Molecular Programming of Lung Disease (MPLD)

Experimentelle Pneumologie

Perinatal Programming defines the process by which environmental factors, such as oxygen mechanical ventilation or nutrition, determine the long-term physiology, structure and function of an organ. Lung development begins during fetal period and alveolarization, the final stage, extends into young adulthood, resulting in formation of alveoli and expansion of the lung surface. Our research group Translational Experimental Pediatrics – Experimental Pulmonology focusses on the impact of mechanical ventilation and oxygen as well as maternal obesity on the early origin of lung disease.

  • Bronchopulmonary Dysplasia (BPD) affects more than 20% of preterm born infants and leads to long-term pulmonary changes persisting beyond adolescence. While oxygen supply, mechanical ventilation and nutritive support offer life-saving treatments to these patients, they also disrupt crucial processes in lung development and induce perinatal Programming of lung diseases. CLD is characterized by defective formation of alveoli, bronchi and micro-vessels coupled with fibroproliferative processes. The molecular mechanisms directing alveolarization and pulmonary angiogenesis, however, to promote regeneration and develop preventive/therapeutic strategies remain elusive.
  • Childhood obesity is a growing health and socioeconomic problem. Prior studies of our group have shown that early postnatal overweight is intimately linked with an asthma-like phenotype. Metabolic influences, e.g. maternal obesity, during a critical window of lung development can lead to long-term impaired lung structure and function, predisposing for chronic lung diseases, such as bronchial asthma (metabolic programming). Our group is currently investigating the impact of maternal obesity on the origin of bronchial asthma and the crosstalk of adipose tissue and lung.

The overall objective of the Alcazar Lab is to investigate the molecular mechanisms that direct normal lung development and to elucidate novel signal mediators regulating lung growth and regenerative capacity.

To this end, we not only use experimental animal models of dietary intervention (e.g. high fat diet) and neonatal hyperoxia, but also a unique animal model of mechanical ventilation-induced lung injury of the newborn mouse, established in collaboration with Prof. Richard Bland (Stanford University), a pioneer in neonatal CLD, and lung function testing. Primary cell culture serves as an in vitro model to study the impact of hyperoxia and cell stretch on important signaling pathways regulating survival and differentiation of cells. To achieve a translation and improve the clinical outcome of children we established a close collaboration with the Department of Pulmonology and the Department of Neonatology.

With our research we not only aim to get a profound understanding of the mechanisms that drive lung growth and are disrupted in CLD, but also to develop novel strategies to improve the clinical management of preterm infants.

Current projects

Mechanisms and therapeutic strategies to treat bronchopulmonary dysplasia (BPD)

  • Molecular mechanisms of alveolar and microvascular formation in ventilation- and oxygen-induced neonatal lung injury
  • Maintenance  of  the alveolar regenerative after acute lung injury
  • Identification of novel therapeutic approaches to treat BPD

Perinatal metabolic origin of lung disease

  • Maternal obesity and metabolic programming of lung structure and function
  • Impact of metabolism on the pathogenesis of cardiopulmonary and renal diseases

The Team

Jun.-Prof. Dr. Dr. nat. med. Miguel A. Alejandre Alcázar

Centina Kuiper-Makris, M.D.
Dr. med. Robert Körner
Dr. nat. med. Jasmine Mohr
Dr. rer. nat. Jaco Selle
Jan-Christoph Thomassen
Dharmesh Hirani, M.Sc., Ph.D. Student
Vanessa Jentgen, cand. vet. med.
Rebecca Brückner, Studienassistenz, KIRA-Studie [Deutsches Zentrum für Lungenforschung (DZL)]
Christina Vohlen, Biologielaborantin
Rebecca Wilke, Biologisch technische Assisistentin

Publications since 2012

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

Fischer J, Balleisen J, Holzki J, Cernaianu G, Alejandre Alcazar M, Dubbers M (2019) Tracheoscopic Findings and Their Impact on Respiratory Symptoms in Children with Esophageal Atresia. Eur J Pediatr Surg. doi:10.1055/s-0039-1683871

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

Dinger K, Mohr J, Vohlen C, Hirani D, Hucklenbruch-Rother E, Ensenauer R, Dotsch J, Alejandre Alcazar MA (2018) Intraperitoneal Glucose Tolerance Test, Measurement of Lung Function, and Fixation of the Lung to Study the Impact of Obesity and Impaired Metabolism on Pulmonary Outcomes. J Vis Exp (133). doi:10.3791/56685

Thomassen JC, Mueller MI, Alejandre Alcazar MA, Rietschel E, van Koningsbruggen-Rietschel S (2018) Effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in Phe508del homozygous cystic fibrosis patients. J Cyst Fibros 17 (2):271-275. doi:10.1016/j.jcf.2017.11.016

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

Ferrari N, Bae-Gartz I, Bauer C, Janoschek R, Koxholt I, Mahabir E, Appel S, Alejandre Alcazar MA, Grossmann N, Vohlen C, Brockmeier K, Dotsch J, Hucklenbruch-Rother E, Graf C (2018) Exercise during pregnancy and its impact on mothers and offspring in humans and mice. J Dev Orig Health Dis 9 (1):63-76. doi:10.1017/S2040174417000617

