Study On The Mechanism Of Lung Cancer Induced By Protein Corona Mediated PM2.5 And Cigarette Smoke Particles

Epidemiological studies have shown that inhalable fine particles in the air,such as PM2.5 and cigarette smoke particles,are closely related to the occurrence and development of lung cancer.In this kind of particulate matter,nano-sized particles account for a higher proportion,which can reach the distal airway and eventually deposit in the alveolar area after being inhaled.So these particles have higher health risks.At present,researches on the mechanism of lung diseases caused by fine particles mainly focus on the influence of particulate matter on gene mutation,inflammatory injury and other processes.There is a lack of research on the role of nanometerbiological interface in the development of lung cancer.After entering the blood or tissue interstitial fluid,the surface of nanoparticles will be covered by biomacromolecules in a very short time,that is,the structure of protein corona will be formed and used as the new "biological identity" of nanoparticles in the body,which will affect the properties of particle materials and the proteins adsorbed.Meanwhile,protein corona can affect the biological characteristics of nanoparticles,such as uptake,transport,conditioning and biological distribution,etc.in the body,and play a decisive role in biological effects and the cytotoxicity of nanoparticles.Studies from this perspective are expected to explore new mechanisms of lung cancer induced by PM2.5 and cigarette smoke particles.Firstly,the protein corona formed by the two kinds of particles in lung tissues were analyzed.The results of LC-MS and the clustering analysis of protein showed that a large number of enzymes were adsorbed on the surface of the two kinds of particles.Meanwhile.KEGG database sho that the composition of the protein corona was highly enriched with signaling pathways related to the extracellular matrix(ECM).The change of ECM structure has an influence on the occurrence and development of lung cancer.Thus,by comparing the ECM-related protein in the Reactome database with the enzyme co-adsorbed by the two particles,we can screen out the enzyme with the high correlation and the highest abundance in the ECM-related proteins co-adsorbed by the two particles.namely the peroxidasin(PXDN).PXDN was associated with the cross-linking of collagen Ⅳ and the remodeling of ECM.More importantly,the results of temporal correlation analysis and enzyme activity detection about PXDN adsorbed by particles showed that PXDN could exist stably on the surface of the particles,and the adsorption of particles can enhance its enzyme activity abnormally.The granule perfusion group model also confirmed the above contents.In the experimental groups,the cross-linked collagen Ⅳ and the tissue density in the lung tissue of mice was significantly increased.The cross-linking of collagen represented by Ⅳ collagen can lead to the remodeling of ECM,which will affect the migration of immune cells in the body.Dense fibers can even limit the interaction between immune cells and cancer cells.Because the migration of immune cells in the interstitial tissue is of great significance to remove pathogens and tumor cells,the inhibition of migration may promote the occurrence of cancer and other related diseases.The distribution and migration of immune cells in the granule perfusion model were analyzed by flow cytometry and immunofluorescence real-time photography.The results showed that the degree of cross-linking was increased in the lung tissue of the granule infusion group,which further affected the remodeling of ECM and the structure of lung tissue.The stimulation of T cell chemotactic factor 10(CXCL10)was given,and the migration rate of immune cells in the granule infusion group was slowed down,that is,the migration was inhibited.Lung cancer model showed that particle perfusion group would aggravate the occurrence of lung cancer,which further confirmed our conjecture.Above all,PM2.5 and cigarette smoke particles can form the protein corona after entering the body.The abnormal increase of PXDN enzyme activity mediated by protein coronas will promote the cross-linking of collagen Ⅳ,thereby promoting the remodeling of ECM and increasing the density of lung tissue.These changes will hinder the migration of immune cells and make them unable to timely detect pathogens or tumor cells,thus exacerbating the occurrence of lung cancer.This subject comprehensively applies the technology of material science,chemistry and biomedicine to study the pathological toxicity of PM2.5 and cigarette smoke particles and their impact on the occurrence and development of lung cancer from the perspective of protein corona,which provides a new theoretical explanation for the pathogenesis of lung cancer and is expected to provide new strategies for the prevention and treatment of the disease.