Biology subjects

Pabelick, C.

Publications and source records attributed to Pabelick, C..

3 recordsLinked to original sources

bioRxiv2026

Mechanosensitive Piezo Channels Contribute to Airway Changes in Chronic Obstructive Pulmonary Disease

As an intrinsically mechanosensitive organ, the lung experiences a range of mechanical forces. Chronic obstructive pulmonary disease (COPD) involves abnormal macroscopic cellular and extracellular matrix (ECM) changes that impact mechanical properties of the lung. Mechanosensitive Piezo1/2 channels are expressed in the lung including on airway smooth muscle cells (ASM) that mediate cellular responses to stretch and ECM biomechanics. The expression and roles of Piezos in COPD lung ASM are not known. We hypothesized that Piezo expression and activation are altered in COPD lung ASM influencing ECM regulation. Distribution of Piezo proteins in ASM and epithelium of small airways of COPD stage II and IV vs. non-COPD controls was assessed using immunohistochemistry and ImageJ (n=10-17/group). Isolated ASM cells from control (n=6) vs. COPD stage II and IV patients (n=3 each stage) were exposed to stretch or the Piezo1 agonist Yoda1 followed by measurement of ECM gene and protein expression. Less Piezo2 staining was observed in COPD IV patients compared to controls, with lesser area and intensity of staining in the epithelial layer, and lower intensity of staining in ASM and small airways as a whole. Fura-2-based imaging of ASM Ca2+ showed lower influx after Yoda1 exposure in COPD II compared to control and COPD IV. Gene expression of Piezo1 increased upon stretching in controls but not in COPD ASM, while Piezo2 protein expression decreased with stretching in all groups. Yoda1 treatment resulted in decreased collagen1, fibulin1 and periostin gene and collagen 1 and periostin protein expression in ASM. Overall, these results support a role for Piezo activation in abnormal ECM-ASM cell crosstalk in COPD.

physiology↗

bioRxiv2025

Loss of miRNA-153 promotes endothelial-to-mesenchymal transition and compromises lung vascular integrity

Endothelial-to-mesenchymal transition (EndMT) is a biological process through which lung vascular endothelial cells (ECs) transdifferentiate into mesenchymal-like cells. EndMT has recently been implicated in the development and progression of pulmonary vascular remodeling in pulmonary hypertension (PH); however, its underlying regulatory mechanisms remain incompletely understood. MicroRNAs (miRNAs) are key post-transcriptional regulators of EC gene expression and cellular responses to various stimuli. Notably, microRNA-153 (miR-153) has been shown to directly target SNAI1 to modulate epithelial-to-mesenchymal transition (EMT), a process closely related to EndMT and extensively studied in cancer. Whether miR-153 also participates in EndMT regulation, however, remains unknown. In this study, we demonstrate that 72-hour hypoxic exposure induces SNAI1-mediated EndMT in human lung vascular ECs. Hypoxia also increased cell proliferation and disrupted intercellular junctions, leading to enhanced endothelial permeability. Reduced miR-153 expression was observed in both hypoxia- and TGF-{beta}1-induced EndMT, as well as in ECs isolated from PH patients exhibiting an EndMT phenotype. Similar to hypoxia, TGF-{beta}1 promoted EC permeability. Loss of miR-153 enhanced SNAI1-mediated EndMT, endothelial survival, and permeability under normoxic conditions, whereas miR-153 overexpression attenuated EndMT induced by hypoxia or TGF-{beta}1. However, miR-153 restoration did not completely recover endothelial barrier integrity disrupted by these stimuli. In conclusion, miR-153 serves as a critical regulator of EndMT, maintaining endothelial identity and barrier function. Therapeutic delivery of miR-153 may therefore represent a novel strategy to inhibit EndMT and attenuate pulmonary vascular remodeling in PH.

physiology↗

bioRxiv2018

Thymic Stromal Lymphopoietin Promotes Proliferation and Contractility of Human Pulmonary Artery Smooth Muscle

Hypoxia is a well-recognized risk factor in several pulmonary vascular diseases including pulmonary hypertension (PH). Furthermore, hypoxia-associated inflammatory changes enhance the structural and functional changes in the pulmonary artery (PA) of PH patients. Understanding the mechanisms that link hypoxia and inflammation, particularly early in disease, is key to development of novel therapeutic avenues for PH. Thymic stromal lymphopoietin (TSLP) is an \"early\" inflammatory mediator thought to be critical in diseases such as asthma, chronic obstructive pulmonary disease and atopic dermatitis. TSLP has canonical effects on the immune system, but can also have non-canonical effects on resident lung cells, e.g. airway smooth muscle. Currently, the expression and role of TSLP in the PA is unknown. We hypothesized that locally-produced TSLP potentiates the effects of hypoxia in PA remodeling and contractility relevant to PH. Experiments in human PA endothelial cells (PAECs) and smooth muscle cells (PASMCs) found PAECs to be a larger source of TSLP which targets PASMCs to enhance intracellular Ca2+ responses to vasoconstrictor agonist as well as cell proliferation, acting via a number of signaling cascades including Stat3 and PI3/Akt. Hypoxia, acting via HIF1, enhanced PAEC production of TSLP, and promoted TSLP effects on PASMCs. Interestingly, TSLP per se enhance HIF1a. Overall, these novel data highlight a role for TSLP in hypoxia effects on the PA, and thus relevance for inflammation in PH.

physiology↗