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Yildirim/Conlon Lab

Immunopathology of COPD

We want to understand which subtypes of T-cell play a role in the development of COPD - a major public health problem with prevalence as well as mortality still rising.

We want to understand which subtypes of T-cell play a role in the development of COPD - a major public health problem with prevalence as well as mortality still rising.

COPD - third leading cause of death worldwide

The stimulus of long-term exposure to toxic gases and most often cigarette smoke causes parenchymal lung tissue damage, remodeling of small airways, airway obstruction, and a subsequent decline in lung function. Innate inflammatory immune cells, i.e. neutrophils and macrophages, and CD8+ T cells have been described to be considerably involved in lung tissue damage in COPD. However, increasing evidence suggests that the inflammatory response of other specific immune cells, in particular CD4+ T and B cells present in the lungs of COPD patients, contributes to the pathogenesis of COPD. More studies are needed to understand the exact role and involvement of these immune cells in the chronic inflammatory response in COPD.

Promising therapeutic approach against COPD

In COPD, immune cells (B-cells and T-cells) form newly organized structures in the lung, follicles, which are known to play an important role in the disease progression. The formation of these structures requires the activation of a specific cellular receptor: the lymphotoxin beta receptor which is also a regulator of cell death. The death of epithelial lung cells is another feature of COPD observed in patients, preventing them from breathing effectively. We found that the blocking of lymphotoxin beta receptor signaling leads to the activation of so-called Wnt signaling. Wnt signaling is an essential pathway for lung development. In COPD patients this pathway gets switched off preventing the lung from being able to repair and regenerate.

Our work published in Nature journal offers great potential for implementing lung regenerative medicine approaches in the clinic. To achieve this ultimate goal we are testing the novel dual therapeutic approach in human clinical trials over the coming years. (See "Clinical Trials")

Scientists at Yildirim/Conlon Lab

Dhakad Deepesh

PhD Student

Shruthi Kalgudde Gopal

Doctoral Student (PhD)

Güney Güvenç

PhD Student

Christine Hollauer

Technical Assistant

Henri Hoppe

Biological Lab Assistant

Dr. Aicha Jeridi

Postdoctoral Fellow

Maximilian Kampick

Martin Klotz

PhD Student

Santiago Martin

MD Student

Xiaomei Tan

Doctoral Student

Dr. Henu Kumar Verma

Postdoc

Jasmin Batani

PhD Student

Publications

2022, Scientific Article in European Respiratory Journal

RIPK1 kinase-dependent inflammation and cell death contribute to the pathogenesis of COPD.

RATIONALE: Receptor-interacting protein kinase 1 (RIPK1) is a key mediator of regulated cell death (including apoptosis and necroptosis) and inflammation, both drivers of chronic obstructive pulmonary disease (COPD) pathogenesis. OBJECTIVE: We aimed to define the contribution of RIPK1 kinase-dependent cell death and inflammation in the pathogenesis of COPD. METHODS: We assessed RIPK1 expression in single-cell RNA-sequencing data from human and mouse lungs and validated RIPK1 levels in lung tissue of COPD patients via immunohistochemistry. Next, we assessed the consequences of genetic and pharmacological inhibition of RIPK1 kinase activity in experimental COPD, using Ripk1S25D /S25D kinase deficient mice and the RIPK1 kinase inhibitor GSK'547. MEASUREMENTS AND MAIN RESULTS: RIPK1 expression increased in alveolar type I (AT1), AT2, ciliated and neuroendocrine cells in human COPD. RIPK1 protein levels were significantly increased in airway epithelium of COPD patients, compared to never smokers and smokers without airflow limitation. In mice, exposure to cigarette smoke (CS) increased Ripk1 expression similarly in AT2 cells, and further in alveolar macrophages and T cells. Genetic and/or pharmacological inhibition of RIPK1 kinase activity significantly attenuated airway inflammation upon acute and subacute CS-exposure, as well as airway remodeling, emphysema and apoptotic and necroptotic cell death upon chronic CS-exposure. Similarly, pharmacological RIPK1 kinase inhibition significantly attenuated elastase-induced emphysema and lung function decline. Finally, RNA-sequencing on lung tissue of CS-exposed mice revealed downregulation of cell death and inflammatory pathways upon pharmacological RIPK1 kinase inhibition. CONCLUSIONS: RIPK1 kinase inhibition is protective in experimental models of COPD and may represent a novel promising therapeutic approach.

