The Role Of Autophagy In The Airway Inflammation Induced By PM2.5

A lot of previous studies have shown that exposure to environmental particulate matter (PM) is associated with adverse health effects, including the development of pulmonary disease, cardiovascular diseases and cancer, and lead to increased morbidity and mortality. PM is mainly generated from industrial processes and burning of biomass and fossil fuels. It is capable of depositing in the respiratory tract or coming into alveolar, consequently induces or worsens pulmonary diseases. Studies have demonstrated that PM exposure is able to cause airway inflammation and airway hyperresponsiveness to methacholine, when co-administered ovalbumin, it would lead to increased allergic sensitization and exacerbation of asthmatic symptoms. Several studies also have established relationships between PM exposure and epithelial to mesenchymal transition (EMT).Autophagy is an essential process by which cells eliminate their own cytoplasmic materials and produce new building blocks and energy for cellular renovation and homeostasis. There are three types of autophagy: macroautophagy, microautophagy and chaperone-mediated autophagy. Macroautophagy which is thought to be the best characterized way of autophagy, is often referred to as autophagy. During autophagy, An double-membrane derived from the endoplasmic reticulum, the Golgi complex, the mitochondria, and the plasma membrane encapsulates a small portion of the cytoplasm to form autophagosome, subsequently fuses with the lysosome and delivers its contents to the lysosome for a degradation process. To date, there are increasing evidences suggest that autophagy is relevant to the pathogenesis of human disease, including pulmonary disease. Autophagy may play an important role in asthma, COPD, acute lung injury, respiratory infection, pulmonary hypertension and cystic fibrosis.Moreover, PM exposure can induce autophagy. These studies have suggested a strong relationship between autophagy and PM-induced airway inflammation, which remains to be addressed.Objective:to investigate the role of autophagy in the airway inflammation induced by PM2.5.Method:In vitro, IL-8mRNA level were measured using real-time PCR. To monitor autophagy, we measured increased LC3B by Western blot and to observe the typical autophagosome in the images of transmission electron microscopy (TEM). Autophagy deficiency in HBE cells was achieved using autophagy related gene siRNA and autophagy inhibitor.In vivo, mice were randomly divided into four groups:saline-exposed wild type (WT/NS), Beclinl+/-/NS, PM-exposed wild type (WT/PM2.5), Beclinl+/-/PM2.5. The WT/PM2.5and Beclinl-/-/PM2.5mice were intranasal injection of PM2.5(100μg in50μl saline). The WT/NS and Beclinl+/-/NS mice received the same volume of vehicle. After24h, airway inflammation was determined by the leukocyte recruitment and cytokine levels in the bronchoalveolar lavage fluid (BALF). Additionally, in order to investigate the changes in pathology, lung tissue was examined by histology.Results:Increased autophagy was observed in HBE cells after exposure to PM2.5for24h, as indicated by electron microscopic analysis, as well as by increased activation of autophagic protein LC3B. In addition, PM2.5exposure increased the expression of IL-8. After transfection with autophagy related siRNA or pretreatment with autophagy inhibitor, the autophagy decreased, and the IL-8expression in response to PM2.5was significantly blocked.In animal model using airway exposure, PM2.5has been shown the capability of causing airway inflammation. Exposure to PM2.5increased total cells" and neutrophils in BALF, and increased the level of KC and MLP-2expression both in BALF and lung. The Beclinl+/-/mice resisted PM2.5-induced airway inflammation. Compared with group WT/PM2.5, the total cells and neutrophils in BALF decreased in the Beclinl+/-/PM2.5mice, and the expression of KC and MIP-2also down-regulated. What’s more, according to the pathological assay, the inflammation cells infiltration was attenuated in the Beclinl+/-/PM2.5mice compared with the WT/PM2.5mice.Conclusion:We demonstrated a critical role for autophagy in IL-8expression in human bronchial epithelial cells and airway inflammation in response to PM2.5in vitro and in vivo. The induction of autophagy suggests novel therapeutic targets for the treatment of PM2.5-induced airway inflammation.