Acute respiratory distress syndrome (ARDS), caused by noncardiogenic pulmonary edema (PE), contributes significantly to Coronavirus 2019 (COVID-19)-associated morbidity and mortality. We explored the effect of transmembrane osmotic pressure (OP) gradients in PE using a fluorescence resonance energy transfer-based Intermediate filament (IF) tension optical probe. Angiotensin-II- and bradykinin-induced increases in intracellular protein nanoparticle (PN)-OP were associated with inflammasome production and cytoskeletal depolymerization. Intracellular protein nanoparticle production also resulted in cytomembrane hyperpolarization and L-VGCC-induced calcium signals, which differed from diacylglycerol-induced calcium increment via TRPC6 activation. Both pathways involve voltage-dependent cation influx and OP upregulation via SUR1-TRPM4 channels. Meanwhile, intra/extracellular PN-induced OP gradients across membranes upregulated pulmonary endothelial and alveolar barrier permeability. Attenuation of intracellular PN, calcium signals, and cation influx by drug combinations effectively relieved intracellular OP and pulmonary endothelial nonselective permeability, and improved epithelial fluid absorption and PE. Thus, PN-OP is pivotal in pulmonary edema in ARDS and COVID-19, and transmembrane OP recovery could be used to treat pulmonary edema and develop new drug targets in pulmonary injury. Graphical Abstract
Kai-chao Wen,Zheng-an Li,Ji-heng Liu,Chuan Zhang,Feng Zhang,Feng-qian Li
The implantation of bare metal ureteral stents may lead to bacterial colonization and scar hyperplasia. To effectively address these issues, PLGA nanoparticles co-loaded with tranilast and gallium phytate (PG-TRL-PLGA-NPs) were prepared using an emulsifying solvent volatilization technique. The PG-TRL-PLGA-NPs possess a dual function of antibacterial and proliferation inhibition, which could be used for stent functional coating. The PG-TRL-PLGA-NPs displayed a regular spherical morphology with a smooth surface, and average particle size of 163 ± 1.37 nm, Zeta potential of −16.09 mV, drug loading capacity of 9.4 ± 0.6%, and encapsulation efficiency of 97.5 ± 0.4% could be achieved. FTIR, XRD, and DSC analysis demonstrated that PG-TRL-PLGA-NPS was successfully nano-encapsulated without chemical reaction among TRL, PG, and PLGA. In vitro release profiles of TRL and gallium ions from PG-TRL-PLGA-NPs exhibited a sustained-release effect, with 89.7 ± 0.9% and 3.2 ± 0.15 mg/L released in 14 days, respectively. Furthermore, it was observed the potent antibacterial activity (against S. aureus and E. coli .) of PG-TRL-PLGA-NPs, also significantly inhibited SV-HUC-1 cell proliferation through experiments involving cell migration, cell cycle, and apoptosis studies. These results provide valuable insights into the stent coatings of PG-TRL-PGLA NPs with potential functions of antibacterial and proliferative inhibitory.
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