{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T00:07:05Z","timestamp":1790986025775,"version":"4.1.0"},"reference-count":61,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2010,7,1]],"date-time":"2010-07-01T00:00:00Z","timestamp":1277942400000},"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":[[2010,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Rationale<\/jats:title>\n                    <jats:p>The molecular mechanisms underlying Hermansky-Pudlak syndrome\u2013associated interstitial pneumonia (HPSIP) are poorly understood but, as in idiopathic pulmonary fibrosis, may be linked to chronic alveolar epithelial type II cell (AECII) injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We studied the development of fibrosis and the role of AECII injury in various murine models of HPS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>HPS1, HPS2, and HPS6 monomutant mice, and HPS1\/2 and HPS1\/6 double-mutant and genetic background mice, were killed at 3 and 9 months of age. Quantitative morphometry was undertaken in lung sections stained with hemalaun\u2013eosin. The extent of lung fibrosis was assessed by trichrome staining and hydroxyproline measurement. Surfactant lipids were analyzed by electrospray ionization mass spectrometry. Surfactant proteins, apoptosis, and lysosomal and endoplasmic reticulum stress markers were studied by Western blotting and immunohistochemistry. Cell proliferation was measured by water-soluble tetrazolium salt-1 and bromodeoxyuridine assays.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Measurements and Main Results<\/jats:title>\n                    <jats:p>Spontaneous and slowly progressive HPSIP was observed in HPS1\/2 double mutants, but not in other HPS mutants, with subpleural onset at 3 months and full-blown fibrosis at 9 months. In these mice, extensive surfactant abnormalities were encountered in AECII and were paralleled by early lysosomal stress (cathepsin D induction), late endoplasmic reticulum stress (activating transcription factor-4 [ATF4], C\/EBP homologous protein [CHOP] induction), and marked apoptosis. These findings were fully corroborated in human HPSIP. In addition, cathepsin D overexpression resulted in apoptosis of MLE-12 cells and increased proliferation of NIH 3T3 fibroblasts incubated with conditioned medium of the transfected cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Extensively impaired surfactant trafficking and secretion underlie lysosomal and endoplasmic reticulum stress with apoptosis of AECII in HPSIP, thereby causing the development of HPSIP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1164\/rccm.200909-1414oc","type":"journal-article","created":{"date-parts":[[2010,4,8]],"date-time":"2010-04-08T22:20:27Z","timestamp":1270765227000},"page":"207-219","source":"Crossref","is-referenced-by-count":90,"title":["Epithelial Stress and Apoptosis Underlie Hermansky-Pudlak Syndrome\u2013associated Interstitial Pneumonia"],"prefix":"10.1093","volume":"182","author":[{"given":"Poornima","family":"Mahavadi","sequence":"first","affiliation":[{"name":"Department of Internal Medicine II, University of Giessen Lung Center, Giessen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Korfei","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University of Giessen Lung Center, Giessen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingrid","family":"Henneke","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University of Giessen Lung Center, Giessen"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerhard","family":"Liebisch","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerd","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernadette R.","family":"Gochuico","sequence":"additional","affiliation":[{"name":"Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Markart","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University of Giessen Lung Center, Giessen"},{"name":"Excellence Cluster \u201cCardiopulmonary System,\u201d University of Giessen Lung Center, Giessen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saverio","family":"Bellusci","sequence":"additional","affiliation":[{"name":"Excellence