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

Dinger K, Kasper P, Hucklenbruch-Rother E, Vohlen C, Jobst E, Janoschek R, Bae-Gartz I, van Koningsbruggen-Rietschel S, Plank C, Dotsch J, Alejandre Alcazar MA (2016) Early-onset obesity dysregulates pulmonary adipocytokine/insulin signaling and induces asthma-like disease in mice. Sci Rep 6:24168. doi:10.1038/srep24168

Dotsch J, Alejandre-Alcazar M, Janoschek R, Nusken E, Weber LT, Nusken KD (2016) Perinatal programming of renal function. Curr Opin Pediatr 28 (2):188-194. doi:10.1097/MOP.0000000000000312

Janoschek R, Bae-Gartz I, Vohlen C, Alcazar MA, Dinger K, Appel S, Dotsch J, Hucklenbruch-Rother E (2016) Dietary intervention in obese dams protects male offspring from WAT induction of TRPV4, adiposity, and hyperinsulinemia. Obesity (Silver Spring) 24 (6):1266-1273. doi:10.1002/oby.21486

Bae-Gartz I, Janoschek R, Kloppe CS, Vohlen C, Roels F, Oberthur A, Alejandre Alcazar MA, Lippach G, Muether PS, Dinger K, Ferrari N, Graf C, Dotsch J, Hucklenbruch-Rother E (2015) Running Exercise in Obese Pregnancies Prevents IL-6 Trans-signaling in Male Offspring. Med Sci Sports Exerc. doi:10.1249/MSS.0000000000000835

Diebold I, Hennigs JK, Miyagawa K, Li CG, Nickel NP, Kaschwich M, Cao A, Wang L, Reddy S, Chen PI, Nakahira K, Alcazar MA, Hopper RK, Ji L, Feldman BJ, Rabinovitch M (2015) BMPR2 preserves mitochondrial function and DNA during reoxygenation to promote endothelial cell survival and reverse pulmonary hypertension. Cell Metab 21 (4):596-608. doi:10.1016/j.cmet.2015.03.010

Hilgendorff A, Parai K, Ertsey R, Navarro E, Jain N, Carandang F, Peterson J, Mokres L, Milla C, Preuss S, Alcazar MA, Khan S, Masumi J, Ferreira-Tojais N, Mujahid S, Starcher B, Rabinovitch M, Bland R (2015) Lung matrix and vascular remodeling in mechanically ventilated elastin haploinsufficient newborn mice. Am J Physiol Lung Cell Mol Physiol 308 (5):L464-478. doi:10.1152/ajplung.00278.2014 ajplung.00278.2014 [pii]

Alcazar MA, Dinger K, Rother E, Ostreicher I, Vohlen C, Plank C, Dotsch J (2014) Prevention of early postnatal hyperalimentation protects against activation of transforming growth factor-beta/bone morphogenetic protein and interleukin-6 signaling in rat lungs after intrauterine growth restriction. J Nutr 144 (12):1943-1951. doi:10.3945/jn.114.197657jn.114.197657 [pii]

Appel S, Turnwald EM, Ankerne J, Wohlfarth M, Appel J, Rother E, Janoschek R, Alejandre Alcazar MA, Schnare M, Meissner U, Dotsch J (2015) Hypoxia-Mediated Soluble Fms-Like Tyrosine Kinase 1 Increase Is Not Attenuated in Interleukin 6-Deficient Mice. Reprod Sci 22 (6):735-742. doi:10.1177/1933719114557898

Appel S, Turnwald EM, Alejandre-Alcazar MA, Ankerne J, Rother E, Janoschek R, Wohlfarth M, Vohlen C, Schnare M, Meissner U, and Dotsch J (2014) Leptin does not induce an inflammatory response in the murine placenta. Horm Metab Res 46: 384-389.

Appel S, Turnwald EM, Alejandre-Alcazar MA, Ankerne J, Rother E, Janoschek R, Wohlfarth M, Vohlen C, Schnare M, Meissner U, Dotsch J (2014) Leptin does not induce an inflammatory response in the murine placenta. Horm Metab Res 46 (6):384-389. doi:10.1055/s-0034-1368710

Lartey FM, Ahn GO, Ali R, Rosenblum S, Miao Z, Arksey N, Shen B, Colomer MV, Rafat M, Liu H, Alejandre-Alcazar MA, Chen JW, Palmer T, Chin FT, Guzman R, Loo BW, Jr., Graves E (2014) The relationship between serial [(18) F]PBR06 PET imaging of microglial activation and motor function following stroke in mice. Mol Imaging Biol 16 (6):821-829. doi:10.1007/s11307-014-0745-0

Alejandre Alcazar MA, Ostreicher I, Appel S, Rother E, Vohlen C, Plank C, and Dotsch J. Developmental regulation of inflammatory cytokine-mediated Stat3 signaling: the missing link between intrauterine growth restriction and pulmonary dysfunction? J Mol Med (Berl) 90: 945-957, 2012.

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