Paradigm Of The Expressions Of Notchs And Transcription Factors That Drives Th1 Polarization In Cigarette Smoke Induced Pulmonary Emphysema

Background:Several signaling pathways, including Notch pathway, modulate and affect T cells development and differentiation, but little is known about the role of these pathways in chronic obstructive pulmonary disease (COPD) and emphysema.Objective:To clarify if there is a specific express pattern of Notch and relevant transcription factors that drives the imbalance of Th1/Th2 response in cigarette smoke induced pulmonary inflammation.Methods:C57BL/6 mice were randomized into 2 groups, e.g. with cigarette smoke exposure and air exposure for 24 weeks. Real-time PCR was applied to examine the expressions of T-bet, Gata3, Foxp3 and Notch-related genes, and immunohistochemistry was used to evaluate expression of key Notch-related proteins in paratracheal lymph nodes from the two groups. The contents of cytokines in bronchoalveolar lavage fluid (BALF) were also evaluated simultaneously.Results:Chronic smoke exposure caused, as compared to those in controls, an increase in mean linear intercept (+22%) and a decrease in internal surface area (-16%). The ratio of IL-4 / IFN-γin BALF was significantly reduced, whereas T-bet/Gata3 and T-bet/Foxp3 in paratracheal lymph nodes were increased compared to control group. Real-time PCR confirmed that the expressions of the receptors Notch1, Notch3 and the ligands Dll4, Jag1 were up-regulated in cigarette smoke exposure group. Immunohistochemistry demonstrated expression of Notch1, Notch3 and Dll4 in paratracheal lymph nodes.Conclusions:Present study indicates that chronic cigarette smoke exposure would induce emphysema-like damage to the lungs which is associated with a remark Th1 inflammation bias. Paradigm of upregulation of Notch1, Notch3, Dll4 , T-bet, and downregulation of Foxp3 leads to Th1 polarized response.