Aberrant lung structure, composition, and function in a murine model of Hermansky-Pudlak syndrome

Abstract

Hermansky-Pudlak syndrome (HPS) is a genetically heterogeneous inherited disease causing hypopigmentation and prolonged bleeding times. An additional serious clinical problem of HPS is the development of lung pathology, which may lead to severe lung disease and premature death. No cure for the disease exists, and previously, no animal model for the HPS lung abnormalities has been reported. A mouse model of HPS, which is homozygously recessive for both the Hps1 (pale ear) and Hps2 (pearl) genes, exhibits striking abnormalities of lung type II cells. Type II cells and lamellar bodies of this mutant are greatly enlarged, and the lamellar bodies are engorged with surfactant. Mutant lungs accumulate excessive autofluorescent pigment. The air spaces of mutant lungs contain age-related elevations of inflammatory cells and foamy macrophages. In vivo measurement of lung hysteresivity demonstrated aberrant lung function in mutant mice. All these features are similar to the lung pathology described in HPS patients. Morphometry of mutant lungs indicates a significant emphysema. These mutant mice provide a model to further investigate the lung pathology and therapy of HPS. We hypothesize that abnormal type II cell lamellar body structure/function may predict future lung pathology in HPS.

Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

“…In our prior study we normalized total SP-D immunoblotting data to BAL total protein and total phospholipid. This normalization presented a problem in retrospect because of elevated total protein and reduced total phospholipid in BAL from EPPE mice, as we and others have reported (4,7), leading us to conclude that total SP-D was not altered in the EPPE mice. In the present study we instead reported total SP-D in equivalent volumes of BAL from EPPE mice ( Figure 3) and patients with HPS1 ( Figure 5), and found dramatic differences that progressed with age in EPPE mice, and with disease severity in patients with HPS1.…”

“…The advantage of the EPPE mouse model is that it recapitulates all the features of adult HPS lung disease with the presence of giant lamellar bodies in alveolar epithelial cells, inflammation, and lung remodeling including fibrosis, albeit also in the context of airspace enlargement not reported in human HPS (4,8). The present study uses this animal model to establish the temporal relationships between each facet of the disease.…”

“…Mouse models of HPS, including the mouse homologs of HPS1 (pale ear) and HPS2 (pearl), similarly display foamy degeneration of alveolar type 2 cells of adult animals. Adult pale ear and pearl animals exhibit a macrophage-predominant alveolar inflammation (4,5) and develop emphysema with aging but do not develop pulmonary fibrosis unless exposed to fibrogenic stimuli such as bleomycin, albeit at much lower doses than for littermate controls (6). Intercrossing HPS1/pale ear and HPS2/pearl strains results in a more severe phenotype (4) that more closely resembles the pulmonary manifestations of human HPS.…”

“…Intercrossing HPS1/pale ear and HPS2/pearl strains results in a more severe phenotype (4) that more closely resembles the pulmonary manifestations of human HPS. Adult pale ear/pearl doubly homozygous (EPPE) mice exhibit foamy alveolar type 2 cells associated with defective surfactant secretion (7), macrophage-predominant alveolar inflammation, and lung remodeling most notable for tissue destruction (4). Older animals have been shown also to exhibit epithelial cell apoptosis and spontaneous pulmonary fibrosis (8).…”

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

“…Interestingly, murine models of HPS-1 (Pale ear) and HPS-2 (Pearl) show activation of alveolar macrophages in the lung, but not in the blood or peritoneum (47,48). Pale ear HPS-1 mice do not develop spontaneous fibrosis, but have higher baseline collagen deposition and show increased inflammation and collagen expression in response to silica challenge (47,49,50). In response to bleomycin, HPS-1 and HPS-2 mice developed fibrosis significantly earlier and to a greater extent than wild-type mice (48).…”