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DOI: 10.1055/s-0034-1376807
Deficient Autophagy in Hermansky-Pudlak Syndrome associated lung fibrosis
Hermansky-Pudlak syndrome (HPS) is a lysosome realated disorder. Patients with HPS types -1, -2 & -4 develop pulmonary fibrosis called Hermansky-Pudlak syndrome associated Interstitial Pneumonia (HPSIP). HPSIP lungs show enlarged alveolar type II cells (AECII) with giant lamellar bodies. We previously reported lung fibrosis in a HPSIP mouse model (HPS1/2), accompanied with surfactant accumulation and apoptosis of AECII due to severe lysosomal stress and ER stress. Data from human HPS1 patient corroborated with the HPS1/2 mice data. Here, we aim to analyze autophagy, an important lysosomal degradation pathway, under HPSIP conditions.
Immunohistochemistry was performed and on serial paraffin lung sections from HPS1, HPS2, HPS1/2 and WT control mice and on lung sections from human HPS1 patients and healthy donors for autophagy related proteins LC3B, p62 and TFEB and for AECII marker, pro SP-C. Immunogold labelling for LC3B was performed on mice lungs fixed in paraformaldehyde and gluteraldehyde.
Immunohistochemistry revealed that the AECII of HPS1/2 mice and human HPS1 did not stain for LC3B, while a convincing signal was observed within macrophages of the same sections and within AECII & macrophages of WT mice and healthy donors. Electron microscopy results confirm the qualitative observation of less labeling of LC3B on the limiting membrane of lamellar bodies in HPS mice compared to WT mice. Immunohistochemistry showed decreased staining for p62 and TFEB within AECII of HPS1/2 compared to WT mice.
Our results point towards defective autophagy within AECII under HPSIP conditions both in mice and men. An in depth analysis of this pathway is underway to further understand the role of defective autophagy in the development of HPSIP.