PM2.5引起腸道細胞的氧化壓力、發炎反應、細胞增生、Nrf2活化、細胞自噬與腸道菌相失衡之間的互相影響

Air pollution can have a serious impact on human health. The aerosol concentration detected in various emission sources reveal the importance of air pollution issues in Taiwan. PM enter into the human gut from the lungs via the mucociliary transport system, which is also considered to affect the occurrence of inflammatory bowel disease (IBD). Epidemiological study reported that long-term exposure to higher concentrations of nitrogen dioxide and PM were associated with an increased risk of early-onset Crohn's disease. In addition, a rise in total measured air pollutants was associated with an increased risk of hospitalization for inflammatory bowel disease. A majority of limitation of epidemiologic air pollution studies is air pollution exposures generally based on regional estimates, not personal monitoring. Therefore, it is urgently need for basic biological studies to clarify the relationship and molecular mechanisms between PM and intestinal inflammation. Recent studies reported that gut dysbiosis is associated with intestinal inflammatory diseases. Exposure to PM may trigger oxidative stress and the increase expressions of inflammatory cytokines and gut permeability. The increased ROS may result in altering dynamics of the gut microbiota and imbalances of microbiome community. Moreover, ROS regulated autophagy may participate the gut immunity homeostasis. Our preliminary data showed that reduced colon length occur in mice exposure with PM2.5 collected from Kaohsiung for eight and twenty-four weeks. PM exposures also increased colon epithelial cell proliferations and gut dysbiosis. In vitro study with human colorectal epithelial cells also showed that PM trigger oxidative stress, NFkB activation, IL-8 production, and enhanced cell proliferations. We also found that autophagy formations, and increasing levels of NAD(P)H:quinone acceptor oxidoreductases 1 (NQO1) and heme oxygenase-1 (HO-1) after PM treatment. Meanwhile, long term exposure to PM enhanced AKT phosphorylation, Nrf2 and HO-1 expressions in human colorectal epithelial cells. Therefore, the main goal of our project proposal is to clarify the molecular mechanism of PM-induced intestinal inflammation, including oxidative stress, inflammation, cell proliferation, Nrf2 activation, autophagy formation, and gut dysbiosis. We have two major specific aims, AIM 1 is to investigate roles of ROS in gut inflammation, and dysbiosis after PM2.5 oropharyngeal aspirations in a mouse model. AIM 2 is to investigate the crosstalk between ROS, inflammation, cell proliferation, Nrf2 activation, and autophagy formation after PM2.5 treatments in cell model. Taken together, this project will help to clarify the underlying molecular mechanisms of intestinal inflammation induced by PM2.5. Additionally, our finding about PM2.5 may provide scientific evidences to reduce the impacts of PM2.5 on public health.