title: Loss of Shp2 in alveoli epithelia induces deregulated surfactant homeostasis, resulting in spontaneous pulmonary fibrosis.
abstract: Type II alveolar epithelial (AT-II) cells produce pulmonary surfactant proteins that are essential for alveolar function. AT-II is a major target in lung injury, and ineffective repair of damaged alveolar epithelia has been postulated to cause pulmonary fibrosis. Previous studies have shown that tyrosine phosphatase Shp2 is expressed highly in the embryonic lung epithelial buds, and Shp2 activity is required for FGF-induced lung branching morphogenesis. To investigate in vivo function of pulmonary Shp2, we generated alveoli epithelia-specific Shp2-knockout (Shp2(Δ/Δ)) mice. Shp2(Δ/Δ) mice exhibit marked reduction in surfactant proteins, disorganized lamellar bodies, increased alveolar epithelial apoptosis, and interstitial pulmonary fibrosis without preceding inflammation. Mechanistically, Shp2 acts to mediate expression of thyroid transcription factor 1 (TTF1) and ATP-binding cassette subfamily A member 3 (ABCA3). Shp2 also plays a central role in mediating FGF/GAB/ERK activity, required for epithelial repair program. Together, our results identify a novel role of tyrosine phosphatase Shp2 in surfactant homeostasis, and deregulation of Shp2 triggers spontaneous pulmonary fibrosis with minimal inflammation.
authors.affiliation: Department of Pathology and Pathophysiology, Zhejiang University School of Medicine, P.O. Box 59, 866 Yuhangtang Rd., Hangzhou 310058, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Bo
authors.initials: B
authors.lastname: Tao
authors.forename: Li
authors.initials: L
authors.lastname: Teng
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Li
authors.forename: Rui
authors.initials: R
authors.lastname: Cao
authors.forename: Qiu
authors.initials: Q
authors.lastname: Gui
authors.forename: Madong
authors.initials: M
authors.lastname: Ye
authors.forename: Xiaozhou
authors.initials: X
authors.lastname: Mou
authors.forename: Hongqiang
authors.initials: H
authors.lastname: Cheng
authors.forename: Hu
authors.initials: H
authors.lastname: Hu
authors.forename: Ren
authors.initials: R
authors.lastname: Zhou
authors.forename: Ximei
authors.initials: X
authors.lastname: Wu
authors.forename: Qiangmin
authors.initials: Q
authors.lastname: Xie
authors.forename: Wen
authors.initials: W
authors.lastname: Ning
authors.forename: Maode
authors.initials: M
authors.lastname: Lai
authors.forename: Huahao
authors.initials: H
authors.lastname: Shen
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.forename: Yuehai
authors.initials: Y
authors.lastname: Ke
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D005346:Fibroblast Growth Factors / Q000502:physiology; D006706:Homeostasis; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000096:biosynthesis; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000172:deficiency*; D011650:Pulmonary Alveoli / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000209:etiology* / Q000473:pathology; D037661:Pulmonary Surfactant-Associated Proteins / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000378:metabolism; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000096:biosynthesis
chemical_list: D018528:ATP-Binding Cassette Transporters; C512026:Abca3 protein, mouse; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D037661:Pulmonary Surfactant-Associated Proteins; D011663:Pulmonary Surfactants; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D005346:Fibroblast Growth Factors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; C516725:Ptpn11 protein, mouse