Alveolar Macrophage ABCG1 Deficiency Promotes Pulmonary Granulomatous Inflammation

McPeek, Matthew; Malur, Anagha; Tokarz, Debra A; Lertpiriyapong, Kvin; Gowdy, Kymberly M.; Murray, Gina; Wingard, Christopher J.; Fessler, Michael B.; Barna, Barbara P.; Thomassen, Mary Jane

doi:10.1165/rcmb.2018-0365oc

Cited by 18 publications

(24 citation statements)

References 34 publications

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“…Paraffin embedded slides were sectioned at 7 μm, and stained with hematoxylin and eosin (H&E) or Gomori’s trichrome stain as previously described ( 4 , 16 ). A previously described semiquantitative scoring system ( 7 , 16 , 17 ) was used to calculate a relative comparison of the numbers and quality of granulomas formed in MWCNT-instilled mice. Trichrome stain was evaluated using modified Ashcroft method ( 16 , 18 ).…”

Section: Methodsmentioning

confidence: 99%

Matrix Metalloproteinase-12 Is Required for Granuloma Progression

et al. 2020

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Background Sarcoidosis is a chronic inflammatory disease of unknown cause characterized by granuloma formation. Mechanisms for chronic persistence of granulomas are unknown. Matrix Metalloproteinase-12 (MMP12) degrades extracellular matrix elastin and enables infiltration of immune cells responsible for inflammation and granuloma formation. Previous studies report increased MMP12 in sarcoidosis patients and association between MMP12 expression and disease severity. We also observed elevated MMP12 in our multiwall carbon nanotube (MWCNT) murine model of granulomatous inflammation. Here we hypothesized that MMP12 is important to acute and late phases of granuloma pathogenesis. To test this hypothesis, we analyzed granulomatous and inflammatory responses of Mmp12 knock-out (KO) mice at 10 (acute) and 60 days (late) after MWCNT instillation. Methods C57BL/6 (wildtype) and Mmp12 KO mice underwent oropharyngeal instillation of MWCNT. Lungs were harvested at 3, 10, 20, and 60 days post instillation for evaluation of MMP12 expression and granulomatous changes. Bronchoalveolar lavage (BAL) cells were analyzed 60 days after MWCNT instillation for expression of mediators thought to play a role in sarcoid granulomatosis: peroxisome proliferator-activated receptor-gamma (PPARγ), interferon-gamma (IFN-γ), and CCL2 (MCP-1). Results Pulmonary granuloma appearance at 10 days after MWCNT instillation showed no differences between wildtype and Mmp12 KO mice. In contrast, by 60 days after MWCNT instillation, Mmp12 KO mice revealed markedly attenuated granuloma formation together with elevated PPARγ and reduced IFNγ expression in BAL cells compared to wildtype. Unexpectedly, Mmp12 KO mice further demonstrated increased alveolar macrophages with increased CCL2 at 60 days. Conclusions The striking reduction of granuloma formation at day 60 in Mmp12 KO mice suggests that MMP12 is required to maintain chronic granuloma pathophysiology. The increased PPARγ and decreased IFNγ findings suggest that these mediators also may be involved since previous studies have shown that PPARγ suppresses IFNγ and PPARγ deficiency amplifies granuloma formation. Interestingly, a role of MMP12 in granuloma resolution is also suggested by increases in both macrophage influx and CCL2. Overall, our results strongly implicate MMP12 as a key factor in granuloma persistence and as a possible therapeutic target in chronic pulmonary sarcoidosis.

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Section: Methodsmentioning

confidence: 99%

Matrix Metalloproteinase-12 Is Required for Granuloma Progression

et al. 2020

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“…ABCA1 de ciency would induce decreased cholesterol e ux about the macrophages. In cell and animal models, ABCA1 de ciency macrophages were correlated with enhanced in ammatory mediators and gene expression such as IL-6, TNF-α, IL-1β, etc (27). In addition, ABCA1 was act as anti-in ammatory mediator that ABCA1 knockout mice might increase the in ltration of in ammatory cells in vessel wall, tissue, and blood.…”

Section: Discussionmentioning

confidence: 98%

The Mechanism Study of Xiao-Xian-Xiong Decoction in the Treatment of Atherosclerosis with Network Pharmacology

Xiao¹,

Li²,

Fan³

et al. 2020

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Background: Xiao-Xian-Xiong decoction is a useful formula in the treatment of atherosclerosis in traditional Chinese medicine. In this study, we aimed to investigate the function of Xiao-Xian-Xiong decoction in the treatment of atherosclerosis. Methods: In this study, we conducted the method of network pharmacology and molecular docking to discover the mechanism of Xiao-Xian-Xiong decoction against atherosclerosis. Then, we validated the function of Xiao-Xian-Xiong decoction in atherosclerosis in vitro. We investigated the function and mechanism of Xiao-Xian-Xiong decoction in RAW264.7 macrophage-derived foam cells.Results: We identified 213 targets of Xiao-Xian-Xiong decoction and 331 targets of atherosclerosis. The PPI networks of Xiao-Xian-Xiong decoction and atherosclerosis were constructed. Furthermore, the two PPI networks were merged and the core PPI network was obtained. Then, functional enrichment analysis was conducted with GO and KEGG signaling pathway analysis. KEGG analysis indicated Xiao-Xian-Xiong decoction was correlated with ubiquitin mediated proteolysis pathway, PI3K-AKT pathway, MAPK pathway, Notch signaling pathway, and TGF-β signaling pathway. At last, we validated the function of Xiao-Xian-Xiong decoction with atherosclerosis in vitro. Xiao-Xian-Xiong decoction reduced lipid accumulation and promoted the outflow of cholesterol in RAW264.7-derived foam cells. Xiao-Xian-Xiong decoction increased the expression of ABCA1 and ABCG1 protein in foam cells. ABCA1 and ABCG1 were related with regulation of the inflammatory pathway and cell proliferation in atherosclerosis.Conclusions: Combined the mechanism of available treatments of atherosclerosis, we inferred Xiao-Xian-Xiong decoction could alleviate atherosclerosis by inhibiting inflammatory response and cell proliferation.

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“…Despite these model limitations, the study by McPeek and colleagues (3) lends credence to a growing body of evidence linking ABC transporters to the pathogenesis of chronic inflammatory and fibrotic lung diseases. In keeping with the results of the MWCNT model, ABC transporters, particularly ABCG1, were shown to promote the clearance of lipids from macrophages in the setting of bleomycin-induced lung injury in mice, thereby attenuating progression to pulmonary fibrosis (7).…”

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confidence: 97%

“…The findings of that study, presented by McPeek and colleagues in this issue of the Journal (pp. 332–340), more conclusively implicate ABC transporters in the pathogenesis of foreign body–induced granulomatous lung disease (3). Instead of pharmacological manipulation of ABC transporters, as reported previously (2), this study used mice harboring selective and conditional gene knockouts of Abca1 or Abcg1 or both that were treated with inhaled MWCNT or surfactant (negative controls).…”

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confidence: 99%

“…On the basis of findings in the MWCNT granuloma model (3), the authors imply that ABCG1 could also play a role in the pathogenesis of other granulomatous disorders, such as sarcoidosis. This conclusion may be overreaching, given that the mechanisms by which foreign body granulomas form, such as induced by MWCNT, are mechanistically distinct from “immune granulomas,” such as sarcoidosis, Crohn’s disease, or infectious granulomas.…”

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confidence: 99%

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