Molecular Mechanism Of PM2.5-induced Airborne Inflammatory Stress Injury And Vascular Endothelial Dysfunction

PM2.5,also known as fine particulate matter,refers to atmospheric particles whose aerodynamic diameter is less than or equal to 2.5?m.Epidemiological and clinical studies have increasingly shown that PM2.5 exposure is a risk factor mainly associated with respiratory and cardiovascular morbidity and mortality.Therefore,elucidating the toxicological mechanisms that link inhaled particles with damage to the respiratory and cardiovascular systems in vivo and in vitro is an active area of research.In previous studies,PM2.5 treatment induced p53-DRAM1 pathway activation,which was critical for mediating autophagy induction,and increased VEGF production by activating the SRC-STAT3 pathway in bronchial epithelial cells(Beas2B).Therefore,these have revealed that PM2.5 induced respiratory inflammation,which is the core of VEGF induction.The first part of this work tried to further understand how PM2.5 triggers inflammatory responses in the respiratory system,which is crucial for the study of PM2.5 toxicity.By exploring the upstream signaling events responsible for p53 activation,we revealed the expression of its upstream protein kinases ATR/ATM and found that ATR was the key to PM2.5-induced p53 activation,autophagy and VEGF induction,not for ATM.Further investigations showed a potential role of CHEK1 downstream of ATR in mediating PM2.5-induced responses.Moreover,PM2.5 exposure strongly induced the activation of the LKB1,which can also activated p53 and subsequently triggered p53-DRAM1/TIGAR-dependent autophagy and VEGF production in Beas2 B cells.But the expression of the LKB1 is not controlled by ATR/CHK1.These results thus indicate that the ATR/CHEK1-p53-DRAM1 pathway activation is critical for mediating autophagy-dependent VEGFA induction in PM2.5-treated Beas2 B cells.In addition,activating the LKB1-p53-DRAM1/TIGAR pathway mediated PM2.5-induced responses.Therefore,these findings suggest a novel link between processes regulating genomic integrity and airway inflammation via autophagy induction in bronchial epithelial cells under PM2.5 exposure.PM2.5 can not only reach the deep parts of the respiratory tract,but also penetrate deeply into the lung alveoli and enter the bloodstream to cause cardiovascular damage.Previously,we concluded that HIF1? was involved in the transcriptional induction of ACE/ANGII/AT1 R axis components,which mediated proinflammatory response,in the vascular endothelial cells under PM2.5 exposure.In the second part of our work,we further revealed the molecular mechanism of PM2.5-induced endothelial dysfunction.Rats after intratracheally instillation with PM2.5 displayed increased circulating level of ANGII,as well as the elevation of local AGT,ACE and AT1 R expressions in the vascular endothelium.In vitro studies in primary rat aortic endothelial cells(RAEC)also demonstrated upregulation of AGT,ACE and AT1 R synthesis and increased ANGII generation after PM2.5 exposure.Furthermore,activation of IRE1?/XBP1 s is essential for local augmented ACE/ANGII/AT1 R axis components,and the assembly of XBP1s/ HIF1? transcriptional complex contributed largely to the induction of AGT,ACE and AT1 R transcription in the PM2.5-treated vascular endothelial cells.Moreover,ablation of IRE1?/XBP1s/HIF?-dependent ACE/ANGII/AT1 R axis activation inhibited oxidative stress and pro-inflammatory response in the vascular endothelial cells induced by PM2.5.PM2.5 exposure induces endoplasmic reticulum(ER)instability,leading to the activation of IRE1?/XBP1 s branch of UPR and links HIF1? transactivation to mediate ANGII-dependent endothelial dysfunction.Thus,identifying novel therapeutic targets to alleviate ER stress and restore local RAS homeostasis in the endothelium may be helpful for the management of CV burden under PM2.5 exposure.In the follow-up study,we also explored whether PM2.5 can induce damage protection effect.The results showed that HO-1 induced by PM2.5,inhibited the expression of RAS,adhesion molecules and chemokines by antagonizing HIF1? expression.Therefore,these findings show that HO-1 can mediate the protective effect of inflammatory injury under PM2.5 exposure.The prevention and control strategy of damage effects on cadiovascular system induced by PM2.5 should be discussed in depth by targeting "HO-1-HIF1?-AGT/ACE/AT1R" signal pathway.