scholarly journals Studies in a Murine Granuloma Model of Instilled Carbon Nanotubes: Relevance to Sarcoidosis

2021 ◽  
Vol 22 (7) ◽  
pp. 3705
Author(s):  
Barbara P. Barna ◽  
Anagha Malur ◽  
Mary Jane Thomassen
Keyword(s):  
Carbon Nanotubes ◽  
Inflammatory Mediators ◽  
Inflammatory Responses ◽  
Multiwall Carbon Nanotubes ◽  
Peroxisome Proliferator ◽  
Granulomatous Disease ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out ◽  
Pulmonary Granuloma

Poorly soluble environmental antigens, including carbon pollutants, are thought to play a role in the incidence of human sarcoidosis, a chronic inflammatory granulomatous disease of unknown causation. Currently, engineered carbon products such as multiwall carbon nanotubes (MWCNT) are manufactured commercially and have been shown to elicit acute and chronic inflammatory responses in experimental animals, including the production of granulomas or fibrosis. Several years ago, we hypothesized that constructing an experimental model of chronic granulomatosis resembling that associated with sarcoidosis might be achieved by oropharyngeal instillation of MWCNT into mice. This review summarizes the results of our efforts to define mechanisms of granuloma formation and identify potential therapeutic targets for sarcoidosis. Evidence is presented linking findings from the murine MWCNT granuloma model to sarcoidosis pathophysiology. As our goal was to determine what pulmonary inflammatory pathways might be involved, we utilized mice of knock-out (KO) backgrounds which corresponded to deficiencies noted in sarcoidosis patients. A primary example of this approach was to study mice with a myeloid-specific knock-out of the lipid-regulated transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) which is strikingly depressed in sarcoidosis. Among the major findings associated with PPARγ KO mice compared to wild-type were: (1) exacerbation of granulomatous and fibrotic histopathology in response to MWCNT; (2) elevation of inflammatory mediators; and (3) pulmonary retention of a potentially antigenic ESAT-6 peptide co-instilled with MWCNT. In line with these data, we also observed that activation of PPARγ in wild-type mice by the PPARγ-specific ligand, rosiglitazone, significantly reduced both pulmonary granuloma and inflammatory mediator production. Similarly, recognition of a deficiency of ATP-binding cassette (ABC) lipid transporter ABCG1 in sarcoidosis led us to study MWCNT instillation in myeloid-specific ABCG1 KO mice. As anticipated, ABCG1 deficiency was associated with larger granulomas and increased levels of inflammatory mediators. Finally, a transcriptional survey of alveolar macrophages from MWCNT-instilled wild-type mice and human sarcoidosis patients revealed several common themes. One of the most prominent mediators identified in both human and mouse transcriptomic analyses was MMP12. Studies with MMP12 KO mice revealed similar acute reactions to those in wild-type but at chronic time points where wild-type maintained granulomatous disease, resolution occurred with MMP12 KO mice suggesting MMP12 is necessary for granuloma progression. In conclusion, these studies suggest that the MWCNT granuloma model has relevance to human sarcoidosis study, particularly with respect to immune-specific pathways.

Contribution of PPARγ in modulation of acrolein-induced inflammatory signaling in gp91phox knock-out mice

2017 ◽  
Vol 95 (4) ◽  
pp. 482-490 ◽  
Author(s):  
Zivar Yousefipour ◽  
Neha Chug ◽  
Katarzyna Marek ◽  
Alicia Nesbary ◽  
Joseph Mathew ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Body Mass ◽  
Total Antioxidant Status ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out ◽  
Total Antioxidant ◽  
In The Wild ◽  
Knock Out Mice

