Susceptibility of Hermansky-Pudlak Mice to Bleomycin-Induced Type II Cell Apoptosis and Fibrosis

Abstract

Pulmonary inflammation, abnormalities in type II cell and macrophage morphology, and pulmonary fibrosis are features of Hermansky-Pudlak Syndrome (HPS), a recessive disorder associated with intracellular trafficking defects. We have previously reported that "Pearl" (HPS2) and "Pale Ear" (HPS1) mouse models have pulmonary inflammatory dysregulation and constitutive alveolar macrophage (AM) activation (Young LR et al., J Immunol 2006;176:4361-4368). In the current study, we used these HPS models to investigate mechanisms of lung fibrosis. Unchallenged HPS1 and HPS2 mice have subtle airspace enlargement and foamy AMs, but little or no histologic evidence of lung fibrosis. Seven days after intratracheal bleomycin (0.025 units), HPS1 and HPS2 mice exhibited increased mortality and diffuse pulmonary fibrosis compared to strain-matched C57BL/6J wildtype (WT) mice. HPS mice had significantly increased collagen deposition, and reduced quasi-static and static compliance consistent with a restrictive defect. The early airway and parenchymal cellular inflammatory responses to bleomycin were similar in HPS2 and WT mice. Greater elevations in levels of TGF-␤ and IL-12p40 were produced in the lungs and AMs from bleomycin-challenged HPS mice than in WT mice. TUNEL staining revealed apoptosis of type II cells as early as 5 h after low-dose bleomycin challenge in HPS mice, suggesting that type II cell susceptibility to apoptosis may play a role in the fibrotic response. We conclude that the trafficking abnormalities in HPS promote alveolar apoptosis and pulmonary fibrosis in response to bleomycin challenge.

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

“…Like others (6,8), we are unable to determine from our present studies whether the observed inflammatory signals in EPPE animals directly contribute to the development of fibrosis in animal models of HPS, or are simply an earlier marker of a failing epithelial cell. Although inflammation may be a secondary manifestation of alveolar type 2 cell dysfunction, it represents a reliable early end point for future studies as well as a potential therapeutic target.…”

“…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.…”

Pulmonary Fibrosis in Hermansky-Pudlak Syndrome

“…At least six mouse models have the orthologous mutations to the human genes (41)(42)(43)(44)(45)(46). 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).…”

“…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). Also, higher levels of transforming growth factor (TGF)-b were detected in bleomycin-treated HPS mice.…”

The role of infection in the pathogenesis of idiopathic pulmonary fibrosis

“…In vivo, in human IPF biopsy samples, LAWSON et al [29] have shown co-localisation of latent HHV and markers of ER stress and apoptosis [29]. Activation of these pathways has been highlighted in the development of both IPF and the pulmonary fibrosis associated with the rare genetic disorder HumanskyPudlak syndrome [30,31]. In the murine bleomycin model, chronic MHV-68 infection results in deposition of collagen, increased tumour growth factor (TGF)-b expression and the altered synthesis of surfactant proteins [22].…”