title: Increased and prolonged pulmonary fibrosis in surfactant protein C-deficient mice following intratracheal bleomycin.
abstract: Recent reports have linked mutations in the surfactant protein C gene (SFTPC) to familial forms of pulmonary fibrosis, but it is uncertain whether deficiency of mature SP-C contributes to disease pathogenesis. In this study, we evaluated bleomycin-induced lung fibrosis in mice with genetic deletion of SFTPC. Compared with wild-type (SFTPC+/+) controls, mice lacking surfactant protein C (SFTPC-/-) had greater lung neutrophil influx at 1 week after intratracheal bleomycin, greater weight loss during the first 2 weeks, and increased mortality. At 3 and 6 weeks after bleomycin, lungs from SFTPC-/- mice had increased fibroblast numbers, augmented collagen accumulation, and greater parenchymal distortion. Furthermore, resolution of fibrosis was delayed. Although remodeling was near complete in SFTPC+/+ mice by 6 weeks, SFTPC-/- mice did not return to baseline until 9 weeks after bleomycin. By terminal dUTP nick-end labeling staining, widespread cell injury was observed in SFTPC-/- and SFTPC+/+ mice 1 week after bleomycin; however, ongoing apoptosis of epithelial and interstitial cells occurred in lungs of SFTPC-/- mice, but not SFTPC+/+ mice, 6 weeks after bleomycin. Thus, SP-C functions to limit lung inflammation, inhibit collagen accumulation, and restore normal lung structure after bleomycin.
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary, and Critical Care, Vanderbilt University School of Medicine, T-1218 MCN, Nashville, TN 37232-2650, USA. william.lawson@vanderbilt.edu
authors.forename: William E
authors.initials: WE
authors.lastname: Lawson
authors.forename: Vasiliy V
authors.initials: VV
authors.lastname: Polosukhin
authors.forename: Georgios T
authors.initials: GT
authors.lastname: Stathopoulos
authors.forename: Ornella
authors.initials: O
authors.lastname: Zoia
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Kirk B
authors.initials: KB
authors.lastname: Lane
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.forename: Edwin F
authors.initials: EF
authors.lastname: Donnelly
authors.forename: George E
authors.initials: GE
authors.lastname: Holburn
authors.forename: Kenneth G
authors.initials: KG
authors.lastname: Lewis
authors.forename: Robert D
authors.initials: RD
authors.lastname: Collins
authors.forename: William M
authors.initials: WM
authors.lastname: Hull
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Glasser
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
mesh_terms: D000818:Animals; D017209:Apoptosis; D001761:Bleomycin / Q000633:toxicity; D002477:Cells / Q000473:pathology; D003094:Collagen / Q000032:analysis; D004195:Disease Models, Animal; D005347:Fibroblasts; D006909:Hydroxyproline / Q000032:analysis; D020287:In Situ Nick-End Labeling; D007958:Leukocyte Count; D008168:Lung / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils; D009195:Peroxidase / Q000032:analysis; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D037721:Pulmonary Surfactant-Associated Protein C / Q000235:genetics / Q000502:physiology*; D015431:Weight Loss
chemical_list: D037721:Pulmonary Surfactant-Associated Protein C; D001761:Bleomycin; D003094:Collagen; D009195:Peroxidase; D006909:Hydroxyproline