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.

Our Team

Dr. med. Dr. nat. med. Miguel A. Alejandre Alcazar, leader
E-Mail miguel.alejandre-alcazar@uk-koeln.de

Dr. vet. med. Katharina Dinger
Dr. Philipp Kasper
Celien Kulper, M.D.
Dr. Nava Mehdiani
Dr. Jan-Christoph Thomassen
Christina Vohlen, Technische Assistentin
Dharmesh Hirani, M.Sc., Ph.D. Student
Jasmine Mohr, M.Sc., Ph.D. Student

Current projects

  1. Maternal obesity and Perinatal Programming of lung structure and function in the offspring
  2. Role of Inflammation in normal alveolarization and neonatal lung injury
  3. Mechanisms regulating cell survival and alveolarization during mechanical ventilation of newborn mice
  4. Effects of maternal obesity on the developmental origins of cardiovascular diseases in the offspring
Publications

Alejandre Alcázar MA, Dinger K, Vohlen C, Rother E, Plank C, Dötsch J. Prevention of postnatal hyperalimentation protects against disrupted TGF-β and IL-6 signaling in Lungs after IUGR. J Nutr. 2014

Appel S, Turnwald EM, Alejandre Alcazar MA, Ankerne J, Rother E, Kuschewski R, Wohlfarth M, Schnare M, Meissner U, Dötsch, J. Leptin does not induce a preeclampsia-like inflammatory response in the murine placenta. Horm Metab Res, 2014

Alejandre Alcázar MA, Östreicher I, Appel S, Rother E, Vohlen C, Plank C, Dötsch J. Developmental regulation of Stat3-mediated inflammation: the missing link between intrauterine growth restriction and pulmonary dysfunction? J Mol Med, 2012

Alejandre-Alcázar MA, Boehler E, Rother E, Amann K, von Hörsten S, Plank C, Dötsch J. Early postnatal hyperalimentation leads to impaired renal function partially via renal postreceptor leptin resistance, Endocrinology, 2012

Rother E, Kuschewski R, Alejandre Alcázar MA, Oberthuer A, Bae-Gartz I, Vohlen C, Roth B, Dötsch J, Hypothalamic JNK1 and IKKβ Activation and Impaired Early Postnatal Glucose Metabolism after Maternal Perinatal High-Fat Feeding, Endocrinology. 2012

Alejandre Alcázar MA, Morty RE, Lendzian L, Vohlen C, Oestreicher I, Plank C, Schneider H, Dötsch J. Inhibition of TGF-β Signaling and Decreased Apoptosis in IUGR-Associated Lung Disease in Rats, PLoS One, 2011

Alejandre Alcázar MA, Boehler E, Amann K, Klaffenbach D, Hartner A, Allabauer I, Wagner L., v. Hörsten S., Plank C., Dötsch J. Persistent changes within the intrinsic kidney-associated NPY system and tubular function by litter size reduction,  Nephrol Dial Transplant, 2011

Alejandre Alcázar MA, Michiels-Corsten M, Vicencio AG, Reiss I, Ryu J, de Krijger RR, Haddad GG, Tibboel D, Seeger W, Eickelberg O, Morty RE. TGF-beta signaling is dynamically regulated during the alveolarization of rodent and human lungs, Dev Dyn, 2008

Alejandre Alcázar MA, Shalamanov PD, Amarie OV, Sevilla-Pérez J, Seeger W, Eickelberg O, Morty RE. Temporal and spatial regulation of bone morphogenetic protein signaling in late lung development, Dev Dyn, 2007

Alejandre Alcázar MA
, Kwapiszewska G, Reiss I, Amarie OV, Marsh LM, Sevilla-Pérez J, Wygrecka M, Eul B, Köbrich S, Hesse M, Shermuly RT, Seeger W, Eickelberg O, Morty RE. Hyperoxia modulates TGF-β/BMP signaling in the neonatal lung: implications for the pathogenesis of bronchopulmonary dysplasia, Am J Physiol Lung Cell Mol Physiol, 2007

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