Cigarette Smoke-induced Lung Injury With The Relevant Of Tyrosine Phosphatase PTPNⅡ Activity

The protein tyrosine phosphatase (PTP) SHP-2 is encoded by a gene PTPN11. This PTP contains two tandem Src homology-2 domains and it is widely expressed in most tissues.SHP-2 plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome, LEORARD syndrome and acute myeloid leukemia.The primary risk factor for COPD is chronic tobacco smoking. However, the relationship between SHP-2 and diseases caused by cigarette smoke have not been reported in the relevant reports. Thus, our current study was set to study whether a SHP-2 inhibitor-PHPS1 is a novel anti-inflammation drug and whether SHP-2 is a novel therapeutic target for COPD.We used ICR mice intratracheal instillated of CES to observerd the effects of PHPS1 on the CSE-induced inflammation. We also investigate the effects of PHPS1 on 1 day or 4 consecutive days exposed to cigarettes smoke in the C57B1/6 mice. The results include:(1) The CSE instillated from airway can lead to a cute inflammation. The total cells, neutrophil and macrophage numbers were significantly increased in the broncho alveolarlavage fluid (BALF). ICR mice were intratracheal instillated by 8mg/kg CSE 30minutes after an intraperitoneal injection of lmg/kg PHPSl. The total numbers of inflammatory cells and neutrophil were significantly decreased in the lmg/kg PHPS1 group of mice compared to model. IL-8 and MCP-1 mRNA expression were also inhibited by PHPS1 and PHPS1 markedly attenuated CSE-induced eosinophil infiltration in lung tissues.(2) On 4 consecutive days C57B1/6 mice were exposed to CS.30 min before and 4h after CS exposure mice were treated by an intraperitoneal injection of PHPS1. The total numbers of inflammatory cells and neutrophil in BALF were decreased by 0.3,1 and 3 mg/kg PHPS1 in a dose-dependent manner. PHPS1 also markedly attenuated CS-induced eosinophil infiltration in lung tissues and the MMP9 protein were also dose-dependently decreased by PHPS1 in the small airway.(3) On 4 consecutive days C57B1/6 mice were exposed to CS. CS-exposed mice exhibited an obvious AHR with a significant and dose-dependent increase in RL as compared with air-exposed mice. The provocation concentration (PC) of methacholine which cumulatively produced a 200% increase in lung resistance (PC200) in model group was 37% as the value of control group. Intraperitoneal injection of PHPS1 at the doses of 6 mg/kg significantly reduced AHR provoked by MCh. The PC200 of 6mg/kg PHPS1 was twice as much as the value of model group.(4) KC and IL-8 mRNA expression and IL-8 protein expression were increased 12 hours after the CS expose of 10 3R4F reference cigarettes. IL-8 protein level in lung tissues was significantly reduced by 3mg/kg and 6mg/kg PHPS1.In conclusion, our results showed that PHPS1 reduced the expression of inflammatory chemokines induced by cigarette smoke (CS) and cigarette smoke extract (CSE).Meanwhile, PHPS1 can decrese cigarette smoke-induced small airway remodeling. Treatment with BCQB at the doses of 6mg/kg significantly reduced AHR provoked by MCh. It is the first time that we show the regulation of a PTP inhibitor-PHPS1 on cigarette smoke-induced inflammation and airway remodeling. These results imply that SHP-2 may be a novel therapeutic target for COPD and PHPS1 may be a novel anti-inflammation and anti-airway remodeling agent.