Inhibition of integrin alpha(v)beta6, an activator of latent transforming growth factor-beta, prevents radiation-induced lung fibrosis.
BACKGROUND
In experimental models, lung fibrosis is dependent on transforming growth factor (TGF)-beta signaling. TGF-beta is secreted in a latent complex with its propeptide, and TGF-beta activators release TGF-beta from this complex. Because the integrin alpha(v)beta6 is a major TGF-beta activator in the lung, inhibition of alpha(v)beta6-mediated TGF-beta activation is a logical strategy to treat lung fibrosis.


OBJECTIVE
To determine, by genetic and pharmacologic approaches, whether murine radiation-induced lung fibrosis is dependent on alpha(v)beta6.


METHODS
Wild-type mice, alpha(v)beta6-deficient (Itgb6-/-) mice, and mice heterozygous for a Tgfb1 mutation that eliminates integrin-mediated activation (Tgfb1(+/RGE)) were exposed to 14 Gy thoracic radiation. Some mice were treated with an anti-alpha(v)beta6 monoclonal antibody or a soluble TGF-beta receptor fusion protein. Alpha(v)beta6 expression was determined by immunohistochemistry. Fibrosis, inflammation, and gene expression patterns were assessed 20-32 weeks postirradiation.


RESULTS
Beta6 integrin expression increased within the alveolar epithelium 18 weeks postirradiation, just before onset of fibrosis. Itgb6-/- mice were completely protected from fibrosis, but not from late radiation-induced mortality. Anti-alpha(v)beta6 therapy (1-10 mg/kg/wk) prevented fibrosis, but only higher doses (6-10 mg/kg/wk) caused lung inflammation similar to that in Itgb6-/- mice. Tgfb1-haploinsufficient mice were also protected from fibrosis.


CONCLUSIONS
Alpha(v)beta6-mediated TGF-beta activation is required for radiation-induced lung fibrosis. Together with previous data, our results demonstrate a robust requirement for alpha(v)beta6 in distinct fibrosis models. Inhibition of alphavbeta6-mediated TGF-beta activation is a promising new approach for antifibrosis therapy.
Puthawala
Khalid
K
New York University School of Medicine, Department of Medicine, New York, NY 10282, USA.
Hadjiangelis
Nicos
N
Jacoby
Steven C
SC
Bayongan
Emmanuel
E
Zhao
Zhicheng
Z
Yang
Zhiwei
Z
Devitt
Mary Louise
ML
Horan
Gerald S
GS
Weinreb
Paul H
PH
Lukashev
Matvey E
ME
Violette
Shelia M
SM
Grant
Kristen S
KS
Colarossi
Cristina
C
Formenti
Silvia C
SC
Munger
John S
JS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000235:genetics / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006239:Haplotypes; D006579:Heterozygote; D016023:Integrins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D016023:Integrins; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C073878:integrin alphavbeta6