The Association Between PM_2.5 Exposure And Outpatient Visits For Respiratory Diseases And The Mechanism Of HIF-1α In PM_2.5 Induced Lung Injury

【Background】Air pollution is an important public health problem.As the primary air pollutant in cities,PM_2.5,which is widely concerned by the public,has significant adverse effects on human health,especially respiratory system.Due to its small volume（diameter<2.5μm）,PM_2.5 can reach the pulmonary alveoli through all levels of bronchi,leading to the increase of cytokines level and inflammatory response,damaging pulmonary vascular permeability,causing pulmonary edema,and ultimately causing lung injury.Some studies have confirmed that HIF-1αexpression is increased in lung injury models caused by multiple factors such as lung contusion,LPS,sea water drowning,etc.It can activate a variety of inflammatory factors to cause lung inflammation,and the expression of HIF-1αprotein level is closely related to the aggravation of pulmonary vascular barrier damage.In order to find the epidemiological evidence that PM_2.5 causes or aggravates lung injury,this study conducted a meta-analysis of the association between PM_2.5 exposure and outpatient visits for respiratory diseases in China,based on the mechanism of PM_2.5induced lung inflammation and pulmonary edema leading to lung injury and the important role of HIF-1αin response to pneumonia and changes in pulmonary vascular permeability,this study investigated whether HIF-1αplays a role in PM_2.5 induced lung injury and its mechanism.【Objective】1.To explore the association between PM_2.5 exposure and the outpatient visits for respiratory diseases in China.2.To explore the lung injury and HIF-1αexpression of rats exposed to different concentrations of PM_2.5.3.To explore the role of HIF-1αin the mechanism of PM_2.5 induced lung injury.【Methods】1.Literature on the association between PM_2.5 exposure and outpatient visits for respiratory diseases in China published in Chinese and foreign databases from January 1,2012 to January 1,2022 was retrieved and sorted out,and meta-analysis was performed by using Stata12.0 software.2.Animal models of lung injury induced by different concentrations of PM_2.5suspension（0,0.375,1.5,6,24mg/kg）were constructed.Lung tissues of rats were dissected after death,and the pathological injury degree of lung tissues was observed by HE staining.ROS and TUNEL staining were used to observe the ROS generation and apoptosis of lung tissues of rats.Bronchoalveolar lavage fluid（BALF）was collected for leukocyte classification and counting.The levels of inflammatory factors IL-6 and TNF-αin BALF were detected by ELISA.The wet-dry weight of lung tissue was weighed to determine the wet-dry ratio of lung tissue of rats.The levels of HIF-1αin rat lung were determined by western blotting.3.The rats were divided into 5 groups,including PBS,PM_2.5（1.5mg/kg）,PM_2.5（1.5mg/kg）+Acri,PM_2.5（6mg/kg）and PM_2.5（6mg/kg）+Acri,according to whether PM_2.5was dripped and added HIF-1αinhibitor Acri.The levels of HIF-1α,p-p65 and VEGF in rat lung tissues were detected by western blotting,and the levels of inflammatory factors IL-6 and TNF-αin BALF were detected by ELISA.The level of albumin in BALF of rats was detected with albumin detection kit,and the wet-dry weight of lung tissues was weighed to determine the wet-dry ratio of lung tissues.【Results】1.A total of 23 literatures were included and 26 groups of data were extracted.The relative risk（RR）of outpatient visits for respiratory diseases in China was 1.0068（95%CI:1.0052,1.0083）for every 10μg/m³ increase in PM_2.5 mass concentration.2.Compared with the control group,pathological damage such as edema,inflammatory cell infiltration and alveolar wall thickening occurred in the lung tissues of rats after PM_2.5 exposure,ROS level,apoptosis rate and wet-dry ratio increased in the lung tissues of rats,inflammatory cell count and inflammatory factors IL-6 and TNF-αlevels increased in BALF,and HIF-1αlevel increased in the lung tissues of rats.The above effects are correlated with PM_2.5 exposure concentration.3.Compared with PM_2.5 exposure group,HIF-1αlevel in lung tissue of rats in PM_2.5+Acri group was significantly decreased,and inhibition of HIF-1αcould reduce the expression of NF-κB in lung tissue of rats,and the levels of inflammatory factors IL-6 and TNF-αin BALF.Inhibition of HIF-1αcan decrease VEGF expression,albumin level in BALF and wet-dry ratio of lung tissue in rats.【Conclusions】1.There is a certain correlation between PM_2.5 exposure and outpatient visits for respiratory diseases in China.With every 10μg/m³ increase of PM_2.5 mass concentration,the incidence of outpatient visits for respiratory diseases in China increased by 0.68%.2.PM_2.5 exposure leads to lung injury in rats,and this process is accompanied by increased HIF-1αprotein level,which is related to PM_2.5 exposure dose.3.Inhibition of HIF-1αdecreased NF-κB expression level and reduced lung inflammation induced by PM_2.5 exposure.Inhibition of HIF-1αcan reduce VEGF expression level,ameliorate the damage of pulmonary vascular barrier caused by PM_2.5exposure,and alleviate pulmonary edema.