Role of impaired lysosomal trafficking in pulmonary fibrosis

Rationale: Hermansky-Pudlack Syndrome (HPS) is an autosomal recessive disorder in which mutations on one of the six human genes HPS1, ADB3A, HPS3, HPS4, HPS5 and HPS6 results in impairment of lysosomal transport. Along with melanosomes, platelet dense bodies and lysosomes, HPS also results in impaired processing of lamellar bodies of type II pneumocytes – the lysosome related organelles, responsible for surfactant trafficking in the lungs. The most serious complication of HPS is severe pulmonary fibrosis, which is almost indistinguishable from clinical Idiopathic Pulmonary Fibrosis (IPF). In the present study, we investigated biochemical surfactant alterations in lung tissue and bronchoalveolar lavage fluid (BALF) from HPS1/6 (ep/ru) double mutant mice. Results: Using immunoblotting, increased levels of pro SP-B and decreased levels of mature SP-B were found in the lung tissue and in the BALF respectively, of ep/ru double mutant mice as compared to wild type control mice of the same background. No major alterations of pro and mature forms of SP-C were detected. High Performance Thin Layer Chromatographic analysis showed that the levels of phosphatidylcholine (PC) and phosphatidylglycerol (PG) were strongly increased in the lung tissue of ep/ru double mutant mice as compared to control mice. In parallel, the fatty acid profiles by means of gas-liquid chromatography showed that the relative content of palmitic acid in lung tissue PC of ep/ru mice was significantly increased when compared to control mice. Conclusion: Altered post-translational processing of surfactant components leads to an impairment of lamellar body genesis, which might be involved in the pathogenesis of IPF and pulmonary fibrosis associated with HPS.