Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Wallbank AM

PROVIDER: S-EPMC10129905 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Wallbank Alison M AM Vaughn Alyssa E AE Niemiec Steve S Bilodeaux Jill J Lehmann Tanner T Knudsen Lars L Kolanthai Elayaraja E Seal Sudipta S Zgheib Carlos C Nozik Eva E Liechty Kenneth W KW Smith Bradford J BJ

Nanomedicine : nanotechnology, biology, and medicine 20230426

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 ceriu ...[more]

PMID: 37116556

Similar Datasets

Project description:Acute respiratory distress syndrome (ARDS) and acute lung injury have a diverse spectrum of causative factors including sepsis, aspiration of gastric contents, and near drowning. Clinical management of severe lung injury typically includes mechanical ventilation to maintain gas exchange which can lead to ventilator-induced lung injury (VILI). The cause of respiratory failure is acknowledged to affect the degree of lung inflammation, changes in lung structure, and the mechanical function of the injured lung. However, these differential effects of injury and the role of etiology in the structure-function relationship are not fully understood. To address this knowledge gap we caused lung injury with intratracheal hydrochloric acid (HCL) or endotoxin (LPS) 2 days prior to ventilation or with an injurious lavage (LAV) immediately prior to ventilation. These injury groups were then ventilated with high inspiratory pressures and positive end expiratory pressure (PEEP) = 0 cmH2O to cause VILI and model the clinical course of ARDS followed by supportive ventilation. The effects of injury were quantified using invasive lung function measurements recorded during PEEP ladders where the end-expiratory pressure was increased from 0 to 15 cm H2O and decreased back to 0 cmH2O in steps of 3 cmH2O. Design-based stereology was used to quantify the parenchymal structure of lungs air-inflated to 2, 5, and 10 cmH2O. Pro-inflammatory gene expression was measured with real-time quantitative polymerase chain reaction and alveolocapillary leak was estimated by measuring bronchoalveolar lavage protein content. The LAV group had small, stiff lungs that were recruitable at higher pressures, but did not demonstrate substantial inflammation. The LPS group showed septal swelling and high pro-inflammatory gene expression that was exacerbated by VILI. Despite widespread alveolar collapse, elastance in LPS was only modestly elevated above healthy mice (CTL) and there was no evidence of recruitability. The HCL group showed increased elastance and some recruitability, although to a lesser degree than LAV. Pro-inflammatory gene expression was elevated, but less than LPS, and the airspace dimensions were reduced. Taken together, those data highlight how different modes of injury, in combination with a 2nd hit of VILI, yield markedly different effects.

Project description:Ventilator?associated lung injury (VALI) remains a significant medical problem in intensive care units. The present study aimed to investigate the role of sphingosine kinase 1 (SPHK1) in VALI using a two?hit model and explore the potential underlying molecular mechanism. Mice were divided into five groups: i) Non?ventilated group; ii) non?ventilated + lipopolysaccharide (LPS) group; iii) ventilated group; iv) ventilated + LPS group; and v) ventilated + LPS + SPHK1 inhibitor group. Mice were administered LPS (1 mg/kg) via an intraperitoneal injection. After 12 h, the mice were anesthetized and connected to a ventilator (10 ml/kg at 150 breaths/min) for 4 h. SPHK1 inhibitor (50 mg/kg) was injected intraperitoneally 1 h prior to ventilation. Mouse lung vascular endothelial cells were treated with LPS and SPHK1 inhibitor, and then subjected to cyclic stretch for 4 h. The present results suggested that the expression of SPHK1 and sphingosine 1 phosphate was upregulated in the two?hit model of VALI; SPHK1 inhibitor could attenuate VALI in the two?hit model as observed by hematoxylin and eosin staining, and affected the cell count and the protein content levels in the bronchoalveolar lavage fluid. In addition, treatment with SPHK1 inhibitor reduced the wet?to?dry ratio of the lungs and suppressed Evans blue dye leakage into the lung tissue. Furthermore, SPHK1 inhibitor exhibited protective effects on the two?hit model of VALI by inhibiting the Ras homolog family member a?mediated phosphorylation of myosin phosphatase target subunit 1 (MYPT?1) and endothelial hyperpermeability. Additionally, mice were divided into five additional groups: i) Non?ventilated group; ii) non?ventilated + LPS group; iii) ventilated group; iv) ventilated + LPS group; and v) ventilated + LPS + Rho?associated coiled?coil forming protein kinase (ROCK)1 inhibitor group. ROCK1 inhibitor (10 mg/kg) was injected intraperitoneally 1 h prior to ventilation. The present results suggested that ROCK1 inhibitor could attenuate mechanical stretch?induced lung endothelial injury and the phosphorylation of MYPT?1 in vivo and in vitro. Collectively, the present findings indicated that upregulation of SPHK1 may contribute to VALI in a two?hit model.

