Peroxisome Proliferator–activated Receptor-γ Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model

Malur, Anagha; Mohan, Arjun; Barrington, Robert A.; Leffler, Nancy R.; Malur, Amrita; Muller‐Borer, Barbara J.; Murray, Gina; Kew, Kimberly; Zhou, Chuanzhen; Russell, Joshua; Jones, Jacob L.; Wingard, Christopher J.; Barna, Barbara P.; Thomassen, Mary Jane

doi:10.1165/rcmb.2018-0346oc

Cited by 20 publications

(13 citation statements)

References 38 publications

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“…Briefly, mice were sedated with isofluorane and by gently pulling forward the mouse tongue the epiglottis was exposed and a 50 µl volume was instilled using a pipette. MWCNTs (900-1201, lot-GS1802, SES Research, Houston, TX, United States) were freshly prepared and have been described previously (16). Sham controls received vehicle alone.…”

Section: Multiwall Carbon Nanotube Modelmentioning

confidence: 99%

“…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: Histological Analysismentioning

confidence: 99%

“…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: Histological Analysismentioning

confidence: 99%

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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: Multiwall Carbon Nanotube Modelmentioning

confidence: 99%

Section: Histological Analysismentioning

confidence: 99%

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Matrix Metalloproteinase-12 Is Required for Granuloma Progression

et al. 2020

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“…A murine model of multiwall carbon nanotube (MWCNT) elicited chronic granulomatous disease, which resembles human sarcoidosis pathology, including alveolar macrophage PPARγ deficiency. PPARγ deficiency promotes pulmonary mycobacterial early secreted antigenic target protein 6 (ESAT-6) retention, exacerbates macrophage responses to MWCNT + ESAT-6 and intensifies pulmonary fibrosis [ 160 ]. The cells overexpressing CYP1A1 infected with Micoplasma hyopneumoniae led to an increase in PPARγ expression, resulting in lower production of IL-1b, IL-6, IL-8 and TNF-α in pigs [ 116 ].…”

Section: Pharmacologic and Therapeutic Potentials Of Pparγ Ligandsmentioning

confidence: 99%

PPAR Gamma: From Definition to Molecular Targets and Therapy of Lung Diseases

Carvalho

Gonçalves-de-Albuquerque

Silva

2021

IJMS

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily that regulate the expression of genes related to lipid and glucose metabolism and inflammation. There are three members: PPARα, PPARβ or PPARγ. PPARγ have several ligands. The natural agonists are omega 9, curcumin, eicosanoids and others. Among the synthetic ligands, we highlight the thiazolidinediones, clinically used as an antidiabetic. Many of these studies involve natural or synthetic products in different pathologies. The mechanisms that regulate PPARγ involve post-translational modifications, such as phosphorylation, sumoylation and ubiquitination, among others. It is known that anti-inflammatory mechanisms involve the inhibition of other transcription factors, such as nuclear factor kB(NFκB), signal transducer and activator of transcription (STAT) or activator protein 1 (AP-1), or intracellular signaling proteins such as mitogen-activated protein (MAP) kinases. PPARγ transrepresses other transcription factors and consequently inhibits gene expression of inflammatory mediators, known as biomarkers for morbidity and mortality, leading to control of the exacerbated inflammation that occurs, for instance, in lung injury/acute respiratory distress. Many studies have shown the therapeutic potentials of PPARγ on pulmonary diseases. Herein, we describe activities of the PPARγ as a modulator of inflammation, focusing on lung injury and including definition and mechanisms of regulation, biological effects and molecular targets, and its role in lung diseases caused by inflammatory stimuli, bacteria and virus, and molecular-based therapy.

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“…Comparison of both models showed that although these models were capable of recruiting macrophages, as well as T, B, and Treg lymphocytes, the innate immunity profile and the cytokine production were clearly different, with a more severe inflammation in the QDOT model [ 101 ]. Interestingly, Malur et al showed additive effects on granuloma formation by using a combination of MWCT with microbial antigens (mycobacterial antigen ESAT-6, a T cell activator associated with tuberculosis and sarcoidosis) [ 102 , 103 ]. The double-hit strategy promoted increased granulomas, fibrosis, and inflammatory mediators, indicating that trigger multiplication could be responsible for granuloma persistence associated with pulmonary fibrosis.…”

Section: In Vivo Modelsmentioning

confidence: 99%

Models Contribution to the Understanding of Sarcoidosis Pathogenesis: “Are There Good Models of Sarcoidosis?”

Besnard

Jeny

2020

JCM

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Sarcoidosis is a systemic, granulomatous, and noninfectious disease of unknown etiology. The clinical heterogeneity of the disease (targeted tissue(s), course of the disease, and therapy response) supports the idea that a multiplicity of trigger antigens may be involved. The pathogenesis of sarcoidosis is not yet completely understood, although in recent years, considerable efforts were put to develop novel experimental research models of sarcoidosis. In particular, sarcoidosis patient cells were used within in vitro 3D models to study their characteristics compared to control patients. Likewise, a series of transgenic mouse models were developed to highlight the role of particular signaling pathways in granuloma formation and persistence. The purpose of this review is to put in perspective the contributions of the most recent models in the understanding of sarcoidosis.

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Peroxisome Proliferator–activated Receptor-γ Deficiency Exacerbates Fibrotic Response to Mycobacteria Peptide in Murine Sarcoidosis Model

Cited by 20 publications

References 38 publications

Matrix Metalloproteinase-12 Is Required for Granuloma Progression

Matrix Metalloproteinase-12 Is Required for Granuloma Progression

PPAR Gamma: From Definition to Molecular Targets and Therapy of Lung Diseases

Models Contribution to the Understanding of Sarcoidosis Pathogenesis: “Are There Good Models of Sarcoidosis?”

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