Cluster \u201cCardiopulmonary System,\u201d University of Giessen Lung Center, Giessen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Seeger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University of Giessen Lung Center, Giessen"},{"name":"Excellence Cluster \u201cCardiopulmonary System,\u201d University of Giessen Lung Center, Giessen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clemens","family":"Ruppert","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University of Giessen Lung Center, Giessen"},{"name":"Excellence Cluster \u201cCardiopulmonary System,\u201d University of Giessen Lung Center, Giessen; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Guenther","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine II, University of Giessen Lung Center, Giessen"},{"name":"Excellence Cluster \u201cCardiopulmonary System,\u201d University of Giessen Lung Center, Giessen; and"},{"name":"Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2010,7,15]]},"reference":[{"key":"2026032101474982600_BIB1","first-page":"162","volume-title":"Blood","year":"1959"},{"key":"2026032101474982600_BIB2","first-page":"616","volume-title":"Bioessays","year":"2004"},{"key":"2026032101474982600_BIB3","first-page":"451","volume-title":"Curr Mol Med","year":"2002"},{"key":"2026032101474982600_BIB4","first-page":"10","volume-title":"Hum Genet","year":"2003"},{"key":"2026032101474982600_BIB5","first-page":"19","volume-title":"Pigment Cell Res","year":"2006"},{"key":"2026032101474982600_BIB6","first-page":"234","volume-title":"Mol Genet Metab","year":"2002"},{"key":"2026032101474982600_BIB7","first-page":"737","volume-title":"Am J Med","year":"1979"},{"key":"2026032101474982600_BIB8","first-page":"617","volume-title":"J Lab Clin Med","year":"1994"},{"key":"2026032101474982600_BIB9","first-page":"617","volume-title":"Thorax","year":"1994"},{"key":"2026032101474982600_BIB10","first-page":"304","volume-title":"Virchows Arch","year":"2002"},{"key":"2026032101474982600_BIB11","first-page":"382","volume-title":"Respiration","year":"2000"},{"key":"2026032101474982600_BIB12","first-page":"L643","volume-title":"Am J Physiol Lung Cell Mol Physiol","year":"2003"},{"key":"2026032101474982600_BIB13","first-page":"14","volume-title":"Am J Respir Cell Mol Biol","year":"2005"},{"key":"2026032101474982600_BIB14","first-page":"A823","volume-title":"Am J Respir Crit Care Med","year":"2008"},{"key":"2026032101474982600_BIB15","first-page":"A192","volume-title":"Am J Respir Crit Care Med","year":"2006"},{"key":"2026032101474982600_BIB16","first-page":"440","volume-title":"Arch Biochem Biophys","year":"1961"},{"key":"2026032101474982600_BIB17","first-page":"449","volume-title":"Am J Respir Cell Mol Biol","year":"2004"},{"key":"2026032101474982600_BIB18","first-page":"659","volume-title":"Am J Respir Cell Mol Biol","year":"2002"},{"key":"2026032101474982600_BIB19","first-page":"946","volume-title":"Traffic","year":"2004"},{"key":"2026032101474982600_BIB20","first-page":"420","volume-title":"J Invest Dermatol","year":"2005"},{"key":"2026032101474982600_BIB21","first-page":"159","volume-title":"Folia Histochem Cytobiol","year":"2007"},{"key":"2026032101474982600_BIB22","first-page":"1592","volume-title":"FASEB J","year":"2001"},{"key":"2026032101474982600_BIB23","first-page":"137","volume-title":"Pathol Int","year":"2005"},{"key":"2026032101474982600_BIB24","first-page":"1265","volume-title":"Am J Pathol","year":"2008"},{"key":"2026032101474982600_BIB25","first-page":"410","volume-title":"J Lipid Res","year":"1978"},{"key":"2026032101474982600_BIB26","first-page":"162","volume-title":"Proc Soc Exp Biol Med","year":"2003"},{"key":"2026032101474982600_BIB27","first-page":"4361","volume-title":"J Immunol","year":"2006"},{"key":"2026032101474982600_BIB28","first-page":"1114","volume-title":"Am J Respir Crit Care Med","year":"2009"},{"key":"2026032101474982600_BIB29","first-page":"6366","volume-title":"Proc Natl Acad Sci USA","year":"2001"},{"key":"2026032101474982600_BIB30","first-page":"601","volume-title":"Annu Rev