Journal article

Publication year: 2010

Pages: 207-219

Journal: American Journal of Respiratory and Critical Care Medicine

Volume number: 182

Issue number: 2

ISSN: 1073-449X

eISSN: 1535-4970

Open access status: Green

DOI Link: https://doi.org/10.1164/rccm.200909-1414OC

Publisher: American Thoracic Society

Abstract: 

Rationale. The molecular mechanisms underlying Hermansky-Pudlak syndrome associated interstitial pneumonia (HPSIP) are poorly understood but, as in idiopathic pulmonary fibrosis, may be linked to chronic alveolar epithelial type II cell (AECII) injury.

Objectives: We studied the development of fibrosis and the role of AECII injury in various murine models of HPS.

Methods: 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 eosin. 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.

Measurements and Main Results: 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.

Conclusions: Extensively impaired surfactant trafficking and secretion underlie lysosomal and endoplasmic reticulum stress with apoptosis of AECII in HPSIP, thereby causing the development of HPSIP.

Harvard Citation style: Mahavadi, P., Korfei, M., Henneke, I., Liebisch, G., Schmitz, G., Gochuico, B., et al. (2010) Epithelial Stress and Apoptosis Underlie Hermansky-Pudlak Syndrome-associated Interstitial Pneumonia, American Journal of Respiratory and Critical Care Medicine, 182(2), pp. 207-219. https://doi.org/10.1164/rccm.200909-1414OC

APA Citation style: Mahavadi, P., Korfei, M., Henneke, I., Liebisch, G., Schmitz, G., Gochuico, B., Markart, P., Bellusci, S., Seeger, W., Ruppert, C., & Guenther, A. (2010). Epithelial Stress and Apoptosis Underlie Hermansky-Pudlak Syndrome-associated Interstitial Pneumonia. American Journal of Respiratory and Critical Care Medicine. 182(2), 207-219. https://doi.org/10.1164/rccm.200909-1414OC