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Hilgendorff Lab

Mechanism of Neonatal Chronic Lung Disease

The development of chronic lung disease in the neonate, also described as Bronchopulmonary Dysplasia (BPD), affects more than 30% of all infants born with a functionally and structurally immature lung. Our aim is a profound understanding of the molecular mechanisms induced by pre- and postnatal injury that result in sustained changes to the gas exchange area.

The development of chronic lung disease in the neonate, also described as Bronchopulmonary Dysplasia (BPD), affects more than 30% of all infants born with a functionally and structurally immature lung. Our aim is a profound understanding of the molecular mechanisms induced by pre- and postnatal injury that result in sustained changes to the gas exchange area.

About our Research

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To understand the induction of injury and subsequent onset of chronic disease in the developing lung, we investigate the impact of shear stress, oxygen and other toxins on alveolar and vascular development using unique preclinical models. We focus on aberrant growth factor signaling in the context of lung development and translate our findings into clinical studies for the development of diagnostic tools and exploration of treatment strategies We address across-organ morbidity to evaluate the lung as a driver of these complications. 

The development of chronic lung disease in the neonate, also described as Bronchopulmonary Dysplasia (BPD), affects more than 30% of all infants born with a functionally and structurally immature lung. While mechanical ventilation (MV) and oxygen therapy offer live saving support after birth, they significantly contribute to disease development in this patent population at the same time.

The significant changes that characterize the disease include extensive remodeling of the extracellular matrix and sustained inflammatory changes, ultimately resulting in the formation of a simplified and dysmorphic gas exchange area. Despite the clinical significance, a profound understanding of the molecular mechanisms underlying the structural changes is still missing. Here, the need to interpret the complex interplay of deregulated growth factor signaling beyond the background organ development render this task especially challenging.

Clinically, markers that allow for the early postnatal prediction of BPD development are urgently needed, as the diagnostic process solely relies on clinical parameters derived from end-stage pulmonary function.  

 

Our aim is a profound understanding of the molecular mechanisms induced by pre- and postnatal injury that result in sustained changes to the gas exchange area with a focus on alveolar septation and vessel formation. We design our in vivo and in vitro models to closely mimic clinical conditions and further translate our findings by the use of our unique clinical cohort. In the AIRR (Attention to Infants at Respiratory Risks) cohort, deep-phenotyping of very immature preterm infants and term neonates with chronic lung disease include imaging strategies and lung function testing and is paired with multi-omics and AI strategies, enabling the development of new diagnostic tools for tomorrow`s clinical care. Future steps include the development of a clinical test for the biomarkers identified (patent filed) and a clinical study to implement them into clinical use.

In close collaboration within the Comprehensive Pneumology Center (CPC) and the German Center for Lung Research (DZL), we furthermore engage our knowledge in understanding adult forms of chronic lung disease that share the pattern of emphysematous changes and interstitial fibroproliferation.

To understand the induction of injury and subsequent onset of chronic disease in the developing lung, we investigate the impact of shear stress, oxygen and other toxins on alveolar and vascular development using unique preclinical models. We focus on aberrant growth factor signaling in the context of lung development and translate our findings into clinical studies for the development of diagnostic tools and exploration of treatment strategies We address across-organ morbidity to evaluate the lung as a driver of these complications. 

The development of chronic lung disease in the neonate, also described as Bronchopulmonary Dysplasia (BPD), affects more than 30% of all infants born with a functionally and structurally immature lung. While mechanical ventilation (MV) and oxygen therapy offer live saving support after birth, they significantly contribute to disease development in this patent population at the same time.

The significant changes that characterize the disease include extensive remodeling of the extracellular matrix and sustained inflammatory changes, ultimately resulting in the formation of a simplified and dysmorphic gas exchange area. Despite the clinical significance, a profound understanding of the molecular mechanisms underlying the structural changes is still missing. Here, the need to interpret the complex interplay of deregulated growth factor signaling beyond the background organ development render this task especially challenging.

Clinically, markers that allow for the early postnatal prediction of BPD development are urgently needed, as the diagnostic process solely relies on clinical parameters derived from end-stage pulmonary function.  

 

Our aim is a profound understanding of the molecular mechanisms induced by pre- and postnatal injury that result in sustained changes to the gas exchange area with a focus on alveolar septation and vessel formation. We design our in vivo and in vitro models to closely mimic clinical conditions and further translate our findings by the use of our unique clinical cohort. In the AIRR (Attention to Infants at Respiratory Risks) cohort, deep-phenotyping of very immature preterm infants and term neonates with chronic lung disease include imaging strategies and lung function testing and is paired with multi-omics and AI strategies, enabling the development of new diagnostic tools for tomorrow`s clinical care. Future steps include the development of a clinical test for the biomarkers identified (patent filed) and a clinical study to implement them into clinical use.

