title: Pathogenesis of pulmonary fibrosis: platelet-derived growth factor precedes structural alterations in the Hermansky-Pudlak syndrome.
abstract: Peptides that modulate mesenchymal cell function have been detected in the fibrotic lung disorders once physiologic dysfunction is present. Despite this close association with manifest disease, their role in initiating alveolar remodeling remains unknown. We examined the hypothesis that one potent peptide, platelet-derived growth factor (PDGF), would be present at the alveolar surface before the onset of physiologic dysfunction in patients in whom pulmonary fibrosis subsequently develops. Bronchoalveolar lavage and physiologic assessment were performed in asymptomatic patients with the Hermansky-Pudlak syndrome (n = 30), obligate heterozygous (n = 9), and normal volunteers (control group). Lavage cell number and profile were normal, but alveolar macrophages demonstrated characteristic autofluorescence and ultrastructural features of ceroid. Lavage fluid from physiologically normal patients with Hermansky-Pudlak syndrome and from those with occult restrictive disease demonstrated two PDGF-related peptides (14 kd and 38 kd). Radioligand binding and fibroblast proliferation assay demonstrated that the peptides were functional. By immunoassay the concentration of PDGF in lavage fluid was six times greater than control values (p < 0.01). In situ hybridization together with bioassay indicated that alveolar macrophages were one cellular source of PDGF. Similar results were obtained for heterozygotes. These data identify macrophage-derived PDGF peptides as important candidate molecules in the initiation of alveolar remodeling in the fibrotic lung disorders.
authors.affiliation: Department of Medicine, Park Nicollet Medical Center, Minneapolis, MN 55416.
authors.forename: K R
authors.initials: KR
authors.lastname: Harmon
authors.forename: C J
authors.initials: CJ
authors.lastname: Witkop
authors.forename: J G
authors.initials: JG
authors.lastname: White
authors.forename: R A
authors.initials: RA
authors.lastname: King
authors.forename: M
authors.initials: M
authors.lastname: Peterson
authors.forename: D
authors.initials: D
authors.lastname: Moore
authors.forename: J
authors.initials: J
authors.lastname: Tashjian
authors.forename: W A
authors.initials: WA
authors.lastname: Marinelli
authors.forename: P B
authors.initials: PB
authors.lastname: Bitterman
mesh_terms: D000293:Adolescent; D000328:Adult; D016115:Albinism, Oculocutaneous / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D001483:Base Sequence; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D006579:Heterozygote; D006801:Humans; D017403:In Situ Hybridization; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism*; D011869:Radioligand Assay
chemical_list: D010982:Platelet-Derived Growth Factor