title: Inflammatory response and cathepsins in silica-exposed Hermansky-Pudlak syndrome model pale ear mice.
abstract: Hermansky-Pudlak syndrome (HPS) is a hereditary disorder involving the sorting processes of intracellular organelles such as lysosomes of reticuloendothelial cells. Pale ear (ep) mouse is known to have the HPS1 gene mutation, which is seen in patients with HPS and pulmonary fibrosis. As pulmonary fibrosis is not spontaneously observed in ep mice, we hypothesized that external stimuli are necessary for the genetic predisposition of its development. We used silica as the external stimulus to induce the alveolar macrophage-mediated inflammatory response and evaluated the pathological changes of the lung and biochemical analysis of collagenolytic lysosomal enzymes cathepsins L and B in ep mice. Treatment with silica induced the following: persistent accumulation of activated macrophages; delayed clearance of silica from alveolar spaces; and increased collagen fibers in alveolar tissues, which were shown with trichrome staining in ep mice. The comparison of bronchoalveolar lavage cells between the naïve ep and control mice revealed: decreased enzymatic activities but increased antigenic levels of cathepsins L and B, resulting in significantly lower ratios of activity to antigen; increased ceroid deposits and cathepsin L antigens in lysosomes; and no abnormal forms of cathepsins were detected. After silica instillation, activities of cathepsin L in the ep mice increased but ratios of activity to antigen were still significantly low. These phenomena induced by silica suggest that external stimuli bring forth fibrogenesis in the animal models or humans that have HPS1 gene mutation.
authors.affiliation: Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan. yoshioka@med.juntendo.ac.jp
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Yoshioka
authors.forename: Toshio
authors.initials: T
authors.lastname: Kumasaka
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ishidoh
authors.forename: Eiki
authors.initials: E
authors.lastname: Kominami
authors.forename: Keiko
authors.initials: K
authors.lastname: Mitani
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hosokawa
authors.forename: Yoshinosuke
authors.initials: Y
authors.lastname: Fukuchi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D018893:Bronchoalveolar Lavage; D002403:Cathepsins / Q000378:metabolism*; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D020022:Genetic Predisposition to Disease; D022861:Hermanski-Pudlak Syndrome / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D016676:Macrophages, Alveolar / Q000378:metabolism* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D009154:Mutation; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D012822:Silicon Dioxide / Q000009:adverse effects
chemical_list: C491131:Hps1 protein, mouse; D008565:Membrane Proteins; D012822:Silicon Dioxide; D002403:Cathepsins