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.

Transient receptor potential (TRP) channels as a therapeutic target for intervention of respiratory effects and lethality from phosgene

“…This would suggest that administration a second dose of RR around the 8-12 hr time point.. This agrees with what was reported when inhaled RR was used to prevent ventilator-induced lung edema, where the protection provided by RR alone was efficient for less than two hours unless the RR therapy was administered in a sustained released delivery system using inhaled poly-lactic-co-glycolic acid (PLGA) nanoparticles (Jurek, Hirano-Kobayashi et al 2014). …”

“…TRP channels are involved in signal transduction of various pathways following activation and involve cells that are not directly exposed to air, e.g. macrophages, endothelial cells, vascular endothelial cells (Freichel, Suh et al 2001, Alvarez, King et al 2006, Willette, Bao et al 2008, Grace, Baxter et al 2014, Jurek, Hirano-Kobayashi et al 2014). CG is hydrophobic in nature and, therefore, it passes through the upper respiratory tract with less absorption and concentrates mostly in the deep lung to cause toxicity in the alveoli and microvascular system.…”

“…Inhibitors of TRPA1, TRPV1 and TRPV4 have been developed to prevent activation of chemosensory TRP channels that are believed to be involved in pulmonary edema (Nilius, Owsianik et al 2007, Billeter, Hellmann et al 2014, Grace, Baxter et al 2014, Jurek, Hirano-Kobayashi et al 2014) and abnormal blood pressure as well as abnormal fluid and electrolyte balance resulting from COPD (Li, Kanju et al 2011), heart failure (Thorneloe, Cheung et al 2012), chronic asthma (Lee and Gu 2009), exposure to isocyanates and tear gases (Bessac, Sivula et al 2009), and exposure to chlorine gas (Balakrishna, Song et al 2014). Typically acute reactions to CG from its exposure at levels higher than the odor threshold and standard permissible levels include irritation, bronchoconstriction, and vasoconstriction, disruption of the alveolar membrane barrier function, pulmonary edema, asthma-like symptoms and respiratory distress.…”

Mechanisms of ventilator-induced lung injury in healthy lungs

“…In line with these data, one recent study showed that the inhalation of nanoparticles (NPs) containing the TRPV4 inhibitor ruthenium red prevented VILI in mice, emphasizing the importance of macrophage function and highlighting nanoparticles as potential vehicle-delivering agents 38 .…”

Cytokine–Ion Channel Interactions in Pulmonary Inflammation

“…In CF, TRPV4 appears to play paradoxical roles in CBF/mucociliary clearance and epithelial cell pro-inflammatory chemokine (IL-8/KC) secretion ( 317 , 318 ). Depending on the underlying etiology, TRPV4 may play different roles in ARDS ( 307 , 310 , 314 , 319 ). Also, in pulmonary fibrosis, TRPV4 has been shown to mediate the mechano-sensing that drives myofibroblast differentiation and experimental lung fibrosis in mice ( 308 ).…”