Molecular Programming of Lung Disease (MPLD)
The concept of perinatal programming states that influences during a sensitive window of development have long-term effects on lung structure and function and predispose to chronic lung disease later in life.
The Alcázar research group aims to understand how antenatal, perinatal, and postnatal influences can adversely affect metabolism and lung development and determine the susceptibility for chronic lung diseases later in life. The overall goal is the identification of novel converging signaling nodes to develop new preventive and therapeutic strategies to preserve physiological alveolarization, promote lung health and prevent the early origins of chronic lung diseases.
Based on our previous studies, we focus on the following two major research areas:
- Mechanical ventilation and oxygen administration, although life-saving measures in preterm infants, induce a chronic lung disease known as bronchopulmonary dysplasia (BPD). Lungs of infants with BPD are characterized reduced alveolar and microvascular formation and fibroproliferative processes. BPD affects more than 30% of preterm infants and is a risk factor for later development of emphysema, COPD or pulmonary arterial hypertension.
- Obesity is a steadily increasing health as well as socioeconomic problem. We have shown that early postnatal obesity affects lung development and leads to chronic bronchial obstruction and pulmonary hypertension. Disturbed metabolic influences, as present in maternal obesity, have been identified as a risk factor for these lung changes (metabolic programming). Current studies focus on the influence of maternal obesity on lung development and the inter-organ communication between adipose tissue and the lung.
Our research focuses on the investigation of molecular mechanisms controlling alveolarization, bronchogenesis and pulmonary angiogenesis. We aim to uncover novel signaling pathways that induce perinatal (metabolic) programming of chronic lung diseases in order to develop preventive and therapeutic strategies.
For this purpose, the Alcázar lab has established several neonatal animal models, including hyperoxia- and ventilation induced lung injury, intrauterine growth restriction and perinatal obesity, along with transgenic animal models and perinatal therapeutic approaches. These in vivo models are complemented by functional and structural analyses of the lung, ex vivo models (e.g. precision cut lung slices), transcriptomic, proteomic and metabolic analyses as well as a variety of state-of-the art molecular biology techniques in vitro.
Mechanisms and therapy of bronchopulmonary dysplasia (BPD)
- Molecular mechanisms of alveolarization and angiogenesis in ventilation- and oxygen-induced lung injury of the newborn mouse
- Alveolar regeneration after acute lung injury
- Identification of novel therapeutic approaches for the treatment of BPD
Perinatal metabolic origin of chronic lung disease
- Maternal obesity and metabolic programming of lung structure and function
- Role of metabolic influences on the pathogenesis of cardiopulmonary and renal diseases
Trojan, T., M. A. Alejandre Alcazar, G. Fink, J. C. Thomassen, M. V. Maessenhausen, E. Rietschel, P. M. Schneider and S. van Koningsbruggen-Rietschel (2022). "The effect of TGF-β(1) polymorphisms on pulmonary disease progression in patients with cystic fibrosis." BMC Pulm Med 22(1): 183.
Selle, J., K. Dinger, V. Jentgen, D. Zanetti, J. Will, T. Georgomanolis, C. Vohlen, R. Wilke, B. Kojonazarov, O. Klymenko, J. Mohr, V. K.-R. S, C. J. Rhodes, A. Ulrich, D. Hirani, T. Nestler, M. Odenthal, E. Mahabir, S. Nayakanti, S. Dabral, T. Wunderlich, J. Priest, W. Seeger, J. Dötsch, S. S. Pullamsetti and M. A. Alejandre Alcazar (2022). "Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life." Nat Commun 13(1): 4352.
Obst, S., J. Herz, M. A. Alejandre Alcazar, S. Endesfelder, M. A. Möbius, M. Rüdiger, U. Felderhoff-Müser and I. Bendix (2022). "Perinatal Hyperoxia and Developmental Consequences on the Lung-Brain Axis." Oxid Med Cell Longev 2022: 5784146
Hirani, D., C. M. Alvira, S. Danopoulos, C. Milla, M. Donato, L. Tian, J. Mohr, K. Dinger, C. Vohlen, J. Selle, V. K.-R. S, V. Barbarino, C. Pallasch, S. Rose-John, M. Odenthal, G. S. Pryhuber, S. Mansouri, R. Savai, W. Seeger, P. Khatri, D. Al Alam, J. Dötsch and M. A. Alejandre Alcazar (2022). "Macrophage-derived IL-6 trans-signalling as a novel target in the pathogenesis of bronchopulmonary dysplasia." Eur Respir J 59(2).
Vohlen, C., J. Mohr, A. Fomenko, C. Kuiper-Makris, T. Grzembke, R. Aydogmus, R. Wilke, D. Hirani, J. Dötsch and M. A. Alejandre Alcazar (2021). "Dynamic Regulation of GH-IGF1 Signaling in Injury and Recovery in Hyperoxia-Induced Neonatal Lung Injury." Cells 10(11).
