Immunostimulatory DNA inhibits allergen-induced peribronchial angiogenesis in mice.
BACKGROUND
Airway remodeling in asthma is associated with angiogenesis.


OBJECTIVE
We have examined whether immunostimulatory sequences of DNA (ISSs) inhibit allergen-induced airway angiogenesis and expression of angiogenic cytokines in a mouse model of airway remodeling.


METHODS
Mice sensitized to ovalbumin were challenged repetitively with ovalbumin for three months to develop airway remodeling and angiogenesis. Levels of angiogenesis were compared in ISS-treated and control mice.


RESULTS
Mice challenged with ovalbumin developed significantly increased levels of peribronchial angiogenesis (increase in the number of CD31+ peribronchial small blood vessels) and an increase in the peribronchial vascular area as assessed by image analysis. Ovalbumin-induced peribronchial angiogenesis was associated with increased bronchoalveolar lavage levels of vascular endothelial growth factor (VEGF) and an increase in the number of peribronchial cells expressing VEGF. Treatment of mice with ISS before repetitive ovalbumin challenge significantly reduced the levels of peribronchial angiogenesis as well as the levels of bronchoalveolar lavage VEGF and the number of peribronchial cells expressing VEGF. ISS is unlikely to act directly on endothelial cells to inhibit angiogenesis because lung endothelial cells did not express Toll receptor 9, the receptor for ISS as assessed by RT-PCR. In vitro studies demonstrated that ISS inhibited macrophage expression of VEGF.


CONCLUSIONS
The ability of ISS to inhibit angiogenesis in vivo is likely to be mediated by several mechanisms, including ISS reducing the number of peribronchial inflammatory cells that express VEGF, ISS inhibiting expression of TH2 cytokines such as IL-13 that promote VEGF expression, and direct effects of ISS on macrophages to inhibit VEGF expression.
Lee
Sook Young
SY
Department of Medicine, University of California San Diego, La Jolla 92093-0635, USA, and Kangnam St Mary's Hospital, Seoul, Korea.
Cho
Jae Youn
JY
Miller
Marina
M
McElwain
Kirsti
K
McElwain
Shauna
S
Sriramarao
Pragada
P
Raz
Eyal
E
Broide
David H
DH
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000485:Allergens; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001980:Bronchi / Q000098:blood supply* / Q000187:drug effects / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid; D004247:DNA / Q000494:pharmacology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology; D004804:Eosinophils / Q000276:immunology; D005260:Female; D018793:Interleukin-13 / Q000096:biosynthesis; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000276:immunology*; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010047:Ovalbumin; D018418:Th2 Cells / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D000485:Allergens; C408982:CPG-oligonucleotide; D018793:Interleukin-13; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9; D042461:Vascular Endothelial Growth Factor A; D010047:Ovalbumin; D004247:DNA