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2022, Scientific Article in American Journal of Physiology - Regulatory, Integrative and Comparative Physiology

Aqp5--/-- mice exhibit reduced maximal O2 consumption under cold exposure, normal pulmonary gas exchange, and impaired formation of brown adipose tissue.

The fundamental body functions that determine maximal O2 uptake (VO2,max) have not been studied in Aqp5 --/-- (aquaporin 5, AQP5) mice. We measured VO2,max to globally assess these functions and then investigated why it was found altered in Aqp5 --/-- mice. VO2,max was measured by the Helox technique, which elicits maximal metabolic rate by intense cold exposure of the animals. We found VO2,max reduced in Aqp5 --/-- mice by 20 - 30% compared to WT. Since AQP5 has been implicated to act as a membrane channel for respiratory gases, we studied whether this is due to the known lack of AQP5 in the alveolar epithelial membranes of Aqp5 --/-- mice. Lung function parameters as well as arterial O2 saturation were normal and identical between Aqp5 --/-- and WT mice, indicating that AQP5 does not contribute to pulmonary O2 exchange. The cause for the decreased VO2,max thus might be found in decreased O2 consumption of an intensely O2-consuming peripheral organ such as activated BAT. We found indeed that absence of AQP5 greatly reduces the amount of interscapular BAT formed in response to 4 weeks' cold exposure, from 63% in WT to 25% in Aqp5 --/-- animals. We conclude that lack of AQP5 does not affect pulmonary O2 exchange, but greatly inhibits transformation of white to brown adipose tissue. Since under cold exposure BAT is a major source of the animals' heat production, reduction of BAT likely causes the decrease in VO2,max under this condition.

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2022, Scientific Article in Patient preference and adherence

Basic determinants of disease knowledge in COPD patients: Results from COSYCONET.

Introduction: In many chronic diseases, including COPD, the patients' basic knowledge of the disorder has been shown to be relevant for the course of the disease. We studied which clinical and functional characteristics were related to this knowledge as well as the patients' satisfaction with their knowledge about COPD. Methods: The study population comprised 645 patients of GOLD grades 1-4 who participated in Visit 6 of the COSYCONET cohort (COPD and Systemic Consequences - Comorbidities Network). The assessments covered a broad panel of clinical and functional characteristics, including generic and disease-specific quality of life and the COPD Assessment Test (CAT). The study aim was addressed by two questions, referring to patients' knowledge of the meaning of FEV1 and the overall satisfaction with their knowledge of COPD. Results: Knowledge of FEV1 was higher in patients of higher spirometric GOLD grades or exacerbation risk, in males, with higher educational level, and after participation in a prior educational training on COPD. Patients with more detailed knowledge showed a higher satisfaction with their knowledge. Satisfaction was associated with higher generic quality of life and a lower CAT score. Furthermore, satisfaction was higher in patients with a treatment plan but lower in patients with cardiac comorbidities. It appeared that females with basic education, high burden from COPD and low quality of life had the greatest knowledge deficits. Discussion: The results suggest room for education programs adapted to the educational level of the participants. They also emphasize the major role of a disease management plan for the patients.

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2022, Review in Cells

Endolysosomal cation channels and lung disease.

Endolysosomal cation channels are emerging as key players of endolysosomal function such as endolysosomal trafficking, fusion/fission, lysosomal pH regulation, autophagy, lysosomal exocytosis, and endocytosis. Diseases comprise lysosomal storage disorders (LSDs) and neurode-generative diseases, metabolic diseases, pigmentation defects, cancer, immune disorders, autophagy related diseases, infectious diseases and many more. Involvement in lung diseases has not been a focus of attention so far but recent developments in the field suggest critical functions in lung physiology and pathophysiology. Thus, loss of TRPML3 was discovered to exacerbate emphysema formation and cigarette smoke induced COPD due to dysregulated matrix metalloproteinase 12 (MMP-12) levels in the extracellular matrix of the lung, a known risk factor for emphysema/COPD. While direct lung function measurements with the exception of TRPML3 are missing for other endolysosomal cation channels or channels expressed in lysosome related organelles (LRO) in the lung, links between those channels and important roles in lung physiology have been established such as the role of P2X4 in surfactant release from alveolar epithelial Type II cells. Other channels with demonstrated functions and disease relevance in the lung such as TRPM2, TRPV2, or TRPA1 may mediate their effects due to plasma membrane expression but evidence accumulates that these channels might also be expressed in endolysosomes, suggesting additional and/or dual roles of these channels in cell and intracellular membranes. We will discuss here the current knowledge on cation channels residing in endolysosomes or LROs with respect to their emerging roles in lung disease.

