title: The αvβ1 integrin plays a critical in vivo role in tissue fibrosis.
abstract: Integrins are transmembrane heterodimeric receptors that contribute to diverse biological functions and play critical roles in many human diseases. Studies using integrin subunit knockout mice and inhibitory antibodies have identified important roles for nearly every integrin heterodimer and led to the development of a number of potentially useful therapeutics. One notable exception is the αvβ1 integrin. αv and β1 subunits are individually present in numerous dimer pairs, making it challenging to infer specific roles for αvβ1 by genetic inactivation of individual subunits, and αvβ1 complex-specific blocking antibodies do not yet exist. We therefore developed a potent and highly specific small-molecule inhibitor of αvβ1 to probe the function of this understudied integrin. We found that αvβ1, which is highly expressed on activated fibroblasts, directly binds to the latency-associated peptide of transforming growth factor-β1 (TGFβ1) and mediates TGFβ1 activation. Therapeutic delivery of this αvβ1 inhibitor attenuated bleomycin-induced pulmonary fibrosis and carbon tetrachloride-induced liver fibrosis, suggesting that drugs based on this lead compound could be broadly useful for treatment of diseases characterized by excessive tissue fibrosis.
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Nilgun I
authors.initials: NI
authors.lastname: Reed
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Hyunil
authors.initials: H
authors.lastname: Jo
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tsujino
authors.affiliation: Department of Pediatrics, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Arnold
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94143, USA. dean.sheppard@ucsf.edu bill.degrado@ucsf.edu.
authors.forename: William F
authors.initials: WF
authors.lastname: DeGrado
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. dean.sheppard@ucsf.edu bill.degrado@ucsf.edu.
authors.forename: Dean
authors.initials: D
authors.lastname: Sheppard
mesh_terms: D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D015195:Drug Design; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006842:Hydrocarbons, Brominated; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D058990:Molecular Targeted Therapy; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D006842:Hydrocarbons, Brominated; D019030:Receptors, Vitronectin; D016212:Transforming Growth Factor beta; C094340:integrin alphavbeta1; D001761:Bleomycin; C031387:carbon tetrabromide