The role of Angptl2 expression in lung for interstitial pneumonia

• Project/Area Number: 25461192
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Kumamoto University
• Principal Investigator: Endo Motoyoshi 熊本大学, 大学院生命科学研究部, 助教 (40398243)
• Co-Investigator(Renkei-kenkyūsha): INOUE Hiromasa 鹿児島大学, 大学院医歯学総合研究科, 教授 (30264039)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 間質性肺炎 / Angptl2 / ブレオマイシン肺臓炎 / 肺線維症 / ブレオマイシン / マクロファージ

Outline of Final Research Achievements

Idiopathic pulmonary fibrosis is defined as progressive interstitial pneumonia with poor prognosis. However, the mechanism of it remains unclear. Angiopoietin-like protein 2 (Angptl2) is a chronic inflammatory mediator, which when deregulated is associated with various pathologies. However, little was known about its potential lung function. To examine the role of Angptl2 for lung function, we generated a rabbit monoclonal antibody that specifically recognizes mouse Angptl2 and then evaluated protein expression in mouse lung tissue. We observed abundant Angptl2 expression in both alveolar epithelial type I and type II cells and in alveolar macrophages under normal conditions. Next, we examined Angptl2 lung function in a mouse interstitial pneumonia model and found that Angptl2 deficiency made fibrosis caused by bleomycin exacerbated fibrosis. Overall, our findings suggest that Angptl2 expression in lung epithelial cells may function in repair of damaged tissue.

