ApoE-Deficient Mice on Cholate-Containing High-Fat Diet Reveal a Pathology Similar to Lung Sarcoidosis

Department of Oral Science, Faculty of Dentistry, 2350 Health Sciences Mall, Life Sciences Institute, Room 4559, University of British Columbia, Vancouver V6T 1Z3, Canada.
American Journal Of Pathology (Impact Factor: 4.59). 03/2010; 176(3):1148-56. DOI: 10.2353/ajpath.2010.090857
Source: PubMed


Sarcoidosis is a chronic disease of unknown etiology characterized by the formation of non-necrotizing epithelioid granulomas in various organs, especially in the lungs. The lack of an adequate animal model reflecting the pathogenesis of the human disease is one of the major impediments in studying sarcoidosis. In this report, we describe ApoE-/- mice on a cholate-containing high-fat diet that exhibit granulomatous lung inflammation similar to human sarcoidosis. Histological analysis revealed well-defined and non-necrotizing granulomas in about 40% of mice with the highest number of granulomas after 16 weeks on a cholate-containing high-fat diet. Granulomas contained CD4+ and CD8+ T cells, and the majority of the cells in granulomas showed immunoreactivity for the macrophage marker Mac-3. Cells with morphological features of epithelioid cells expressed angiotensin-converting enzyme, osteopontin, and cathepsin K, all characteristics of epithelioid and giant cells in granulomas of human sarcoidosis. Giant cells and nonspecific inclusions such as Schaumann's bodies and crystalline deposits were also detected in some lungs. Granulomatous inflammation resulted in progressive pulmonary fibrosis. Removal of cholate from the diet prevented the formation of lung granulomas. The observed similarities between the analyzed mouse lung granulomas and granulomas of human sarcoidosis, as well as the chronic disease character leading to fibrosis, suggest that this mouse model might be a useful tool to study sarcoidosis.

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Available from: Andriy Samokhin, Jun 24, 2014
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    • "This protease is also expressed at lower levels in macrophages, epithelial cells, fibroblasts, smooth muscle cells which can be elevated under pathological conditions (Chapman et al., 1997). Thus, high cathepsin K concentration was found in rheumatoid arthritic joints, in epithelioid and multinucleated giant cells in lungs, and in thyroid glands (Buhling et al., 2004; Samokhin et al., 2010a; Tepel et al., 2000). Cathepsin K is not detectable in normal blood vessels, but is highly expressed in macrophages, smooth muscle cells, endothelial and multinucleated giant cells in atherosclerotic lesions and in giant cell aortitis (Sukhova et al., 1998; Platt et al., 2007; Chapman et al., 1997; Samokhin et al., 2010c). "

    Full-text · Chapter · Dec 2011
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    • "Control Apoe-/- mice used for CD4+ cell quantification in lungs were on normal diet for 22 weeks. Single cathepsin K and L null mice on high fat diet were not evaluated as previous experiments revealed that the induction of lung granuloma formation by high fat diet was dependent on the apolipoprotein E deficiency [6]. All animal procedures were approved by the Canadian Council on Animal Care. "
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    ABSTRACT: Remodeling of lung tissues during the process of granuloma formation requires significant restructuring of the extra-cellular matrix and cathepsins K, L and S are among the strongest extra-cellular matrix degrading enzymes. Cathepsin K is highly expressed in various pathological granulomatous infiltrates and all three enzymes in their active form are detected in bronchoalveolar lavage fluids from patients with sarcoidosis. Granulomatous inflammation is driven by T-cell response and cathepsins S and L are actively involved in the regulation of antigen presentation and T-cell selection. Here, we show that the disruption of the activities of cathepsins K, L, or S affects the development of lung granulomas in a mouse model of sarcoidosis. Apolipoprotein E-deficient mice lacking cathepsin K or L were fed Paigen diet for 16 weeks and lungs were analyzed and compared with their cathepsin-expressing littermates. The role of cathepsin S in the development of granulomas was evaluated using mice treated for 8 weeks with a potent and selective cathepsin S inhibitor. When compared to wild-type litters, more cathepsin K-deficient mice had lung granulomas, but individually affected mice developed smaller granulomas that were present in lower numbers. The absence of cathepsin K increased the number of multinucleated giant cells and the collagen content in granulomas. Cathepsin L deficiency resulted in decreased size and number of lung granulomas. Apoe-/- mice treated with a selective cathepsin S inhibitor did not develop lung granulomas and only individual epithelioid cells were observed. Cathepsin K deficiency affected mostly the occurrence and composition of lung granulomas, whereas cathepsin L deficiency significantly reduced their number and cathepsin S inhibition prevented the formation of granulomas.
    Full-text · Article · Jan 2011 · Respiratory research
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    ABSTRACT: Sarcoidosis is a granulomatous disease of unknown aetiology. We identified immunological targets for the treatment of pulmonary granulomatosis using a murine model generated with Propionibacterium acnes. Sensitisation and challenge using heat-killed P. acnes and dendritic cells (DCs) were performed to produce pulmonary granulomatosis in C57BL/6 mice. Immunological analyses using ELISA as well as cDNA microarray analysis were used to search for cytokines or chemokines associated with the formation of granulomas in the lungs. Co-administration of P. acnes and DCs reproducibly induced the formation of pulmonary granulomas, which resembled sarcoid granulomas. The cDNA microarray assay demonstrated that the gene expression of CXCL9 and CXCL10, ligands for CXCR3, and of CCL4, a ligand for CCR5, was strongly upregulated during granulomatosis. ELISA confirmed that levels of CXCL9 and CXCL10 as well as T-helper (Th)1 cytokines and chemokines including tumour necrosis factor-α and interferon-γ were elevated in bronchoalveolar lavage fluid (BALF). The blockade of Th1 chemokine receptors using TAK-779, a dual blocker for CXCR3 and CCR5, led to reduced numbers of CXCR3+CD4+ and CCR5+CD4+ T-cells in BALF. Furthermore, administration of TAK-779 ameliorated the granulomatosis. The targeted inhibition of Th1 chemokines might be useful for inhibiting Th1-biased granulomatous diseases, including sarcoidosis.
    Preview · Article · Jul 2011 · European Respiratory Journal
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