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Cigarette Smoke-induced Lung Injury with the Relevant of Tyrosine Phosphatase PTPNⅡ Activity

Author: CaoZuo
Tutor: XieQiangMin
School: Zhejiang University
Course: Pharmacology
Keywords: SHP-2 PHPS1: protein tyrosine phosphatase SHP-2 inhibitors Cigarette smoke CSE: cigarette smoke extract IL-8: interleukin-8 MMP-9: matrix metalloproteinase- 9 Mice
CLC: R96
Type: Master's thesis
Year: 2011
Downloads: 62
Quote: 0
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Abstract


Protein tyrosine phosphatase SHP-2 (protein tyrosine phosphatase SHP-2) is a PTPNII gene encoding the protein tyrosine phosphatase enzyme. Cytoplasmic protein tyrosine phosphatase SHP-2 which is one compound containing 2 SH domains, as cytokines, growth factors and other extracellular stimuli factors downstream signaling molecules widely expressed in the body for a variety of tissues and cells , involved in cell proliferation, differentiation, death, and many other cellular activities. In recent years, the study found PTPNII adolescent leukemia, Noonan syndrome, LEOPARD syndrome mutations will lead to disease. Cigarette smoke-induced lung inflammation and lead to the damage of the lung tissue, which is the most common chronic obstructive pulmonary disease (COPD) as a causal factor. Study of the relationship between SHP-2 with cigarette smoke induced lung injury either whole or in vitro showed no relevant reports. In order to study the relationship between the SHP-2 in cigarette smoke cause lung tissue damage and mechanism of action, we were established airway instillation of cigarette smoke extract (CSE) induced acute inflammation model, continuous cigarette smoke exposure induced in four days COPD model and a single cigarette smoke exposure model for the research found that: (1) by airway instillation CSE can produce acute inflammatory response in mice, the lavage fluid (BALF) of the total number of white blood cells, neutrophils there were significant increases in the number of cells and the number of macrophages. The lung tissue homogenates of TNF-a, IL-8, MCP-1 of the mRNA expression increased. Before dropwise CSE 0.5h intraperitoneal injection of SHP-2 inhibitors PHPS1 (1mg/kg) can significantly reduce the number of leukocytes and neutrophils in the BAL fluid. The pathological observation also found PHPS1 able to significantly reduce the infiltration of inflammatory cells. The 1mg/kg PHPS1 also inhibited CSE-induced lung homogenates of MCP-1 and IL-8 mRNA expression rose. (2) Use 3R4F standard cigarette to cigarette smoke exposure COPD model was prepared C5781 / 6 mice for four consecutive days. : BAL fluid model group increased by about four times the total number of white blood cells, neutrophils and macrophages also have a very significant rise in the study. Day in cigarette smoke attack before 0.5h, and cigarette smoke attack after 4h were given 0.3mg/kg, 1mg/kg, and 3mg/kg PHPS1 well 0.5mg/kg dexamethasone phosphate (DXM) treatment, can significantly reduce cigarette smoke exposure caused BALF fluid and biopsy in the total number of leukocytes and neutrophils rose (3) the number of airway resistance in COPD model group and blank group a significant rise compared to the same time, the model group cause airway resistance 200% increase in the required concentration of Mch (RLPC200, its value is smaller experimental animals to external stimuli cause changes in lung function more sensitive) is only 37% of the blank, continuous twice daily intraperitoneal injection 6mg/kgPHPS1 mice can significantly ease the increase in airway resistance, and its RLPC200 relative to the model group increased about 1 times. Further immunohistochemical show, PHPS1 dose dependent reduction in the increase in the cigarette smoke-induced lung tissue peribronchial MMP-9 protein expression. (4) 12h after a single attack of cigarette smoke, the lung tissue of mice in KC and IL-8 mRNA expression was significantly increased, and IL-8 protein expression increased by approximately doubled. 30 minutes ago in cigarette smoke attack pre intraperitoneal injection 6mg/kg PHPS1 KC and IL-8m RNA expression had no significant effect. But after intraperitoneal injection 3mg/kg and 6mg/kgPHPS1 of, which can significantly inhibit the increase in IL-8 protein expression in cigarette smoke-induced lung tissue. Our study is the first to find PHPS1 by inhibiting the activity of SHP-2 protein of lung epithelial cells significantly reduced expression of lung inflammatory chemokines induced by cigarette smoke (CS) and cigarette smoke extract (CSE) thereby affecting inflammatory cell recruitment and chemotaxis, and relieve inflammation of the lungs. , PHPS1 to ease COPD model of airway remodeling in a dose-dependent manner. Compared with model group, twice a day by intraperitoneal injection of 6mg/kg PHPS1 can significantly reduce the increased airway resistance induced by methacholine choline (MCH), and improve administered group RLPC200 value. Through the study, we first found PHPS1 can inhibit the activity of SHP-2, to reduce the release of inflammatory mediators induced by cigarette smoke and reduce the infiltration of inflammatory cells, while reducing by cigarette smoke-induced small airway remodeling and to improve the small rat's lung function. The above findings provide new ideas and new directions to further clarify the pathological mechanisms of COPD as well as for the treatment of COPD.

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