Research Products

• [Journal Article] ANGPTL2 increases renal fibrosis by accelerating TGF-β signaling in chronic kidney disease (2016)
  • Author(s): Jun Morinaga, Tsuyoshi Kadomatsu, Keishi Miyata, Motoyoshi Endo, Kazutoyo Terada, Zhe Tian, Taichi Sugizaki, Hiroki Tanigawa, Jiabin Zhao, Shunshun Zhu, Michio Sato, Kimi Araki, Ken-ichi Iyama, Kengo Tomita, Masashi Mukoyama, Kimio Tomita, Kenichiro Kitamura, Yuichi Oike
  • Journal Title: Kidney Int Volume: 89 Pages: 327-341
  • DOI: 10.1016/j.kint.2015.12.021
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Angiopoietin-like protein 2 is a multistep regulator of inflammatory neovascularization in a murine model of age-related macular degeneration. (2016)
  • Author(s): Hirasawa M, Takubo K, Osada H, Miyake S, Toda E, Endo M, Umezawa K, Tsubota K, Oike Y, & Ozawa Y
  • Journal Title: J Biol Chem. Volume: 291 Pages: 7373-7385
  • DOI: 10.1074/jbc.m115.710186
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice. (2015)
  • Author(s): Tanaka Y, Ishitsuka Y, Hayasaka M, Yamada Y, Miyata K, Endo M, Kondo Y, Moriuchi H, Irikura M, Tanaka K, Mizushima T, Oike Y, Irie T.
  • Journal Title: Pharmacological Research Volume: 99 Pages: 52-62
  • DOI: 10.1016/j.phrs.2015.05.004
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ANGPTL2 increases bone metastasis of breast cancer cells through enhancing CXCR4 signaling (2015)
  • Author(s): Masuda T, Endo M, Yamamoto Y, Odagiri H, Kadomatsu T, Nakamura T, Tanoue H, Ito H, Yugami M, Miyata K, Morinaga J, Horiguchi H, Motokawa I, Terada K, Morioka MS, Manabe I, Iwase H, Mizuta H, Oike Y.
  • Journal Title: Sci. Rep. Volume: 5 Pages: 9170-9170
  • DOI: 10.1038/srep09170
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The Secreted Protein ANGPTL2 Promotes Metastasis of Osteosarcoma Cells Through Integrin α5β1, p38 MAPK, and Matrix Metalloproteinases. (2015)
  • Author(s): Odagiri H, Kadomatsu T, Endo M, Masuda T, Morioka MS, Fukuhara S, Miyamoto T, Kobayashi E, Miyata K, Aoi J, Horiguchi H, Nishimura N, Terada K, Yakushiji T, Manabe I, Mochizuki N, Mizuta H, Oike Y.
  • Journal Title: Sci Signal. Volume: 7
  • DOI: 10.1126/scisignal.2004612
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Angiopoietin-like protein 2 renders colorectal cancer cells resistant to chemotherapy by activating spleen tyrosine kinase-phosphoinositide 3-kinase-dependent anti-apoptotic signaling (2014)
  • Author(s): Horiguchi H, Endo M, Miyamoto Y, Sakamoto Y, Odagiri H, Masuda T, Kadomatsu T, Tanoue H, Motokawa I, Terada K, Morioka MS, Manabe I, Baba H, Oike Y.
  • Journal Title: Cancer Sci Volume: 105 Pages: 1550-1559
  • DOI: 10.1111/cas.12554
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Serum ANGPTL2 levels reflect clinical features of breast cancer patients: implications for the pathogenesis of breast cancer metastasis. (2014)
  • Author(s): Endo M, Yamamoto Y, Nakano M, Masuda T, Odagiri H, Horiguchi H, Miyata K, Kadomatsu T, Motokawa I, Okada S, Iwase H, Oike Y.
  • Journal Title: Int. J. Biol. Markers Volume: 印刷中 Pages: 239-245
  • DOI: 10.5301/jbm.5000080
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of Endothelial Cell-Derived Angptl2 in Vascular Inflammation Leading to Endothelial Dysfunction and Atherosclerosis Progression (2014)
  • Author(s): Horio E, Kadomatsu T, Miyata K, Arai Y, Hosokawa K, Doi Y, et al.
  • Journal Title: Arterioscler. Thromb. Vasc. Biol. Volume: 34 Pages: 790-800
  • DOI: 10.1161/atvbaha.113.303116
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ANGPTL2 in physiology and pathophysiology. (2014)
  • Author(s): Kadomatsu T, Endo M, Miyata K, Oike Y.
  • Journal Title: Trends Endocrinol. Metab. Volume: 25(5) Pages: 245-254
  • DOI: 10.1016/j.tem.2014.03.012
  • Peer Reviewed / Open Access
• [Journal Article] Angiopoietin-like protein 2 induced by mechanical stress accelerates degeneration and hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis. (2014)
  • Author(s): Nakamura T, Okada T, Endo M, Kadomatsu T, Taniwaki T, Sei A, Odagiri H, Masuda T, Fujimoto T, Nakamura T, Oike Y, Mizuta H.
  • Journal Title: PLoS One Volume: 9
  • DOI: 10.1371/journal.pone.0085542
  • Peer Reviewed / Open Access
• [Journal Article] Angiopoietin-like Protein 2 Accelerates Carcinogenesis by Activating Chronic Inflammation and Oxidative Stress. (2014)
  • Author(s): Aoi J, Endo M, Kadomatsu T, Miyata K, Ogata A, Horiguchi H, Odagiri H, Masuda T, Fukushima S, Jinnin M, Hirakawa S, Sawa T, Akaike T, Ihn H and Oike Y
  • Journal Title: Molecular Cancer Research Volume: 12 Pages: 239-249
  • DOI: 10.1158/1541-7786.mcr-13-0336
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] 新規炎症関連因子ANGPTL2による肺がんの浸潤・転移分子機構 (2013)
  • Author(s): 遠藤元誉、本川郁代、羽藤泰
  • Organizer: 第53回 日本呼吸器学会学術講演会
  • Place of Presentation: 東京国際フォーラム
• [Presentation] Angptl2によって惹起される炎症による発がん制御メカニズム解明 (2013)
  • Author(s): 遠藤元誉、小田切陽樹、舛田哲朗、堀口晴紀、中野正啓、尾池雄一
  • Organizer: 第72回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