In close collaboration within the Comprehensive Pneumology Center (CPC) and the German Center for Lung Research (DZL), we furthermore engage our knowledge in understanding adult forms of chronic lung disease that share the pattern of emphysematous changes and interstitial fibroproliferation.

Scientists at Hilgendorff Lab

Friederike Häfner

Doctoral Student (PhD)

Dr. Motaharehsadat Heydarian

Postdoctoral Fellow

Susanne Mehring

Technical Assistant

Aakruti Nayak

PhD Student

Elisabeth Schindler

Lab Manager

Dr. Inga Meincke

Research Assistant & Communication

Publications

2022, Scientific Article in American Journal of Physiology - Lung Cellular and Molecular Physiology

MRI based scoring of the diseased lung in the preterm infant with BPD.

OBJECTIVE: Neonatal chronic lung disease lacks standardised assessment of lung structural changes. METHOD AND RESULTS: We addressed this clinical need by the development of a novel scoring system (UNSEAL BPD (UNiforme Scoring of the disEAsed Lung in BPD)) using T2-weighted single-shot fast-spin-echo sequences from 3T MRI in very premature infants with and without bronchopulmonary dysplasia (BPD). Quantification of interstitial and airway remodeling, emphysematous changes and ventilation inhomogeneity was achieved by consensus scoring on a 5-point Likert scale. We successfully identified moderate and severe disease by logistic regression (AUC 0.89) complemented by classification tree analysis revealing gestational age-specific structural changes. We demonstrated substantial inter-reader reproducibility (weighted Cohen's kappa 0.69) and disease specificity (AUC=0.91). CONCLUSION: Our novel MRI score enables the standardised assessment of disease characteristic structural changes in the preterm lung exhibiting significant potential as a quantifiable endpoint in early intervention clinical trials and long-term disease monitoring.

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2022, Scientific Article in Biochimica et Biophysica Acta - Molecular Basis of Disease

Proteomics reveals antiviral host response and NETosis during acute COVID-19 in high-risk patients.

SARS-CoV-2 remains an acute threat to human health, endangering hospital capacities worldwide. Previous studies have aimed at informing pathophysiologic understanding and identification of disease indicators for risk assessment, monitoring, and therapeutic guidance. While findings start to emerge in the general population, observations in high-risk patients with complex pre-existing conditions are limited. We addressed the gap of existing knowledge with regard to a differentiated understanding of disease dynamics in SARS-CoV-2 infection while specifically considering disease stage and severity. We biomedically characterized quantitative proteomics in a hospitalized cohort of COVID-19 patients with mild to severe symptoms suffering from different (co)-morbidities in comparison to both healthy individuals and patients with non-COVID related inflammation. Deep clinical phenotyping enabled the identification of individual disease trajectories in COVID-19 patients. By the use of the individualized disease phase assignment, proteome analysis revealed a severity dependent general type-2-centered host response side-by-side with a disease specific antiviral immune reaction in early disease. The identification of phenomena such as neutrophil extracellular trap (NET) formation and a pro-coagulatory response characterizing severe disease was successfully validated in a second cohort. Together with the regulation of proteins related to SARS-CoV-2-specific symptoms identified by proteome screening, we not only confirmed results from previous studies but provide novel information for biomarker and therapy development.

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2022, Scientific Article in Scientific Reports

Reference genes for the developing mouse lung under consideration of biological, technical and experimental confounders.

For gene expression analysis, the raw data obtained from RT-qPCR are preferably normalized to reference genes, which should be constantly expressed regardless of experimental conditions. Selection of reference genes is particularly challenging for the developing lung because of the complex transcriptional and epigenetic regulation of genes during organ maturation and injury repair. To date, there are only limited experimental data addressing reliable reference genes for this biological circumstance. In this study, we evaluated reference genes for the lung in neonatal C57BL/6 mice under consideration of biological, technical and experimental conditions. For that, we thoroughly selected candidates from commonly used reference genes side-by-side with novel ones by analyzing publicly available microarray datasets. We performed RT-qPCR of the selected candidate genes and analyzed their expression variability using GeNorm and Normfinder. Cell-specific expression of the candidate genes was analyzed using our own single-cell RNA-sequencing data from the developing mouse lung. Depending on the investigated conditions, i.e., developmental stages, sex, RNA quality, experimental condition (hyperoxia) and cell types, distinct candidate genes demonstrated stable expression confirming their eligibility as reliable reference genes. Our results provide valuable information for the selection of proper reference genes in studies investigating the neonatal mouse lung.

