Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation.
BACKGROUND
Transforming growth factor (TGF)-beta has a central role in driving many of the pathological processes that characterize pulmonary fibrosis. Inhibition of the integrin alpha(v)beta6, a key activator of TGF-beta in lung, is an attractive therapeutic strategy, as it may be possible to inhibit TGF-beta at sites of alpha(v)beta6 up-regulation without affecting other homeostatic roles of TGF-beta.


OBJECTIVE
To analyze the expression of alpha(v)beta6 in human pulmonary fibrosis, and to functionally test the efficacy of therapeutic inhibition of alpha(v)beta6-mediated TGF-beta activation in murine bleomycin-induced pulmonary fibrosis.


METHODS
Lung biopsies from patients with a diagnosis of systemic sclerosis or idiopathic pulmonary fibrosis were stained for alpha(v)beta6 expression. A range of concentrations of a monoclonal antibody that blocks alpha(v)beta6-mediated TGF-beta activation was evaluated in murine bleomycin-induced lung fibrosis.


RESULTS
Alpha(v)beta6 is overexpressed in human lung fibrosis within pneumocytes lining the alveolar ducts and alveoli. In the bleomycin model, alpha(v)beta6 antibody was effective in blocking pulmonary fibrosis. At high doses, there was increased expression of markers of inflammation and macrophage activation, consistent with the effects of TGF-beta inhibition in the lung. Low doses of antibody attenuated collagen expression without increasing alveolar inflammatory cell populations or macrophage activation markers.


CONCLUSIONS
Partial inhibition of TGF-beta using alpha(v)beta6 integrin antibodies is effective in blocking murine pulmonary fibrosis without exacerbating inflammation. In addition, the elevated expression of alpha(v)beta6, an activator of the fibrogenic cytokine, TGF-beta, in human pulmonary fibrosis suggests that alpha(v)beta6 monoclonal antibodies could represent a promising new therapeutic strategy for treating pulmonary fibrosis.
Horan
Gerald S
GS
Department of Exploratory Biology, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA. gerald.horan@biogenidec.com
Wood
Susan
S
Ona
Victor
V
Li
Dan Jun
DJ
Lukashev
Matvey E
ME
Weinreb
Paul H
PH
Simon
Kenneth J
KJ
Hahm
Kyungmin
K
Allaire
Normand E
NE
Rinaldi
Nicola J
NJ
Goyal
Jaya
J
Feghali-Bostwick
Carol A
CA
Matteson
Eric L
EL
O'Hara
Carl
C
Lafyatis
Robert
R
Davis
Gerald S
GS
Huang
Xiaozhu
X
Sheppard
Dean
D
Violette
Shelia M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000276:immunology; D011658:Pulmonary Fibrosis / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D012595:Scleroderma, Systemic / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D003094:Collagen