title: Prevention of ventilator-induced lung edema by inhalation of nanoparticles releasing ruthenium red.
abstract: The acute respiratory distress syndrome (ARDS), a devastating lung disease that has no cure, is exacerbated by life-supportive mechanical ventilation that worsens lung edema and inflammation through the syndrome of ventilator-induced lung injury. Recently, the membrane ion channel transient receptor potential vanilloid 4 (TRPV4) on alveolar macrophages was shown to mediate murine lung vascular permeability induced by high-pressure mechanical ventilation. The objective of this study was to determine whether inhalation of nanoparticles (NPs) containing the TRPV4 inhibitor ruthenium red (RR) prevents ventilator-induced lung edema in mice. Poly-lactic-co-glycolic acid NPs containing RR were evaluated in vitro for their ability to block TRPV4-mediated calcium signaling in alveolar macrophages and capillary endothelial cells. Lungs from adult C57BL6 mice treated with nebulized NPs were then used in ex vivo ventilation perfusion experiments to assess the ability of the NPs to prevent high-pressure mechanical ventilation-induced lung edema. Poly-lactic-co-glycolic acid NPs (300 nm) released RR for 150 hours in vitro, and blocked TRPV4-mediated calcium signaling in cells up to 7 days after phagocytosis. Inhaled NPs deposited in alveoli of spontaneously breathing mice were rapidly phagocytosed by alveolar macrophages, and blocked increased vascular permeability from high-pressure mechanical ventilation for 72 hours in ex vivo ventilation perfusion experiments. These data offer proof of principle that inhalation of NPs containing a TRPV4 inhibitor prevents ventilator damage for several days, and imply that this novel drug delivery strategy could be used to target alveolar macrophages in patients at risk of ventilator-induced lung injury before initiating mechanical ventilation.
authors.affiliation: 1 Department of Medicine.
authors.forename: Samuel C
authors.initials: SC
authors.lastname: Jurek
authors.forename: Mariko
authors.initials: M
authors.lastname: Hirano-Kobayashi
authors.forename: Homer
authors.initials: H
authors.lastname: Chiang
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Kohane
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Matthews
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage*; D010539:Permeability / Q000187:drug effects; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism; D011654:Pulmonary Edema / Q000378:metabolism / Q000517:prevention & control*; D012119:Respiration / Q000187:drug effects; D012121:Respiration, Artificial / Q000379:methods; D012430:Ruthenium Red / Q000008:administration & dosage*; D050916:TRPV Cation Channels / Q000378:metabolism; D055397:Ventilator-Induced Lung Injury / Q000378:metabolism / Q000517:prevention & control*; D012122:Ventilators, Mechanical
chemical_list: D050916:TRPV Cation Channels; C486576:Trpv4 protein, mouse; D012430:Ruthenium Red; D002118:Calcium