Physiol","year":"2004"},{"key":"2026032101474982600_BIB31","first-page":"3305","volume-title":"J Cell Sci","year":"2008"},{"key":"2026032101474982600_BIB32","first-page":"565","volume-title":"Eur Respir J","year":"1999"},{"key":"2026032101474982600_BIB33","first-page":"67","volume-title":"Am J Respir Cell Mol Biol","year":"2007"},{"key":"2026032101474982600_BIB34","first-page":"321","volume-title":"Nat Genet","year":"2002"},{"key":"2026032101474982600_BIB35","first-page":"20332","volume-title":"J Biol Chem","year":"2003"},{"key":"2026032101474982600_BIB36","first-page":"8770","volume-title":"Proc Natl Acad Sci USA","year":"2003"},{"key":"2026032101474982600_BIB37","first-page":"5243","volume-title":"J Cell Sci","year":"2005"},{"key":"2026032101474982600_BIB38","first-page":"458","volume-title":"Curr Opin Cell Biol","year":"2004"},{"key":"2026032101474982600_BIB39","first-page":"7794","volume-title":"J Biol Chem","year":"2010"},{"key":"2026032101474982600_BIB40","first-page":"1790","volume-title":"J Biol Chem","year":"2009"},{"key":"2026032101474982600_BIB41","first-page":"820","volume-title":"J Neurosci","year":"2010"},{"key":"2026032101474982600_BIB42","first-page":"531","volume-title":"J Cell Sci","year":"2007"},{"key":"2026032101474982600_BIB43","first-page":"647","volume-title":"Traffic","year":"2006"},{"key":"2026032101474982600_BIB44","first-page":"11","volume-title":"Mol Cell","year":"1999"},{"key":"2026032101474982600_BIB45","first-page":"1300","volume-title":"J Biol Chem","year":"2000"},{"key":"2026032101474982600_BIB46","first-page":"1651","volume-title":"Blood","year":"2002"},{"key":"2026032101474982600_BIB47","first-page":"41","volume-title":"Bratisl Lek Listy (Tlacene Vyd)","year":"1992"},{"key":"2026032101474982600_BIB48","first-page":"5031","volume-title":"J Cell Sci","year":"2006"},{"key":"2026032101474982600_BIB49","first-page":"G296","volume-title":"Am J Physiol","year":"2007"},{"key":"2026032101474982600_BIB50","first-page":"1213","volume-title":"J Leukoc Biol","year":"2007"},{"key":"2026032101474982600_BIB51","first-page":"L46","volume-title":"Am J Physiol Lung Cell Mol Physiol","year":"2004"},{"key":"2026032101474982600_BIB52","first-page":"223","volume-title":"J Cell Physiol","year":"2007"},{"key":"2026032101474982600_BIB53","first-page":"2057","volume-title":"Biochim Biophys Acta","year":"2006"},{"key":"2026032101474982600_BIB54","first-page":"753","volume-title":"Mol Cell","year":"2004"},{"key":"2026032101474982600_BIB55","first-page":"521","volume-title":"Am J Respir Cell Mol Biol","year":"2005"},{"key":"2026032101474982600_BIB56","first-page":"683","volume-title":"J Cell Sci","year":"2003"},{"key":"2026032101474982600_BIB57","first-page":"838","volume-title":"Am J Respir Crit Care Med","year":"2008"},{"key":"2026032101474982600_BIB58","first-page":"630","volume-title":"FEBS J","year":"2007"},{"key":"2026032101474982600_BIB59","first-page":"1196","volume-title":"Am J Respir Crit Care Med","year":"2009"},{"key":"2026032101474982600_BIB60","first-page":"1683","volume-title":"Invest Ophthalmol Vis Sci","year":"2007"},{"key":"2026032101474982600_BIB61","first-page":"18525","volume-title":"Proc Natl Acad Sci USA","year":"2008"}],"container-title":["American Journal of Respiratory and Critical Care Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/182\/2\/207\/67305925\/ajrccm_182_2_207.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrccm\/article-pdf\/182\/2\/207\/67305925\/ajrccm_182_2_207.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,21]],"date-time":"2026-03-21T05:48:00Z","timestamp":1774072080000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrccm\/article\/182\/2\/207\/8514981"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2010,7]]},"references-count":61,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2010,7,15]]},"published-print":{"date-parts":[[2010,7,15]]}},"URL":"https:\/\/doi.org\/10.1164\/rccm.200909-1414oc","relation":{},"ISSN":["1073-449X","1535-4970"],"issn-type":[{"value":"1073-449X","type":"print"},{"value":"1535-4970","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2010,7]]},"published":{"date-parts":[[2010,7]]}}}