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2022, Scientific Article in Thorax

Relationship between impaired BMP signalling and clinical risk factors at early-stage vascular injury in the preterm infant.

INTRODUCTION: Chronic lung disease, that is, bronchopulmonary dysplasia (BPD) is the most common complication in preterm infants and develops as a consequence of the misguided formation of the gas-exchange area undergoing prenatal and postnatal injury. Subsequent vascular disease and its progression into pulmonary arterial hypertension critically determines long-term outcome in the BPD infant but lacks identification of early, disease-defining changes. METHODS: We link impaired bone morphogenetic protein (BMP) signalling to the earliest onset of vascular pathology in the human preterm lung and delineate the specific effects of the most prevalent prenatal and postnatal clinical risk factors for lung injury mimicking clinically relevant conditions in a multilayered animal model using wild-type and transgenic neonatal mice. RESULTS: We demonstrate (1) the significant reduction in BMP receptor 2 (BMPR2) expression at the onset of vascular pathology in the lung of preterm infants, later mirrored by reduced plasma BMP protein levels in infants with developing BPD, (2) the rapid impairment (and persistent change) of BMPR2 signalling on postnatal exposure to hyperoxia and mechanical ventilation, aggravated by prenatal cigarette smoke in a preclinical mouse model and (3) a link to defective alveolar septation and matrix remodelling through platelet derived growth factor-receptor alpha deficiency. In a treatment approach, we partially reversed vascular pathology by BMPR2-targeted treatment with FK506 in vitro and in vivo. CONCLUSION: We identified impaired BMP signalling as a hallmark of early vascular disease in the injured neonatal lung while outlining its promising potential as a future biomarker or therapeutic target in this growing, high-risk patient population.

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2022, Scientific Article in Nature Communications

The arginine methyltransferase PRMT7 promotes extravasation of monocytes resulting in tissue injury in COPD.

Extravasation of monocytes into tissue and to the site of injury is a fundamental immunological process, which requires rapid responses via post translational modifications (PTM) of proteins. Protein arginine methyltransferase 7 (PRMT7) is an epigenetic factor that has the capacity to mono-methylate histones on arginine residues. Here we show that in chronic obstructive pulmonary disease (COPD) patients, PRMT7 expression is elevated in the lung tissue and localized to the macrophages. In mouse models of COPD, lung fibrosis and skin injury, reduced expression of PRMT7 associates with decreased recruitment of monocytes to the site of injury and hence less severe symptoms. Mechanistically, activation of NF-κB/RelA in monocytes induces PRMT7 transcription and consequential mono-methylation of histones at the regulatory elements of RAP1A, which leads to increased transcription of this gene that is responsible for adhesion and migration of monocytes. Persistent monocyte-derived macrophage accumulation leads to ALOX5 over-expression and accumulation of its metabolite LTB4, which triggers expression of ACSL4 a ferroptosis promoting gene in lung epithelial cells. Conclusively, inhibition of arginine mono-methylation might offer targeted intervention in monocyte-driven inflammatory conditions that lead to extensive tissue damage if left untreated.

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2022, Scientific Article in Science Advances

A transcriptomics-guided drug target discovery strategy identifies receptor ligands for lung regeneration.

Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here, we used a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors, of which we screened the function in lung organoids. We found several drug targets with regenerative potential, of which EP and IP prostanoid receptor ligands had the most profound therapeutic potential in restoring cigarette smoke-induced defects in alveolar epithelial progenitors in vitro and in vivo. Mechanistically, we found, using single-cell RNA sequencing analysis, that circadian clock and cell cycle/apoptosis signaling pathways were differentially expressed in alveolar epithelial progenitor cells in patients with COPD and in a relevant model of COPD, which was prevented by prostaglandin E2 or prostacyclin mimetics. We conclude that specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.

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Contact

Dr. Ali Önder Yildirim

Director & Team Leader

Contact

Dr. Thomas Conlon

Team Leader