Abstract
The pulmonary endothelium is a dynamic semipermeable barrier that orchestrates tissue-fluid homeostasis; regulating physiological and immunological responses. Endothelial abnormalities are caused by inflammatory stimuli interacting with intracellular messengers to remodel cytoskeletal junctions and adhesion proteins. Those phenomena are associated with sepsis, acute lung injury, and acute respiratory distress syndrome. The molecular processes beyond those responses are the main interest of our group. Unfolded protein response (UPR) is a highly conserved molecular pathway resolving protein-folding defects to counteract cellular threats. An emerging body of evidence suggests that UPR is a promising target against lung and cardiovascular disease. In the present study, we reveal that Tunicamycin (TM) (UPR inducer) protects against lipopolysaccharide (LPS)-induced injury. The barrier function of the inflamed endothelium was evaluated in vitro (transendothelial and paracellular permeability); as well as in mice exposed to TM after LPS. Our study demonstrates that TM supports vascular barrier function by modulating actomyosin remodeling. Moreover, it reduces the internalization of vascular endothelial cadherin (VE-cadherin), enhancing endothelial integrity. We suggest that UPR activation may deliver novel therapeutic opportunities in diseases related to endothelial dysregulation.
Highlights
Our lungs are exposed to environmental pathogens and toxins, counteracted by cytokine-mediated host defense mechanisms
We suggest that unfolded protein response (UPR) activation may deliver novel therapeutic opportunities in diseases related to endothelial dysregulation
After the cells reach a steady-state resistance, they were treated with either vehicle (0.1% DMSO) or TM (0.5 μM)
Summary
Our lungs are exposed to environmental pathogens (bacteria, virus) and toxins (cigarette smoke, air pollution, asbestos), counteracted by cytokine-mediated host defense mechanisms. The dysregulation of the endothelial barrier during inflammation results in increased permeability; and accumulation of protein-rich edematous fluid. Endoplasmic reticulum (ER) stress acts upon those stimuli, to maintain homeostasis and activate unfolded protein response (UPR) [3]. Our recent endeavors aim to support a novel therapeutic possibility against pathologies related to endothelial barrier dysfunction, based on targeted UPR activation. Barrier functions are strictly regulated by endothelial adherens (AJs) and tight junctions (TJs). Vascular endothelial cadherin (VE-cadherin) is an AJ protein that mediates intracellular integrity through its extracellular domain [4]. Vascular beds have distinct architectures for interendothelial junctions (IEJs); so to replenish functional requirements. Pro-inflammatory stimuli such as lipopolysaccharide (LPS) and other factors (vascular endothelial growth factors) destabilize
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