A disruption of lung barrier function

A disruption of lung barrier function caused by PM2.5 has been observed in our experiments; however the underlying mechanism has not been investigated. Zhao et al. (2018) reported that PM2.5 down-regulated the expression levels of tight junction (TJ) proteins and resulted in nasal epithelial barrier dysfunction via ROS. The elevation of ROS by PM2.5 has been validated in our study, thus the possible mechanism explaining PM2.5-induced lung barrier dysfunction is ROS generation. Upregulation of connexin (Cx) 43 is another reasonable direction to explore, since it acts as an important mediator in sliver nanoparticles-increased gap junctional intercellular communication (GJIC) (Qin et al., 2018). The chemical adsorbed on the surface of PM2.5 is mainly responsible for the detrimental effects of PM2.5. Both transition metals and PAH are powerful generators of oxidative stress that provokes inflammation and further damage (Miyata and van Eeden, 2011). In comparison with PM10 or other larger PM, PM2.5 has a greater adverse impact on human health because of its relatively small size. The small diameter facilitates inhaled particles to travel through the airways, reach the gas exchange site, deposit in the Calmidazolium chloride and enter circulatory system to trigger lung and cardiovascular inflammation, while larger particulate matters are generally filtered in the nose and throat via cilia and mucus. Besides, PM2.5 has a larger specific surface area compared with larger particles, allowing itself to adsorb more hazardous chemicals. For instance, the percentage of iron concentration in NIST IRM PM2.5 is approximately 4-fold higher than that in NIST SRM 1648 PM10 (Shoenfelt et al., 2009). We have discovered the potential of HMW-HA as an intervention to PM2.5-induced pulmonary injury and revealed that the mechanism involves the antioxidant property of HMW-HA that protects epithelial cells from death. HA has been widely used in the treatment of various diseases including OA and dry eye, surgery, tissue engineering, biomaterials and drug delivery (Labetoulle et al., 2017; Mun et al., 2017; Almond, 2007; Baeva et al., 2014). The application of aerosolized exogenous HA in respiratory diseases has been proposed as well recently. For instance, intermittent nebulization with HA could minimize symptoms and prevent exacerbation of chronic rhinosinusitis (CRS), and aerosol administration of HA reduced muscular exercise-induced bronchoconstriction in patients with asthma (Casale et al., 2014; Petrigni and Allegra, 2006). Interestingly, HMW-HA (∼1000 KDa) rather than LMW-HA (∼300 KDa) restrained methacholine-caused bronchoconstriction in asthmatics, suggesting that the function of HA is size dependent (Allegra et al., 2008). In consistent with our discovery, Jiang et al. (2005) reported that overexpression of HMW-HA exhibited anti-apoptotic feature that promoted lung epithelium integrity and recovery from ALI partially through TLR-dependent basal activation of NF-κB. CD44 is a primary receptor interacting with HMW-HA. It contributes to ROS defense through upregulation of reduced glutathione (GSH) synthesis, bringing about apoptosis resistance (Nagano et al., 2013). Other possible mechanisms related to the protection of HMW-HA include regulatory T-cell activation, adaptive immunity suppression and negative regulation on TLR4 signaling (Garantziotis et al., 2016). We have not noticed any side effects caused by intratracheal instillation of HMW-HA in our rat model (data not shown). Given that HMW-HA might be degraded to pro-inflammatory short-fragments and cause unwanted effects, a study was performed to evaluate the safety of chronic use of inhaled HMW-HA, an adjunct to hypertonic saline for patients with cystic fibrosis (CF) to preserve lung function, increase compliance and prolong life, and the results proved that HMW-HA would not induce the production of inflammatory cytokines in CF airways (Ros et al., 2014; Lamas et al., 2016). Although HMW-HA is relatively innocuous, safety evaluation should be managed carefully before it goes further to clinical practice. Further study may also investigate the therapeutic effect of HMW-HA on PM2.5-disrupted cardiovascular system.