Shp2 plays an important role in acute cigarette smoke-mediated lung inflammation.
Cigarette smoke (CS), the major cause of chronic obstructive pulmonary disease, contains a variety of oxidative components that were implicated in the regulation of Src homology domain 2-containing protein tyrosine phosphatase 2 (Shp2) activity. However, the contribution of Shp2 enzyme to chronic obstructive pulmonary disease pathogenesis remains unclear. We investigated the role of Shp2 enzyme in blockading CS-induced pulmonary inflammation. Shp2 levels were assessed in vivo and in vitro. Mice (C57BL/6) or pulmonary epithelial cells (NCI-H292) were exposed to CS or cigarette smoke extract (CSE) to induce acute injury and inflammation. Lungs of smoking mice showed increased levels of Shp2, compared with those of controls. Treatment of lung epithelial cells with CSE showed elevated levels of Shp2 associated with the increased release of IL-8. Selective inhibition or knockdown of Shp2 resulted in decreased IL-8 release in response to CSE treatment in pulmonary epithelial cells. In comparison with CS-exposed wild-type mice, selective inhibition or conditional knockout of Shp2 in lung epithelia reduced IL-8 release and pulmonary inflammation in CS-exposed mice. In vitro biochemical data correlate CSE-mediated IL-8 release with Shp2-regulated epidermal growth factor receptor/Grb-2-associated binders/MAPK signaling. Our data suggest an important role for Shp2 in the pathological alteration associated with CS-mediated inflammation. Shp2 may be a potential target for therapeutic intervention for inflammation in CS-induced pulmonary diseases.
Department of Pathology and Pathophysiology, Program in Molecular Cell Biology, Zhejiang University School of Medicine, Hangzhou, China 310058.
Fen-Fen
FF
Li
Jian
J
Shen
Hui-Juan
HJ
Shen
Xue
X
Zhang
Rui
R
Cao
Yun
Y
Zhang
Qiu
Q
Qui
Xi-Xi
XX
Lin
Yi-Cheng
YC
Xie
Lin-Hui
LH
Zhang
Yong-Liang
YL
Jia
Xin-Wei
XW
Dong
Jun-Xia
JX
Jiang
Meng-Jing
MJ
Bao
Shanshan
S
Zhang
Wen-Jiang
WJ
Ma
Xi-Mei
XM
Wu
Huahao
H
Shen
Qiang-Min
QM
Xie
Yuehai
Y
Ke
D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D016209:Interleukin-8 / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism / Q000473:pathology*; D062789:Tobacco Products / Q000633:toxicity*
D016209:Interleukin-8; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse