title: Overexpression of SERPIN B3 promotes epithelial proliferation and lung fibrosis in mice.
abstract: SERPIN B3/B4, members of the serpin superfamily, are fundamental for the control of proteolysis through a known inhibitory function of different proteases. Several studies have documented an important role of SERPIN B3 in the modulation of inflammation, programmed cell death and fibrosis. To confirm the role of SERPIN B3 in lung fibrosis and overall investigate its influence on epithelial dysfunction, a stratified controlled trial randomly assigning bleomycin (BLM) treatment was performed on both SERPIN B3 transgenic (TG) and wild-type (WT) mice. TG and WT animals were killed 48 h (group T48 h) and 20 days (group T20d) after BLM treatment. Lung fibrosis was assessed by histology and hydroxyproline measurement. Architectural remodeling, inflammation, epithelial apoptosis and proliferation were quantified. Moreover, the profibrogenetic cytokine transforming growth factor (TGF)-β, cathepsin K, L and S were also investigated. No significant differences were observed between TG and WT mice of group T48 h in any parameters. In group T20d, less inflammation and a significant increase in epithelial proliferation were detected in treated TG than WT mice despite a similar apoptotic index, thus resulting in a different apoptosis/proliferation imbalance with a significant gain of epithelial proliferation. Moreover, TG mice showed higher TGF-β expression and more extended fibrosis. General linear model analysis, applied on morphological data, showed that interaction between SERPIN B3 expression and treatment was mainly significant for fibrosis. This study provides in vivo evidence for a role of SERPIN B3 in inhibiting inflammation and favoring epithelial proliferation with increased TGF-β secretion and thus the likelihood of consequent fibrogenesis.
authors.affiliation: Department of Diagnostic Medical Sciences and Special Therapies, University of Padua, Padua, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lunardi
authors.forename: Gianmarco
authors.initials: G
authors.lastname: Villano
authors.forename: Egle
authors.initials: E
authors.lastname: Perissinotto
authors.forename: Carlo
authors.initials: C
authors.lastname: Agostini
authors.forename: Federico
authors.initials: F
authors.lastname: Rea
authors.forename: Marianna
authors.initials: M
authors.lastname: Gnoato
authors.forename: Alice
authors.initials: A
authors.lastname: Bradaschia
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Valente
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pontisso
authors.forename: Fiorella
authors.initials: F
authors.lastname: Calabrese
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001761:Bleomycin / Q000633:toxicity; D049109:Cell Proliferation; D017931:DNA Primers / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D015843:Serpins; D001761:Bleomycin; D006909:Hydroxyproline