CNP-miR146a improves outcomes in a two-hit acute- and ventilator-induced lung injury model

• Published in: Nanomedicine 2023-06, Vol.50, p.102679, Article 102679
• Main Authors: Wallbank, Alison M., Vaughn, Alyssa E., Niemiec, Steve, Bilodeaux, Jill, Lehmann, Tanner, Knudsen, Lars, Kolanthai, Elayaraja, Seal, Sudipta, Zgheib, Carlos, Nozik, Eva, Liechty, Kenneth W., Smith, Bradford J.
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - drug therapy; Acute Lung Injury - genetics; Animals; Bioactive nanoparticle therapeutic; Humans; Lung - metabolism; Mice; Respiratory Distress Syndrome - metabolism; Stereology; Sterile inflammatory model; Ventilator-induced lung injury; Ventilator-Induced Lung Injury - drug therapy; Ventilator-Induced Lung Injury - genetics; Ventilator-Induced Lung Injury - metabolism
• ISSN: 1549-9634; 1549-9642; 1549-9642
• DOI: 10.1016/j.nano.2023.102679

Acute respiratory distress syndrome (ARDS) has high mortality (~40 %) and requires the lifesaving intervention of mechanical ventilation. A variety of systemic inflammatory insults can progress to ARDS, and the inflamed and injured lung is susceptible to ventilator-induced lung injury (VILI). Strategies to mitigate the inflammatory response while restoring pulmonary function are limited, thus we sought to determine if treatment with CNP-miR146a, a conjugate of novel free radical scavenging cerium oxide nanoparticles (CNP) to the anti-inflammatory microRNA (miR)-146a, would protect murine lungs from acute lung injury (ALI) induced with intratracheal endotoxin and subsequent VILI. Lung injury severity and treatment efficacy were evaluated via lung mechanical function, relative gene expression of inflammatory biomarkers, and lung morphometry (stereology). CNP-miR146a reduced the severity of ALI and slowed the progression of VILI, evidenced by improvements in inflammatory biomarkers, atelectasis, gas volumes in the parenchymal airspaces, and the stiffness of the pulmonary system. There are no pharmaceutical treatments for acute respiratory distress syndrome and management is centered on life-saving mechanical ventilation, but that intervention can cause ventilator-induced lung injury and worse outcomes. Our study utilizes a two-hit murine lung injury model that emulates the clinical course of lung injury and ventilation to test the therapeutic efficacy of cerium oxide nanoparticles (CNPs) conjugated to an anti-inflammatory micro RNA (miR146a). We found the therapeutic, CNP-miR146a, reduced inflammation, prevented atelectasis, restored mechanical function, and protected pre-injured lungs from ventilator-induced lung injury. [Display omitted]