Protective Role Of The Porous Se@SiO₂ Nanoparticles In The Model Of ALI And The Mechanisms Of ALI New-onset Atrial Fibrillation And Development Of Interventional Technique

Background&Objective:Acute lung injury（ALI）and acute respiratory distress syndrome（ARDS）are severe respiratory diseases that seriously threaten human life globally.At present,more than 3 million patients could be diagnosed every year worldwide.The treatment strategies mainly include non-specific anti-inflammatory drugs such as glucocorticoids and traditional Chinese medicines,coordinate with organ supporting methods,such as mechanical ventilation,ECMO,CRRT,artificial liver and etc.However,the overall mortality of ALI/ARDS remained over 40%throughout the world.Therefore,the clinical management of ALI/ARDS still faces lots of challenges.The purpose of the present study is to explore the effect of novel porous Se@SiO₂ nanoparticles and cryo-balloon denervation system on maintaining airway epithelial mitochondrial homeostasis and reducing new-onset atrial fibrillation and to elucidate possible mechanisms.By developing these theranostic tools,we hope to optimize the management of ALI/ARDS and its common complications.Part I:Mitochondria-Targeting Porous Se@SiO₂ Nanoparticles Protect the Mice from LPS-induced ALI by Maintaining Mitochondrial Homeostasis Method:Transmission electron microscope（TEM）and X-ray diffraction（XRD）were used to characterize the physical and chemical properties of porous Se@SiO₂.Laser confocal imaging,RNA-seq,Western blotting,and mitochondrial respiratory chain（MRC）detection were used to evaluate the effects of the novel nanoparticles on mitochondria of airway epithelial cells（AEC）and to further elucidate its possible mechanisms.GO and KEGG pathway analysis were used to explore the general effect on AEC.A mice ALI model induced by lipopolysaccharide（LPS）was used to evaluate the protective effect of the nanoparticles.Results:The present study demonstrates that Se@SiO₂ NPs significantly increase the resistance of AECs under oxidative injury and shift LPS-induced gene expression profile closer to the untreated controls.The cyto-protection of Se@SiO₂ is achieved by maintaining mitochondrial ROS-scavenging activity and elevating the activities of MRC complex I,III and V.Moreover,mitochondrial morphology and dynamics are also ameliorated by the NPs in LPS-stimulated AECs.In an animal model of ALI,pretreated with the NPs improves mitochondrial dysfunction within airways,thus reducing inflammatory responses and diffuse damage in lung tissues.Additionally,RNA-seq analysis provides evidence for the broad modulatory activity of our Se@SiO₂NPs and their potential for clinical translation in various metabolic disorders and inflammatory diseases.Conclusion:The present study demonstrated that the porous Se@SiO₂ NPs enhanced the resistance of airway epithelial cells against LPS-induced acute injury.Possible mechanisms lied in protecting functional stability and preserving structural integrity of mitochondria in AECs.Furthermore,this nanodevice was able to control airway inflammatory responses and attenuate tissue injuries in an LPS-induced ALI mouse model.This study brings new insights into mitochondria-modulating bioactive NPs,with potential applications in treating ALI/ARDS or other human mitochondria-related diseases.Part II:The Role of Vagus Nerve in ALI New-onset Atrial Fibrillation and Feasibility,Effectiveness,and Safety of a Novel Cryo-balloon Denervation Technique.Methods:Western-blot was used to detect the expression of vagus nerve proteins in the lung and heart tissues of ALI mice.Drugs such as atropine and carbachol were used to regulate vagal nerve activity and evaluate the role of vagus nerve in new onset atrial fibrillation of ALI/ARDS by electrophysiological examinations.A preclinical study was performed on twelve sheep,four were tested for airway resistance alterations before and after TLD;two were tested for the Hering-Breuer reflex（HBR）before,immediately after,and 7 days after the surgery;and the remaining six sheep were evaluated for 28 days to assess the safety and effectiveness of the procedure.Results:The expressions of M-cholinergic receptors in the lung and heart tissues and the rate of atrial fibrillation induction of ALI mice were significantly increased.By inhibiting vagus nerve activity,the rate of atrial fibrillation induction in ALI mice could be effectively reduced.After an observation period of 28 days,significant disruption of vagal innervation to the lung could be validated by both histological and physiological assessments.The operation time was shorter than that in the traditional procedure,with minimal adjacent tissue injury and no device-related adverse events.Conclusion:Vagus nerve plays the vital part in the ALI/ARDS new onset atrial fibrillation.Modulating the status of vagus nerve could effectively lower the incidence of atrial fibrillation.The novel cryo-balloon denervation procedure was feasible,safe,and effective.