Kasper, P., S. Breuer, T. Hoffmann, C. Vohlen, R. Janoschek, L. Schmitz, S. Appel, G. Fink, C. Hünseler, A. Quaas, M. Demir, S. Lang, H. M. Steffen, A. Martin, C. Schramm, M. Bürger, E. Mahabir, T. Goeser, J. Dötsch, E. Hucklenbruch-Rother and I. Bae-Gartz (2021). "Maternal Exercise Mediates Hepatic Metabolic Programming via Activation of AMPK-PGC1α Axis in the Offspring of Obese Mothers." Cells 10(5).
Breuer, S., P. Kasper, C. Vohlen, R. Janoschek, T. Hoffmann, S. Appel, E. Müller-Limberger, A. Mesaros, S. Rose-John, C. Garbers, S. Müller, J. W. Lackmann, E. Mahabir, J. Dötsch, E. Hucklenbruch-Rother and I. Bae-Gartz (2021). "Brain-Restricted Inhibition of IL-6 Trans-Signaling Mildly Affects Metabolic Consequences of Maternal Obesity in Male Offspring." Nutrients 13(11).
Thomassen, J. C., T. Trojan, M. Walz, C. Vohlen, G. Fink, E. Rietschel, M. A. Alejandre Alcazar and S. van Koningsbruggen-Rietschel (2021). "Reduced neutrophil elastase inhibitor elafin and elevated transforming growth factor-β(1) are linked to inflammatory response in sputum of cystic fibrosis patients with Pseudomonas aeruginosa." ERJ Open Res 7(3).
Kuiper-Makris, C., D. Zanetti, C. Vohlen, L. Fahle, M. Müller, M. Odenthal, U. Felderhoff-Müser, J. Dötsch and M. A. Alejandre Alcazar (2020). "Mendelian randomization and experimental IUGR reveal the adverse effect of low birth weight on lung structure and function." Sci Rep 10(1): 22395.
Bae-Gartz, I., P. Kasper, N. Großmann, S. Breuer, R. Janoschek, T. Kretschmer, S. Appel, L. Schmitz, C. Vohlen, A. Quaas, M. R. Schweiger, C. Grimm, A. Fischer, N. Ferrari, C. Graf, C. K. Frese, S. Lang, M. Demir, C. Schramm, G. Fink, T. Goeser, J. Dötsch and E. Hucklenbruch-Rother (2020). "Maternal exercise conveys protection against NAFLD in the offspring via hepatic metabolic programming." Sci Rep 10(1): 15424.
Ubags, N. D. J., M. A. Alejandre Alcazar, S. G. Kallapur, S. Knapp, S. Lanone, C. M. Lloyd, R. E. Morty, C. Pattaroni, N. L. Reynaert, R. J. Rottier, H. H. Smits, W. A. A. de Steenhuijsen Piters, D. H. Strickland and J. J. P. Collins (2020). "Early origins of lung disease: towards an interdisciplinary approach." Eur Respir Rev 29(157).
Polányi, L., C. M. Niessen, C. Vohlen, J. Stinn, T. Kretschmer, V. Jentgen, D. Hirani, S. V. Koningsbruggen-Rietschel, J. Dötsch and M. A. Alejandre Alcazar (2020). "Intrauterine growth restriction induces skin inflammation, increases TSLP and impairs epidermal barrier function." J Mol Med (Berl) 98(2): 279-289.
Litzenburger, T., E. K. Huber, K. Dinger, R. Wilke, C. Vohlen, J. Selle, M. Kadah, T. Persigehl, C. Heneweer, J. Dötsch and M. A. Alejandre Alcazar (2020). "Maternal high-fat diet induces long-term obesity with sex-dependent metabolic programming of adipocyte differentiation, hypertrophy and dysfunction in the offspring." Clin Sci (Lond) 134(7): 921-939.
Kuiper-Makris, C., J. Selle, E. Nüsken, J. Dötsch and M. A. Alejandre Alcazar (2021). "Perinatal Nutritional and Metabolic Pathways: Early Origins of Chronic Lung Diseases." Front Med (Lausanne) 8: 667315.
Dinger, K., S. V. Koningsbruggen-Rietschel, J. Dötsch and M. A. Alejandre Alcazar (2020). "Identification of Critical Windows of Metabolic Programming of Metabolism and Lung Function in Male Offspring of Obese Dams." Clin Transl Sci 13(6): 1065-1070.
Bae-Gartz, I., R. Janoschek, S. Breuer, L. Schmitz, T. Hoffmann, N. Ferrari, L. Branik, A. Oberthuer, C. S. Kloppe, S. Appel, C. Vohlen, J. Dötsch and E. Hucklenbruch-Rother (2019). "Maternal Obesity Alters Neurotrophin-Associated MAPK Signaling in the Hypothalamus of Male Mouse Offspring." Front Neurosci 13: 962.
