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http://hdl.handle.net/11375/22319
Title: | ROLE OF THE IRE/XBP-1 PATHWAY IN CIGARETTE SMOKE AFFECTED MACROPHAGE POLARIZATION IN VITRO |
Authors: | Mahmood, Sohail Hassan |
Advisor: | Ask, Kjetil |
Department: | Medical Sciences (Molecular Virology and Immunology Program) |
Keywords: | ER Stress, Cigarette smoke, IRE-1, UPR, macrophage polarization, Chronic Lung Disease |
Publication Date: | 2017 |
Abstract: | Cigarette smoke contributes to 90% of lung cancer cases and 80% of COPD cases. These concerns loom large as lung cancer represents 13% of all cancer deaths and estimates report by 2020 COPD will be the third leading cause of death in the world. The master regulator of the ER stress response, IRE-1, in the context of cigarette smoke exposure lacks study. Interestingly, its downstream pathways are activated. In fact, the 2014 Surgeon General’s report on the health consequences of smoking highlighted the endoplasmic reticulum (ER) stress response as a potential mechanism leading to the development of lung cancer and Chronic Obstructive Pulmonary Disorder (COPD). Following acute cigarette smoke exposure, mouse lung homogenates exhibited increased levels of XBP-1 along with downstream mediators of IRE-1 activation— GRP-78 and CHOP. Specifically observing macrophages, an important immune cell and source of acute inflammation, cigarette smoke induced activation of IRE-1/XBP-1 pathway through splicing of XBP-1 mRNA. However, upon assaying for pro-inflammatory cytokines we were unable to determine that cigarette smoke directly caused inflammation in vitro. Furthermore, cigarette smoke inhibited the activation of M2 macrophages, an anti-inflammatory and tissue healing subset seen through CCL18 inhibition. A majority of M2 and M1 macrophage markers were decreased from IRE-1/XBP-1 inhibition. This suggests a different phenotype than classical M1 or M2 polarization being induced by cigarette smoke. In addition, it suggests the IRE-1/XBP-1 pathway having a robust role in controlling gene expression and balance of cellular proteomics. |
URI: | http://hdl.handle.net/11375/22319 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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MAHMOOD_SOHAIL_H_1707_MSC.pdf | Medical Sciences: Infection & Immunology | 2.29 MB | Adobe PDF | View/Open |
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