Anti-vascular endothelial growth factor gene therapy attenuates lung injury and fibrosis in mice

被引:144
作者
Hamada, N
Kuwano, K
Yamada, M
Hagimoto, N
Hiasa, K
Egashira, K
Nakashima, N
Maeyama, T
Yoshimi, M
Nakanishi, Y
机构
[1] Kyushu Univ, Grad Sch Med Sci, Chest Dis Res Inst, Higashi Ku, Fukuoka 8128582, Japan
[2] Kyushu Univ, Grad Sch Med Sci, Dept Cardiovasc Med, Fukuoka 8128582, Japan
关键词
D O I
10.4049/jimmunol.175.2.1224
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Vascular endothelial growth factor (VEGF) is an angiogenesis factor with proinflammatory roles. Flt-1 is one of the specific receptors for VEGF, and soluble flt-1 (sflt-1) binds to VEGF and competitively inhibits it from binding to the receptors. We examined the role of VEGF in the pathophysiology of bleomycin-induced pneumopathy in mice, using a new therapeutic strategy that comprises transfection of the sflt-1 gene into skeletal muscles as a biofactory for anti-VEGF therapy. The serum levels of sflt-1 were significantly increased at 3-14 days after the gene transfer. Transfection of the sflt-1 gene at 3 days before or 7 days after the intratracheal instillation of bleomycin decreased the number of inflammatory cells, the protein concentration in the bronchoalveolar lavage fluid and with von Willebrand factor expression at 14 days. Transfection of the sflt-1 gene also attenuated pulmonary fibrosis and apoptosis at 14 days. Since the inflammatory cell infiltration begins at 3 days and is followed by interstitial fibrosis, it is likely that VEGF has important roles as a proinflammatory, a permeability-inducing, and an angiogenesis factor not only in the early inflammatory phase but also in the late fibrotic phase. Furthermore, this method may be beneficial for treating lung injury and fibrosis from the viewpoint of clinical application, since it does not require the use of a viral vector or neutralizing Ab.
引用
收藏
页码:1224 / 1231
页数:8
相关论文
共 40 条
[31]   Proinflammatory fimctions of vascular endothelial growth factor in afloimmunity [J].
Reinders, MEJ ;
Sho, M ;
Izawa, A ;
Wang, P ;
Mukhopadhyay, D ;
Koss, KE ;
Geehan, CS ;
Luster, AD ;
Sayegh, MH ;
Briscoe, DM .
JOURNAL OF CLINICAL INVESTIGATION, 2003, 112 (11) :1655-1665
[32]   Interstitial vascularity in fibrosing alveolitis [J].
Renzoni, EA ;
Walsh, DA ;
Salmon, M ;
Wells, AU ;
Sestini, P ;
Nicholson, AG ;
Veeraraghavan, S ;
Bishop, AE ;
Romanska, HM ;
Pantelidis, P ;
Black, CM ;
du Bois, RM .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2003, 167 (03) :438-443
[33]   A ROLE FOR C-C CHEMOKINES IN FIBROTIC LUNG-DISEASE [J].
SMITH, RE ;
STRIETER, RM ;
ZHANG, K ;
PHAN, SH ;
STANDIFORD, TJ ;
LUKACS, NW ;
KUNKEL, SL .
JOURNAL OF LEUKOCYTE BIOLOGY, 1995, 57 (05) :782-787
[34]  
Strieter RM, 2003, AM J RESP CELL MOL, V29, pS67
[35]   A role for vascular endothelial growth factor in acute and resolving lung injury [J].
Thickett, DR ;
Armstrong, L ;
Millar, AB .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2002, 166 (10) :1332-1337
[36]   Vascular endothelial growth factor may contribute to increased vascular permeability in acute respiratory distress syndrome [J].
Thickett, DR ;
Armstrong, L ;
Christie, SJ ;
Millar, AB .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2001, 164 (09) :1601-1605
[37]   Adenovirus-mediated transfer and overexpression of heme oxygenase 1 cDNA in lung prevents bleomycin-induced pulmonary fibrosis via a Fas-Fas ligand-independent pathway [J].
Tsuburai, T ;
Suzuki, M ;
Nagashima, Y ;
Suzuki, S ;
Inoue, S ;
Hashiba, T ;
Ueda, A ;
Ikehara, K ;
Matsuse, T ;
Ishigatsubo, Y .
HUMAN GENE THERAPY, 2002, 13 (16) :1945-1960
[38]  
TURNER-WARWICK MARGARET, 1963, THORAX, V18, P225, DOI 10.1136/thx.18.3.225
[40]   Vascular endothelial growth factor is necessary in the development of arteriosclerosis by Recruiting/Activating monocytes in a rat model of long-term inhibition of nitric oxide synthesis [J].
Zhao, QW ;
Egashira, K ;
Inoue, S ;
Usui, M ;
Kitamoto, S ;
Ni, WH ;
Ishibashi, M ;
Hiasa, KI ;
Ichiki, T ;
Shibuya, M ;
Takeshita, A .
CIRCULATION, 2002, 105 (09) :1110-1115