Editors' ChoicePulmonary fibrosis

Pearls of Wisdom for Pulmonary Fibrosis

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Science Translational Medicine  08 Jun 2011:
Vol. 3, Issue 86, pp. 86ec88
DOI: 10.1126/scitranslmed.3002722

Hermansky Pudlak syndrome (HPS) is a heterogeneous group of rare autosomal recessive disorders. HPS is characterized by a lysosomal dysfunction that results in albinism of the hair, eyes, and skin; bleeding that is due to platelet abnormalities; and accumulation of pathogenic levels of ceroid in body tissues such as lung and kidney. Indeed, adult-onset pulmonary fibrosis is a major complication of two clinical subtypes of this disorder, HPS1 and HPS2. The causative genes for HPS1 and HPS2 were identified several years ago, and HPS1 and HPS2 mutant mice, named pale-ear and pearl respectively, largely recapitulate the human disease, although with a different lung phenotype. However, mice doubly homozygous for the mutant pale-ear and pearl genes (EPPE mice) have abnormalities in alveolar type II epithelial cells in the lung that are strikingly similar to those described in human HPS patients and thus may provide a better model of HPS lung disease. Now, a translational study by Atochina-Vasserman et al. establishes the presence of lung fibrosis in the EPPE mouse model and presents intriguing evidence that suggests a possible mechanism for the development of this disease manifestation that is comparable with human HPS subjects.

In a careful kinetic analysis of EPPE mice ranging from 3 days to 32 weeks of age, the authors showed that increases in both alveolar type II cell lamellar body enlargement and overall lung phospholipid content preceded macrophage-driven lung inflammation. These events were followed by a mild but statistically significant increase in collagen deposition and histologic lung fibrosis. Therefore, the authors hypothesized that alveolar type II epithelial cells played a critical role in disease development. Alveolar epithelial cells from EPPE mice had a proinflammatory phenotype, with increased expression of monocyte chemotactic protein–1 (MCP-1) and inducible nitric oxide synthase (iNOS). EPPE mice also had an increase in S-nitrosylated surfactant protein D (SNO-SP-D), which has previously been implicated in lung inflammation, and in an exciting translation to humans, the authors found that HPS1 patients also had elevated amounts of MCP1 and SNO-SP-D in their lung lavage fluid. Lastly, chemotaxis assays using human and mouse lavage fluid supported a direct role for both of these molecules in mediating macrophage influx. Thus, chronic inflammation mediated by alveolar epithelial cells through macrophages may play an important role in the development of lung fibrosis in HPS patients. There is a lack of effective treatments for this devastating disease, and this study presents important, intriguing evidence of potential therapeutic targets to pursue.

E. N. Atochina-Vasserman et al., Early alveolar epithelial dysfunction promotes lung inflammation in a mouse model of Hermansky Pudlak syndrome. Am. J. Respir. Crit. Care Med. 26 May 2011 (10.1164/rccm.201011-1882OC). [Abstract]

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