Project description:BackgroundSivelestat, a neutrophil elastase inhibitor, is a selective and targeted therapy for acute respiratory distress syndrome (ARDS) in adults; and it is also reported to apply to children with ARDS. However, there is little evidence of its efficacy in children.MethodsThis study recruited 212 patients ranging in age from 28 days to 18 years old, and who met the diagnostic criteria for pediatric ARDS (PARDS) while hospitalized in the Intensive Care Department of the Affiliated Children's Hospital of Xi'an Jiaotong University. A total of 125 patients (case group) received sivelestat treatment, and 87 were assigned to the control group. There were no significant differences in gender (P=0.445) or age (P=0.521). Control group data were collected from the Electronic Case Information System for pediatric patients diagnosed with ARDS between March 2017 to January 2020. Data for the case group were collected from the Electronic Case Information System between February 2020 to February 2022. Demographic data, clinically relevant indicators, respiratory parameters were recorded. The 28-day mortality was the primary endpoint; the Kaplan-Meier and log-rank tests were used to evaluate cumulative survival rate.ResultsFor general demographic and clinical characteristics, no significant differences were observed between the two groups. Compared to the control group, the case group displayed significant improvements in PaO2/FiO2 at 48 h (141±45 vs. 115±21, P<0.001) and 72 h (169±61 vs. 139±40, P<0.001) post-admission, and plateau pressure was lower than that in the control group at 24 h (24±3 vs. 28±7, P<0.001), 48 h (21±4 vs. 26±7, P<0.001), and 72 h (20±2 vs. 25±6, P<0.001) post-admission. Interleukin-8 levels were lower in the case group at 48 and 72 h post-admission. Overall, 28-day mortality was 25.47% (54/212). Twenty-five children died in the sivelestat group, 29 children died in the control group. Survival analysis revealed that cumulative survival in the case group was higher than that in the control group (P=0.028).ConclusionsARDS is expected to have high morbidity and mortality in critical care medicine, and precise targeted drugs are lacking. Our study showed that sivelestat improved prognosis and reduces mortality in children with ARDS.

Project description:ObjectivesTo test the hypothesis that preconditioning animals with amifostine improves ventilator-induced lung injury via induction of antioxidant defense enzymes. Mechanical ventilation at high tidal volume induces reactive oxygen species production and oxidative stress in the lung, which plays a major role in the pathogenesis of ventilator-induced lung injury. Amifostine attenuates oxidative stress and improves lipopolysaccharide-induced lung injury by acting as a direct scavenger of reactive oxygen and nitrogen species. This study tested effects of chronic amifostine administration on parameters of oxidative stress, lung barrier function, and inflammation associated with ventilator-induced lung injury.DesignRandomized and controlled laboratory investigation in mice and cell culture.SettingUniversity laboratory.SubjectsC57BL/6J mice.InterventionsMice received once-daily dosing with amifostine (10-100 mg/kg, intraperitoneal injection) 3 days consecutively before high tidal volume ventilation (30 mL/kg, 4 hrs) at day 4. Pulmonary endothelial cell cultures were exposed to pathologic cyclic stretching (18% equibiaxial stretch) and thrombin in a previously verified two-hit model of in vitro ventilator-induced lung injury.Measurements and main resultsThree-day amifostine preconditioning before high tidal volume attenuated high tidal volume-induced protein and cell accumulation in the alveolar space judged by bronchoalveolar lavage fluid analysis, decreased Evans Blue dye extravasation into the lung parenchyma, decreased biochemical parameters of high tidal volume-induced tissue oxidative stress, and inhibited high tidal volume-induced activation of redox-sensitive stress kinases and nuclear factor-kappa B inflammatory cascade. These protective effects of amifostine were associated with increased superoxide dismutase 2 expression and increased superoxide dismutase and catalase enzymatic activities in the animal and endothelial cell culture models of ventilator-induced lung injury.ConclusionsAmifostine preconditioning activates lung tissue antioxidant cell defense mechanisms and may be a promising strategy for alleviation of ventilator-induced lung injury in critically ill patients subjected to extended mechanical ventilation.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets