title: Partial inhibition of integrin alpha(v)beta6 prevents pulmonary fibrosis without exacerbating inflammation.
abstract: 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.
authors.affiliation: Department of Exploratory Biology, Biogen Idec, 12 Cambridge Center, Cambridge, MA 02142, USA. gerald.horan@biogenidec.com
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Horan
authors.forename: Susan
authors.initials: S
authors.lastname: Wood
authors.forename: Victor
authors.initials: V
authors.lastname: Ona
authors.forename: Dan Jun
authors.initials: DJ
authors.lastname: Li
authors.forename: Matvey E
authors.initials: ME
authors.lastname: Lukashev
authors.forename: Paul H
authors.initials: PH
authors.lastname: Weinreb
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Simon
authors.forename: Kyungmin
authors.initials: K
authors.lastname: Hahm
authors.forename: Normand E
authors.initials: NE
authors.lastname: Allaire
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rinaldi
authors.forename: Jaya
authors.initials: J
authors.lastname: Goyal
authors.forename: Carol A
authors.initials: CA
authors.lastname: Feghali-Bostwick
authors.forename: Eric L
authors.initials: EL
authors.lastname: Matteson
authors.forename: Carl
authors.initials: C
authors.lastname: O'Hara
authors.forename: Robert
authors.initials: R
authors.lastname: Lafyatis
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Davis
authors.forename: Xiaozhu
authors.initials: X
authors.lastname: Huang
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
authors.forename: Shelia M
authors.initials: SM
authors.lastname: Violette
mesh_terms: 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
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D016023:Integrins; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D003094:Collagen