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http://purl.uniprot.org/citations/23043085http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/23043085http://www.w3.org/2000/01/rdf-schema#comment"

Rationale

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.

Objectives

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.

Measurements and main 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."xsd:string
http://purl.uniprot.org/citations/23043085http://purl.org/dc/terms/identifier"doi:10.1164/rccm.201207-1206oc"xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/author"Weaver T.E."xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/author"Bridges J.P."xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/author"Blackwell T.S."xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/author"McCormack F.X."xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/author"Deutsch G.H."xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/author"Young L.R."xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/author"Gulleman P.M."xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/date"2012"xsd:gYear
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/name"Am J Respir Crit Care Med"xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/pages"1014-1024"xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/title"The alveolar epithelium determines susceptibility to lung fibrosis in Hermansky-Pudlak syndrome."xsd:string
http://purl.uniprot.org/citations/23043085http://purl.uniprot.org/core/volume"186"xsd:string
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