Motaharehsadat Heydarian, Ali Doryab, Juan Henao, Benjamin Schubert, Otmar Schmid, Anne Hilgendorff
Helmholtz Zentrum München and German Lung Research Center. University of Cambridge. University Hospital Ludwig-Maximilian University. Carl von Ossietzky University.
Germany and United Kingdom
American Journal of Physiology Lung Cellular and Molecular Physiology
Am J Physiol Lung Cell Mol Physiol 2026;
DOI: 10.1152/ajplung.00002.2026
Abstract
Pulmonary vascular disease (PVD) is a major contributor to morbidity in preterm infants as it is associated with a significant risk to devevlop pulmonary hypertension, especially in infants diagnosed with prematurity-associated lung disease (PLD), also known as bronchopulmonary dysplasia (BPD). However, the earliest events of vascular injury triggered by postnatal mechanical and oxygen-related stress remain poorly understood, largely due to the limitations of existing in vitro models. We therefore developed a biomimetic, miniaturized Pulmonary In Vitro Perfusion (PIPE) system that integrates pathophysiologically relevant shear stress with controlled oxygen exposure for the exposure of a human co-culture of pulmonary microvascular endothelial cells and pulmonary artery smooth muscle cells. Advancing the system to a triple co-culture, circulating THP-1 monocytes capture early endothelial-smooth muscle-immune cell interactions. Shear stress alone induced early proliferative and extracellular matrix-related responses in endothelial cells and resulted in enhanced monocyte recruitment without disrupting barrier integrity. When combined with oxygen exposure, the model revealed a dose-dependent injury pattern: moderate hyperoxia (FiO2 0.40) had minimal acute effects, whereas severe hyperoxia (FiO2 0.85) impaired endothelial barrier function, increased ROS production, promoted monocyte transmigration, activated apoptosis (Caspase 3), and elevated soluble collagen synthesis. This dynamic in vitro system reveals early drivers in vascular injury and recapitulates key characteristics of PVD, thereby introducing a translational platform for the dissection of disease mechanisms and evaluation of therapeutic strategies targeting vascular injury in the developing lung.
Category
Class III. Pulmonary Hypertension Associated with Lung Disease
Mechanical and Computer Models of Pulmonary Vascular Disease and Therapy
Animal Models of Pulmonary Vascular Disease and Therapy
Vascular Cell Biology and Mechanisms of Pulmonary Vascular Disease
Age Focus: Pediatric Pulmonary Vascular Disease
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: Yes