title: Dysregulation of galectin-3. Implications for Hermansky-Pudlak syndrome pulmonary fibrosis.
abstract: The etiology of Hermansky-Pudlak syndrome (HPS) pulmonary fibrosis (HPSPF), a progressive interstitial lung disease with high mortality, is unknown. Galectin-3 is a β-galactoside-binding lectin with profibrotic effects. The objective of this study was to investigate the involvement of galectin-3 in HPSPF. Galectin-3 was measured by ELISA, immunohistochemistry, and immunoblotting in human specimens from subjects with HPS and control subjects. Mechanisms of galectin-3 accumulation were studied by quantitative RT-PCR, Northern blot analysis, membrane biotinylation assays, and rescue of HPS1-deficient cells by transfection. Bronchoalveolar lavage galectin-3 concentrations were significantly higher in HPSPF compared with idiopathic pulmonary fibrosis or that from normal volunteers, and correlated with disease severity. Galectin-3 immunostaining was increased in HPSPF compared with idiopathic pulmonary fibrosis or normal lung tissue. Fibroblasts from subjects with HPS subtypes associated with pulmonary fibrosis had increased galectin-3 protein expression compared with cells from nonfibrotic HPS subtypes. Galectin-3 protein accumulation was associated with reduced Galectin-3 mRNA, normal Mucin 1 levels, and up-regulated microRNA-322 in HPSPF cells. Membrane biotinylation assays showed reduced galectin-3 and normal Mucin 1 expression at the plasma membrane in HPSPF cells compared with control cells, which suggests that galectin-3 is mistrafficked in these cells. Reconstitution of HPS1 cDNA into HPS1-deficient cells normalized galectin-3 protein and mRNA levels, as well as corrected galectin-3 trafficking to the membrane. Intracellular galectin-3 levels are regulated by HPS1 protein. Abnormal accumulation of galectin-3 may contribute to the pathogenesis of HPSPF.
authors.affiliation: 1 Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Cullinane
authors.forename: Caroline
authors.initials: C
authors.lastname: Yeager
authors.forename: Heidi
authors.initials: H
authors.lastname: Dorward
authors.forename: Carmelo
authors.initials: C
authors.lastname: Carmona-Rivera
authors.forename: Hai Ping
authors.initials: HP
authors.lastname: Wu
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: O'Brien
authors.forename: Steven D
authors.initials: SD
authors.lastname: Nathan
authors.forename: Keith C
authors.initials: KC
authors.lastname: Meyer
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Rosas
authors.forename: Amanda
authors.initials: A
authors.lastname: Helip-Wooley
authors.forename: Marjan
authors.initials: M
authors.lastname: Huizing
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.forename: Bernadette R
authors.initials: BR
authors.lastname: Gochuico
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism; D001798:Blood Proteins; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016022:Case-Control Studies; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D037502:Galectin 3 / Q000235:genetics / Q000378:metabolism*; D037161:Galectins; D005786:Gene Expression Regulation; D022861:Hermanski-Pudlak Syndrome / Q000150:complications* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000378:metabolism; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D018396:Mucin-1 / Q000378:metabolism; D021381:Protein Transport; D011658:Pulmonary Fibrosis / Q000175:diagnosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012720:Severity of Illness Index; D014162:Transfection
chemical_list: D001798:Blood Proteins; D037502:Galectin 3; D037161:Galectins; C102160:HPS1 protein, human; C428445:LGALS3 protein, human; C060192:MUC1 protein, human; D008565:Membrane Proteins; D018396:Mucin-1; D012333:RNA, Messenger