Study On Enhancing The Treatment Of Pulmonary Fibrosis With The Help Of Natural "Conveyor Belt"

Pulmonary fibrosis（PF）is a chronic progressive lung disease with extremely high mortality.The average survival time of patients after diagnosis is 3-5 years.The pathogenesis of PF is still unclear and is characterized by excessive deposition of extracellular matrix in interstitial lung and massive collapse of alveolar space,finally leading to death due to respiratory failure.Only Pirfenidone（PFD）and Nintedanib are currently approved for PF therapy.Although these two drugs can delay the decline in vital capacity,they cannot restore lung function.In addition,as an organ of the human body in direct contact with the external environment,the lung has a strong defense system against foreign objects,and the lung surfactant layer is the main barrier for foreign objects to enter the lung tissue.Therefore,achieving lung function recovery and efficient drug transport to the lung tissue are of great significance for improving the survival rate of PF patients.Alveolar is the main place for gas exchange in the lung,and its microstructure directly affects lung function.However,in the pathogenesis of PF,excessive deposition of ECM leads to massive collapse of alveolar space,resulting in blocked gas exchange.Therefore,pulmonary function can be restored by reconstructing alveolar structures.Pulmonary surfactant is the main factor to maintain the stability of alveolar structure,which covers the surface of alveolar epithelium.By reducing the surface tension,it can avoid the collapse of alveolar during expiration,and reduce the respiratory force at the same time,to keep the alveolar relaxation during inhalation.Pulmonary surfactant is synthesized and secreted by TypeⅡalveolar epithelial cell（AECⅡ）.In the lung tissue of PF patients,The function of AECⅡis damaged due to oxidative stress and cannot synthesize pulmonary surfactant.Repairing AECⅡhas become a common method for pulmonary function recovery.However,in fact AEC II is slow to synthesize of pulmonary surfactant.Physiologically,AEC II maintains normal lung function through the recycling of"used"lung surfactants.Therefore,repair of AEC II failed to promptly replenish the damaged alveoli with the missing pulmonary surfactant.After the pulmonary surfactant is synthesized and secreted to the alveolar surface by AEC II,most of the pulmonary surfactant is recycled and secreted by AEC II,that is,from the"inside-outside",and then from the"outside-inside"circulation process.The pulmonary surfactant acts as a natural"conveyor belt",which constantly circulates on the alveolar surface and inside.Bionic lung surfactant,with the help of lung surfactant this natural"conveyor belt",is expected to provide a new strategy for the treatment of PF.With the rapid development of nano-science and technology,nano-bionic technology has made great progress in drug delivery systems.The nanoparticles prepared by the nano bionic technology can freely"wear"through organisms due to the natural characteristics of organisms to efficiently transport drugs.At present,these bionic nanoparticles simulate organisms mainly through the disguise of endogenous substances.This bionic technology preserves the characteristics of organisms to the maximum extent,but is greatly limited by the difficulty in obtaining materials.Pulmonary surfactant is a layer of lipid protein complex covering the alveolar surface,which is difficult to obtain directly from organisms.Therefore,this project intends to simulate the composition and microstructure of pulmonary surfactant,design and construct a pulmonary surfactant nano-bionic body,which integrates repair and treatment,to improve the curative effect of PF treatment.Pulmonary surfactant（PS）is a complex mixture of lipids and proteins consisting of phospholipids（～80%）,neutral lipids（～10%,mainly cholesterol）,and protein（～10%）.Among them,lecithin was the most abundant component in pulmonary surfactant,for example,unsaturated phospholipid-dipalmitoyl phosphatidylcholine in lecithin played an important role in reducing alveolar surface tension.At the same time,pulmonary surfactants can be found in lung tissue in various forms,which can be roughly divided into three categories according to the metabolic process:tubular myelin（a direct conversion of newly secreted pulmonary surfactant with complex structure）,multi-layer structure（which will continue to participate in the circulation on the alveolar surface）,and single-layer corpuscle（formed by the used pulmonary surfactant on the alveolar surface）.Among them,simulating the multi-layer structure of lung surfactant is an effective strategy for the nano-bionic body to enter the circulation of lung surfactant and realize the efficient transport of drugs to the lung tissue.In order to stabilize that stability of the multi-membrane structure,a membrane stabilizer is need to be introduced.The phospholipids in the pulmonary surfactant component are mostly negatively charged or uncharged,so cations need to be introduced as membrane stabilizers.Ca²⁺can not only promote the secretion of pulmonary surfactant by AECⅡ,but also stabilize the structure of pulmonary surfactant in the alveolar tissue.Based on the above analysis,in this study,the nano-bionic technology was used to construct the lung surfactant nano-bionic body-PSBs,using the functional components of lung surfactant as the raw material,to simulate the multi-membrane structure of lung surfactant on the alveolar surface,and to serve as a drug delivery carrier for efficient transport to the lung tissue.In combination with the action sites of anti-fibrosis drug PFD and active oxygen scavenger Astaxanthin（AST）,as well as the pulmonary surfactant circulation characteristics,PFD was encapsulated in the water-soluble core of PSBs,and AST was loaded in the lipid membrane of PSBs to obtain PSBs/AST@PFD.When PSBs reached the alveolar by aerosol inhalation,because of the similar composition and structure to PS,PSBs lipid membrane gradually fused with PS to supplement the functional pulmonary surfactant（adduction）for the alveolar.At the same time,AST loaded with lipid membrane was gradually transported to AEC II along with the circulation of pulmonary surfactant to repair its function（intrinsic）.At the same time,PFD encapsulated in the PSBs was released in situ to the inner side of the lung surfactant layer,and successfully crossed the lung surfactant layer and effectively entered the lung tissue mesenchyme to exert its efficacy.Using this"inside-out"treatment strategy and the natural"conveyor belt"（pulmonary surfactant circulation）to achieve the integration of treatment and repair,and synergistically enhance PF treatment,provides a new strategy for PF treatment.