title: The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky-Pudlak syndrome.
abstract: BACKGROUND
  Hermansky-Pudlak syndrome (HPS) is a family of recessive disorders of intracellular trafficking defects that are associated with highly penetrant pulmonary fibrosis. Naturally occurring HPS mice reliably model important features of the human disease, including constitutive alveolar macrophage activation and susceptibility to profibrotic stimuli.
  
  
  OBJECTIVE
  To decipher which cell lineage(s) in the alveolar compartment is the predominant driver of fibrotic susceptibility in HPS.
  
  
  METHODS
  We used five different HPS and Chediak-Higashi mouse models to evaluate genotype-specific fibrotic susceptibility. To determine whether intrinsic defects in HPS alveolar macrophages cause fibrotic susceptibility, we generated bone marrow chimeras in HPS and wild-type mice. To directly test the contribution of the pulmonary epithelium, we developed a transgenic model with epithelial-specific correction of the HPS2 defect in an HPS mouse model.
  
  
  RESULTS
  Bone marrow transplantation experiments demonstrated that both constitutive alveolar macrophage activation and increased susceptibility to bleomycin-induced fibrosis were conferred by the genotype of the lung epithelium, rather than that of the bone marrow-derived, cellular compartment. Furthermore, transgenic epithelial-specific correction of the HPS defect significantly attenuated bleomycin-induced alveolar epithelial apoptosis, fibrotic susceptibility, and macrophage activation. Type II cell apoptosis was genotype specific, caspase dependent, and correlated with the degree of fibrotic susceptibility.
  
  
  CONCLUSIONS
  We conclude that pulmonary fibrosis in naturally occurring HPS mice is driven by intracellular trafficking defects that lower the threshold for pulmonary epithelial apoptosis. Our findings demonstrate a pivotal role for the alveolar epithelium in the maintenance of alveolar homeostasis and regulation of alveolar macrophage activation.
authors.affiliation: Division of Pulmonary Medicine, Department of Pediatrics, Vanderbilt University School of Medicine, 2200 Children's Way, 11215 Doctor's Office Tower, Nashville, TN 37232, USA. Lisa.Young@vanderbilt.edu
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Young
authors.forename: Peter M
authors.initials: PM
authors.lastname: Gulleman
authors.forename: James P
authors.initials: JP
authors.lastname: Bridges
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Weaver
authors.forename: Gail H
authors.initials: GH
authors.lastname: Deutsch
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Blackwell
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
mesh_terms: D033963:Adaptor Protein Complex 3 / Q000235:genetics; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D020022:Genetic Predisposition to Disease; D022861:Hermanski-Pudlak Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008168:Lung / Q000473:pathology; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D021381:Protein Transport; D011650:Pulmonary Alveoli / Q000503:physiopathology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000150:complications / Q000473:pathology / Q000503:physiopathology*; D020545:Respiratory Mucosa / Q000503:physiopathology*
chemical_list: D033963:Adaptor Protein Complex 3; D001761:Bleomycin