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

Abstract

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 cholatecontaining 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 angiotensinconverting 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.

Blockade of Th1 chemokine receptors ameliorates pulmonary granulomatosis in mice

“…Unlike human sarcoidosis, the condition in our model is not chronic and improved within 2 weeks, which is consistent with the previous reports, but is a limitation of our study [26,28]. Recently, SAMOKHIN et al [33] reported a model of prolonged pulmonary granulomatosis like human sarcoidosis in ApoE -/-mice. Further study is required to confirm the efficacy of TAK-779 in chronic models with therapeutic protocols.…”

Mild Hypercholesterolemia Blunts the Proinflammatory and Prothrombotic Effects of Hypertension on the Cerebral Microcirculation

“…Dietary cholate has been previously shown to induce inflammation and to potentiate the inflammation induced by a high fat diet. [26][27][28] To avoid this potential confounding variable, we used a diet high in cholesterol and fat, but without cholate supplementation, in the present study.…”

Emerging Roles of Apolipoprotein E and Apolipoprotein A-I in the Pathogenesis and Treatment of Lung Disease

“…In another study, feeding a WD to Apoe-deficient mice caused an increase in lung cholesterol content and a progression of pathologic changes that included inflammatory cell infiltration at 4 weeks, lipid-laden lung cells and emphysema at 12 weeks, and granuloma formation at 24 weeks (15). Apoe-deficient mice fed a cholate-containing HFD for 16 weeks also developed granulomatous lung inflammation similar to sarcoidosis, as well as progressive pulmonary fibrosis (16). Hypercholesterolemic Apoedeficient mice fed an HFD for 12 weeks developed marked pulmonary fibrotic changes and lung inflammation (17).…”