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2022, Scientific Article in Frontiers in Cellular and Infection Microbiology

Effects of immunophilin inhibitors and non-immunosuppressive analogs on coronavirus replication in human infection models.

Rationale: Human coronaviruses (HCoVs) seriously affect human health by causing respiratory diseases ranging from common colds to severe acute respiratory diseases. Immunophilins, including peptidyl-prolyl isomerases of the FK506-binding protein (FKBP) and the cyclophilin family, are promising targets for pharmaceutical inhibition of coronavirus replication, but cell-type specific effects have not been elucidated. FKBPs and cyclophilins bind the immunosuppressive drugs FK506 and cyclosporine A (CsA), respectively. Methods: Primary human bronchial epithelial cells (phBECs) were treated with CsA, Alisporivir (ALV), FK506, and FK506-derived non-immunosuppressive analogs and infected with HCoV-229E. RNA and protein were assessed by RT-qPCR and immunoblot analysis. Treatment with the same compounds was performed in hepatoma cells (Huh-7.5) infected with HCoV-229E expressing Renilla luciferase (HCoV-229E-RLuc) and the kidney cell line HEK293 transfected with a SARS-CoV-1 replicon expressing Renilla luciferase (SARS-CoV-1-RLuc), followed by quantification of luminescence as a measure of viral replication. Results: Both CsA and ALV robustly inhibited viral replication in all models; both compounds decreased HCoV-229E RNA in phBECs and reduced luminescence in HCoV-229E-RLuc-infected Huh7.5 and SARS-CoV-1-RLuc replicon-transfected HEK293. In contrast, FK506 showed inconsistent and less pronounced effects in phBECs while strongly affecting coronavirus replication in Huh-7.5 and HEK293. Two non-immunosuppressive FK506 analogs had no antiviral effect in any infection model. Conclusion: The immunophilin inhibitors CsA and ALV display robust anti-coronaviral properties in multiple infection models, including phBECs, reflecting a primary site of HCoV infection. In contrast, FK506 displayed cell-type specific effects, strongly affecting CoV replication in Huh7.5 and HEK293, but inconsistently and less pronounced in phBECs.

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2022, Scientific Article in Nutrients

Improved Macro- and micronutrient supply for favorable growth and metabolomic profile with standardized parenteral nutrition solutions for very preterm infants.

Very preterm infants are at high risk for suboptimal nutrition in the first weeks of life leading to insufficient weight gain and complications arising from metabolic imbalances such as insufficient bone mineral accretion. We investigated the use of a novel set of standardized parenteral nutrition (PN; MUC PREPARE) solutions regarding improving nutritional intake, accelerating termination of parenteral feeding, and positively affecting growth in comparison to individually prescribed and compounded PN solutions. We studied the effect of MUC PREPARE on macro- and micronutrient intake, metabolism, and growth in 58 very preterm infants and compared results to a historic reference group of 58 very preterm infants matched for clinical characteristics. Infants receiving MUC PREPARE demonstrated improved macro- and micronutrient intake resulting in balanced electrolyte levels and stable metabolomic profiles. Subsequently, improved energy supply was associated with up to 1.5 weeks earlier termination of parenteral feeding, while simultaneously reaching up to 1.9 times higher weight gain at day 28 in extremely immature infants (<27 GA weeks) as well as overall improved growth at 2 years of age for all infants. The use of the new standardized PN solution MUC PREPARE improved nutritional supply and short- and long-term growth and reduced PN duration in very preterm infants and is considered a superior therapeutic strategy.

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2022, Review in Molecular and Cellular Pediatrics

Association of immune cell recruitment and BPD development.

In the neonatal lung, exposure to both prenatal and early postnatal risk factors converge into the development of injury and ultimately chronic disease, also known as bronchopulmonary dysplasia (BPD). The focus of many studies has been the characteristic inflammatory responses provoked by these exposures. Here, we review the relationship between immaturity and prenatal conditions, as well as postnatal exposure to mechanical ventilation and oxygen toxicity, with the imbalance of pro- and anti-inflammatory regulatory networks. In these conditions, cytokine release, protease activity, and sustained presence of innate immune cells in the lung result in pathologic processes contributing to lung injury. We highlight the recruitment and function of myeloid innate immune cells, in particular, neutrophils and monocyte/macrophages in the BPD lung in human patients and animal models. We also discuss dissimilarities between the infant and adult immune system as a basis for the development of novel therapeutic strategies.

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Contact

PD Dr. med. Anne Hilgendorff

Team Leader