{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:29:33Z","timestamp":1790418573674,"version":"4.1.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2012,11,1]],"date-time":"2012-11-01T00:00:00Z","timestamp":1351728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,11,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To decipher which cell lineage(s) in the alveolar compartment is the predominant driver of fibrotic susceptibility in HPS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>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\u2013derived, 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.201207-1206oc","type":"journal-article","created":{"date-parts":[[2012,11,15]],"date-time":"2012-11-15T11:38:26Z","timestamp":1352979506000},"page":"1014-1024","source":"Crossref","is-referenced-by-count":99,"title":["The Alveolar Epithelium Determines Susceptibility to Lung Fibrosis in Hermansky-Pudlak Syndrome"],"prefix":"10.1093","volume":"186","author":[{"given":"Lisa R.","family":"Young","sequence":"first","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Pediatrics, and"},{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter M.","family":"Gulleman","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Medicine, Department of Pediatrics, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James P.","family":"Bridges","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy E.","family":"Weaver","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Biology, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail H.","family":"Deutsch","sequence":"additional","affiliation":[{"name":"Department of Pathology, Seattle Children\u2019s Hospital, Seattle, Washington; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy S.","family":"Blackwell","sequence":"additional","affiliation":[{"name":"Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis X.","family":"McCormack","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, The University of Cincinnati College of Medicine, Cincinnati, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2012,11,15]]},"reference":[{"key":"2026032101071630100_bib1","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1016\/S0140-6736(11)60052-4","article-title":"Idiopathic pulmonary fibrosis","volume":"378","author":"King","year":"2011","journal-title":"Lancet"},{"key":"2026032101071630100_bib2","doi-asserted-by":"crossref","first-page":"1258","DOI":"10.1056\/NEJM199804303381803","article-title":"Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome)","volume":"338","author":"Gahl","year":"1998","journal-title":"N Engl J Med"},{"key":"2026032101071630100_bib3","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1016\/j.ajhg.2011.05.009","article-title":"A BLOC-1 mutation screen reveals that PLDN is mutated in Hermansky-Pudlak syndrome type 9","volume":"88","author":"Cullinane","year":"2011","journal-title":"Am J Hum Genet"},{"key":"2026032101071630100_bib4","doi-asserted-by":"crossref","first-page":"56","DOI":"10.2119\/molmed.2011.00198","article-title":"Interstitial lung disease and pulmonary fibrosis in Hermansky-Pudlak syndrome type 2, an adaptor protein-3 complex disease","volume":"18","author":"Gochuico","year":"2012","journal-title":"Mol Med"},{"key":"2026032101071630100_bib5","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1378\/chest.117.1.129","article-title":"Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1","volume":"117","author":"Brantly","year":"2000","journal-title":"Chest"},{"key":"2026032101071630100_bib6","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0002-9343(99)00436-2","article-title":"A new variant of Hermansky-Pudlak syndrome due to mutations in a gene responsible for vesicle formation","volume":"108","author":"Shotelersuk","year":"2000","journal-title":"Am J Med"},{"key":"2026032101071630100_bib7","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1159\/000091609","article-title":"Pulmonary fibrosis in Hermansky-Pudlak syndrome. 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