title: Hydrolysis of Hyaluronic Acid in Lymphedematous Tissue Alleviates Fibrogenesis via TH1 Cell-Mediated Cytokine Expression.
abstract: Although surgery and radiation are beneficial for treating cancer, they can also lead to malfunctions of the lymphatic system such as secondary lymphedema. This abnormality of the lymphatic system is characterized by severe swelling, adipogenesis, inflammation, and fibrosis in the lymphedematous region. Moreover, the proliferation of fibrotic tissue in the lymphedematous region generates edema that is no longer spontaneously reversible. No treatment for fibrosis has been validated in patients with lymphedema. In our efforts to develop a therapeutic agent for lymphedema fibrosis, we used a newly established mouse hind limb model. Previous studies have demonstrated that hyaluronic acid accumulates in the lymphedematous region. Thus, we challenged mice with of hyaluronidase (HYAL), with the aim of reducing fibrogenesis. After subcutaneous injections in the lymphedematous mouse leg every two days, the volume of lymphedema had reduced significantly by 7 days post-operation. Histochemical analysis indicated that collagen accumulation and myofibroblast differentiation were decreased in epidermal tissues after HYAL injection. Moreover, it was associated with upregulation of interferon-gamma, increased numbers of Th1 cells, and downregulation of interleukin-4 and interleukin-6 in the lymphedematous region and spleen. These results indicate that hydrolysis of hyaluronic acid can boost an anti-fibrotic immune response in the mouse lymphedema model.
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Sungrae
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Kangsan
authors.initials: K
authors.lastname: Roh
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Jaehyun
authors.initials: J
authors.lastname: Park
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Yong Seok
authors.initials: YS
authors.lastname: Park
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Minji
authors.initials: M
authors.lastname: Lee
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Seungchan
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Eui-Joon
authors.initials: EJ
authors.lastname: Kil
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Mun-Ju
authors.initials: MJ
authors.lastname: Cho
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Jeong Su
authors.initials: JS
authors.lastname: Oh
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Hee-Seong
authors.initials: HS
authors.lastname: Byun
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Department of Food Science and Biotechnology, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
authors.forename: Kyewon
authors.initials: K
authors.lastname: Park
authors.affiliation: Department of Oriental Medical Science, Graduate School of East-West Medical Science, Kyunghee University, Yongin, 17104, Republic of Korea.
authors.forename: Hee
authors.initials: H
authors.lastname: Kang
authors.affiliation: Natural Products Research Department, Gyeonggi Institute of Science & Technology, Suwon, 16229, Republic of Korea.
authors.forename: Jinmo
authors.identifier: 0000-0003-0218-810X
authors.initials: J
authors.lastname: Koo
authors.affiliation: U-Cell Clinic, Seoul, 06605, Republic of Korea.
authors.forename: Chang-Hwan
authors.initials: CH
authors.lastname: Yeom
authors.affiliation: Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea. cell4u@skku.edu.
authors.forename: Sukchan
authors.identifier: 0000-0002-9964-0176
authors.initials: S
authors.lastname: Lee
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D005355:Fibrosis / Q000188:drug therapy* / Q000276:immunology; D006820:Hyaluronic Acid / Q000378:metabolism*; D006821:Hyaluronoglucosaminidase / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D035002:Lower Extremity; D008209:Lymphedema / Q000188:drug therapy* / Q000276:immunology; D008297:Male; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism; D013154:Spleen / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D015850:Interleukin-6; D015847:Interleukin-4; D007371:Interferon-gamma; D006820:Hyaluronic Acid; D003094:Collagen; D006821:Hyaluronoglucosaminidase