisabeth Paluszkiewicz (Medical Student)
  • Jasmin Malle (Medical Student)
  • Jessica Löffler (Research Technician)​

Contact

​PD Dr. rer. nat. habil. Mandy Laube

Center for Pediatric Research Leipzig (CPL)
Division of Neonatology
Liebigstr. 21
04103 Leipzig
 
Phone: 0341 - 97 20988
E-Mail: mandy.laube@medizin.uni-leipzig.de​

Job Offer


Liebigstraße 20a, Haus 6
04103 Leipzig
Telefon:
0341 - 97 26020
Fax:
0341 - 97 23579
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