Potential role for lectin-like oxidized LDL receptor 1 in pulmonary microvascular endothelial barrier dysfunction caused by inflammatory mediators: implications beyond oxLDL

Introduction: Disruption of the pulmonary microvascular endothelial barrier is a pathological process leading to tissue edema and organ dysfunction in conditions such as sepsis. Despite scientific advances, there are no targeted therapies available for sepsis treatment, and morbidity and mortality rates are still high. Our recent work identified the scavenger receptor lectin-like oxidized LDL receptor 1 (LOX-1) to be an important molecule in mediating pulmonary microvascular endothelial barrier dysfunction, specifically via the oxidation of low-density lipoprotein (LDL) by hemoglobin or heme. Several recent studies have suggested that oxLDL is not the only mediator of LOX-1 signaling. In this study, we hypothesized that various inflammatory stimuli may increase cell surface expression of LOX-1 and disrupt the pulmonary microvascular endothelial barrier. Methods: Human pulmonary microvascular endothelial cells (HPMECs) were cultured and seeded at confluency in 96-well plates. After two days (allowing the cells to form a tight monolayer), the cells were treated over a time course with several different inflammatory mediators implicated in the pathophysiology of sepsis, including hemin, advanced glycation endproducts (AGEs), adenosine triphosphate (ATP), lipopolysaccharide (LPS), palmitic acid (PA), and tumor necrosis factor alpha (TNF-α).Cell surface expression of LOX-1 (rabbit anti-LOX-1 primary antibody, 1:200; Cat. No. PA5-95750, Invitrogen) was assessed using immunofluorescence microscopy in non-permeabilized cells. Barrier dysfunction was assessed using XPerT assay. Results: We identified significant upregulation of LOX-1 receptor cell surface expression in response to stimulation with hemin (50µg/mL), ATP (10µM), palmitic acid (100µM), and TNF-α (50ng/mL) after 1 hour. The increase in LOX-1 preceded the observed barrier dysfunction in response to these mediators, which peaked between 6-24 hours. Conclusions: Together with our previous findings, these data suggest that the LOX-1 receptor may play a role in regulating barrier dysfunction in response to diverse inflammatory stimuli. Further studies will investigate directly whether LOX-1 mediates barrier dysfunction in response to different stimuli in HPMECs, which intracellular signaling pathways might connect LOX-1 to barrier dysfunction, and the importance of LOX-1 in mediating microvascular hyperpermeability in preclinical models of sepsis. Funding: NIH R00HL166865 (NHLBI) and Parker B. Francis Fellowship to JEM This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.