Will JP, Hirani DV, Thielen F, Klein F, Vohlen C, Dinger K, Dotsch J, Alejandre-Alcazar MA (2019) Strain-dependent effects on lung structure, matrix remodeling and Stat3/Smad2 signaling in C57BL/6N and C57BL/6J mice after neonatal hyperoxia. Am J Physiol Regul Integr Comp Physiol. doi:10.1152/ajpregu.00286.2018
Mohr J, Voggel J, Vohlen C, Dinger K, Dafinger C, Fink G, Gobel H, Liebau MC, Dotsch J, Alejandre Alcazar MA (2019) IL-6/Smad2 signaling mediates acute kidney injury and regeneration in a murine model of neonatal hyperoxia. FASEB J:fj201801875RR. doi:10.1096/fj.201801875RR
Nawabi J, Vohlen C, Dinger K, Thangaratnarajah C, Klaudt C, Lopez Garcia E, Hirani DV, Haznedar-Karakaya P, Macheleidt I, Odenthal M, Nusken KD, Dotsch J, Alejandre Alcazar MA (2018) Novel functional role of GH/IGF1 in neonatal lung myofibroblasts and in rat lung growth after intrauterine growth restriction. Am J Physiol Lung Cell Mol Physiol. doi:10.1152/ajplung.00413.2017
Alejandre Alcazar MA, Kaschwich M, Ertsey R, Preuss S, Milla C, Mujahid S, Masumi J, Khan S, Mokres LM, Tian L, Mohr J, Hirani DV, Rabinovitch M, Bland RD (2018) Elafin treatment rescues EGFR-Klf4 signaling and lung cell survival in ventilated newborn mice. Am J Respir Cell Mol Biol. doi:10.1165/rcmb.2017-0332OC
Kasper P, Vohlen C, Dinger K, Mohr J, Hucklenbruch-Rother E, Janoschek R, Koth J, Matthes J, Appel S, Dotsch J, Alejandre Alcazar MA (2017) Renal Metabolic Programming Is Linked to the Dynamic Regulation of a Leptin-Klf15 Axis and Akt/AMPKalpha Signaling in Male Offspring of Obese Dams. Endocrinology 158 (10):3399-3415. doi:10.1210/en.2017-00489
Bultmann-Mellin I, Dinger K, Debuschewitz C, Loewe KMA, Melcher Y, Plum MTW, Appel S, Rappl G, Willenborg S, Schauss AC, Jungst C, Kruger M, Dressler S, Nakamura T, Wempe F, Alejandre Alcazar MA, Sterner-Kock A (2017) Role of LTBP-4 in alveolarization, angiogenesis and fibrosis in lungs. Am J Physiol Lung Cell Mol Physiol:ajplung 00031 02017. doi:10.1152/ajplung.00031.2017
Tojais NF, Cao A, Lai YJ, Wang L, Chen PI, Alcazar MAA, de Jesus Perez VA, Hopper RK, Rhodes CJ, Bill MA, Sakai LY, Rabinovitch M (2017) Codependence of Bone Morphogenetic Protein Receptor 2 and Transforming Growth Factor-beta in Elastic Fiber Assembly and Its Perturbation in Pulmonary Arterial Hypertension. Arterioscler Thromb Vasc Biol 37 (8):1559-1569. doi:10.1161/ATVBAHA.117.309696
Thangaratnarajah C, Dinger K, Vohlen C, Klaudt C, Nawabi J, Lopez Garcia E, Kwapiszewska G, Dobner J, Nuesken KD, van Koningsbruggen-Rietschel S, von Hoersten S, Dotsch J, Alejandre Alcazar MA (2017) Novel role of NPY in neuro-immune interaction and lung growth after intrauterine growth restriction. Am J Physiol Lung Cell Mol Physiol:ajplung 00432 02016. doi:10.1152/ajplung.00432.2016
The Team
Project coordinator
Dr. rer. nat. Ruth Janoschek
Junior workgroup leader
Dr. med. Inga Bae-Gartz
Postdoctoral Fellows (PhD)
Dr. rer. nat. Dharmesh Hirani
Dr. med. Philipp Kasper
Ivana Mižik, PhD
Dr. med. Laura Oberholz
Dr. med. Tobias Trojan
Dr. rer. nat. Jaco Selle
Dr. med. Centina Kuiper-Makris
Technical assistance
Christina Vohlen (biology lab technician)
Rebecca Wilke (biol. techn. assistant)
Students
Christoph Bartz
Clemens Nies
Jill Cornelius
Fabian Brähler
Samantha Krug
