Inhaltspezifische Aktionen


Disturbed proteoglycan homeostasis drives pulmonary hypertension in lung fibrosis

The presence of PH in chronic lung fibrosis is associated with significantly increased morbidity and mortality and is therefore highly clinically relevant. PH arises due to vascular remodeling of distal pulmonary arteries, leading to increased vessel wall thickness and lumen occlusion. This pathology is accompanied by extracellular matrix (ECM) deposition, loss of elasticity, and vessel stiffening. We have previously shown that vascular remodeling is altered in lung fibrosis with specific transcriptomic fingerprints. The most altered pathways have been associated with basement membrane (BM) components and cellular communication. BM components and their degradation/turnover products may affect all aspects of cell life including survival, proliferation, differentiation, and the production of biological factors that may control inflammation as well as humoral and cellular properties of coagulation factors. The latter is supported by our previous findings showing a detrimental role of protease-activated receptor 2 (PAR-2), a receptor which is activated by a plethora of coagulation proteases in PH and lung fibrosis in different cellular contexts. Mechanistically, we demonstrated that BM components may modulate proliferation and migration of vascular smooth muscle cells in PH, sense initial injury in pulmonary angiopathy, and serve as markers of arterial adaptations to changing hemodynamics. Major components of BM are extracellular matrix proteoglycans (PGs), which comprise core proteins to which glycosaminoglycan chains are covalently attached. PGs are abundant in the settings of vascular injury and are facilitators of phenotype modulation, proliferation, and migration of smooth muscle cells (SMC) through cell-ECM interactions. Indeed, the expanding SMC populations in remodeled vessels in IPAH are enriched in proteoglycans. However, to what extent accumulation of individual proteoglycans contributes to the pathological changes in PH, especially in the setting of chronic lung fibrosis, is unknown. Moreover, endothelial cells (EC) might respond to pathological insults with enhanced production of PGs, which in turn may further modulate EC behavior. This bidirectional communication between EC and BM components may activate the coagulation cascade, triggering not only fibrin clot formation but also exacerbation of the inflammatory responses and profound changes in mechanical properties of the vessels. All these changes can contribute to blood vessel remodeling driving PH in pulmonary fibrosis (PH-PF) progression.

We hypostatize in our project that PG serves a "code" that categorizes each cell and provides it with a unique function and immunological/coagulatory identity driving PH in PF. To test this hypothesis, we plan to 1) understand the spatial and temporal localization/dynamics of BM PGs in the lungs of PH-PF and in respective animal models, 2) investigate the effects/mechanistic properties of PGs on EC and pulmonary SMC behavior, 3) unmask bidirectional communication between BM PGs and EC/pulmonary SMC and systemic consequences thereof, 4) delineate therapeutic potentials of PGs/PG mimetics for reverse remodeling in PH-PF models, and 5) establish the properties of PGs to serve as biomarkers of disease severity. By application of state-of-the-art technology (e.g. single cell sequencing, deep proteome profiling, multicolor-immunofluorescence analysis, and bioengineering to recreate local cellular matrixes), transgenic animal models, and tissue and plasma biobank samples we aim to identify the fundamental molecular and translational aspects of BM PGs in PH-PF.