Oxidative stress and inflammation are major contributors to acrolein toxicity. Peroxisome proliferator activated receptor gamma (PPARγ) has antioxidant and anti-inflammatory effects. We investigated the contribution of PPARγ ligand GW1929 to the attenuation of oxidative stress in acrolein-induced insult. Male gp91phox knock-out (KO) mice were treated with acrolein (0.5 mg·(kg body mass)–1 by intraperitoneal injection for 7 days) with or without GW1929 (GW; 0.5 mg·(kg body mass)–1·day–1, orally, for 10 days). The livers were processed for further analyses. Acrolein significantly increased 8-isoprostane and reduced PPARγ activity (P < 0.05) in the wild type (WT) and KO mice. GW1929 reduced 8-isoprostane (by 32% and 40% in WT and KO mice, respectively) and increased PPARγ activity (by 81% and 92% in WT and KO, respectively). Chemokine activity was increased (by 63%) in acrolein-treated WT mice, and was reduced by GW1929 (by 65%). KO mice exhibited higher xanthine oxidase (XO). Acrolein increased XO and COX in WT mice and XO in KO mice. GW1929 significantly reduced COX in WT and KO mice and reduced XO in KO mice. Acrolein significantly reduced the total antioxidant status in WT and KO mice (P < 0.05), which was improved by GW1929 (by 75% and 74%). The levels of NF-κB were higher in acrolein-treated WT mice. GW1929 reduced NF-κB levels (by 51%) in KO mice. Acrolein increased CD36 in KO mice (by 43%), which was blunted with GW1929. Data confirms that the generation of free radicals by acrolein is mainly through NAD(P)H, but other oxygenates play a role too. GW1929 may alleviate the toxicity of acrolein by attenuating NF-κB, COX, and CD36.

scholarly journals The M2a Macrophage Phenotype Accompanies Pulmonary Granuloma Resolution in Mmp12 Knock-Out Mice Instilled with Multiwall Carbon Nanotubes

2021 ◽  
Vol 22 (20) ◽  
pp. 11019
Author(s):  
David Ogburn ◽  
Sophia Bhalla ◽  
Nan Leffler ◽  
Arjun Mohan ◽  
Anagha Malur ◽  
...  
Keyword(s):  
Carbon Nanotubes ◽  
Matrix Metalloproteinase ◽  
Multiwall Carbon Nanotubes ◽  
Granuloma Formation ◽  
Unknown Etiology ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Knock Out ◽  
Pulmonary Granuloma ◽  
Multiwall Carbon

Sarcoidosis is a chronic disease with unknown etiology and pathophysiology, characterized by granuloma formation. Matrix Metalloproteinase-12 (MMP12) is an elastase implicated in active granulomatous sarcoidosis. Previously, we reported that oropharyngeal instillation of multiwall carbon nanotubes (MWCNT) into C57Bl/6 mice induced sarcoid-like granulomas and upregulation of MMP12. When Mmp12 knock-out (KO) mice were instilled with MWCNT, granuloma formation occurred 10 days post-instillation but subsequently resolved at 60 days. Thus, we concluded that MMP12 was essential to granuloma persistence. The aim of the current study was to identify potential mechanisms of granuloma resolution in Mmp12KO mice. Strikingly, an M2 macrophage phenotype was present in Mmp12KO but not in C57Bl/6 mice. Between 10 and 60 days, macrophage populations in MWCNT-instilled Mmp12KO mice demonstrated an M2c to M2a phenotypic shift, with elevations in levels of IL-13, an M2 subtype-regulating factor. Furthermore, the M2 inducer, Apolipoprotein E (ApoE), and Matrix Metalloproteinase-14 (MMP14), a promoter of collagen degradation, were upregulated in 60-day MWCNT-instilled Mmp12KO mice. In conclusion, alveolar macrophages express two M2 phenotypes in Mmp12KO mice: M2c at 10 days when granulomas form, and M2a at 60 days when granulomas are resolving. Findings suggest that granuloma resolution in 60-day Mmp12KO mice requires an M2a macrophage phenotype.

scholarly journals Effect of pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modular (SPPARMα), in atherosclerosis model using low density lipoprotein receptor knock-out swine with balloon injury

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241195
Author(s):  
Hirokazu Konishi ◽  
Katsumi Miyauchi ◽  
Akira Onishi ◽  
Shunichi Suzuki ◽  
Daiichiro Fuchimoto ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Peroxisome Proliferator ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Balloon Injury ◽  
Peroxisome Proliferator Activated Receptor ◽  
Knock Out ◽  
Density Lipoprotein Receptor

Background Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor that has key roles of lipid metabolism and inflammation. The PPARα may affects the initiation and progression of atherosclerosis by reducing inflammatory responses. Pemafibrate (K-877) is a novel selective PPARα modulator (SPPARMα), which was designed to possess higher PPARα potency and selectivity than existing PPARα agonists. The aim of this study is to evaluate the effect of pemafibrate on vascular response in coronary atherosclerosis model using low density lipoprotein receptor knock-out (LDLR-KO) pigs with balloon injury. Methods and results Ten LDLR-KO pigs were randomly allocated to two groups [pemafibrate (n = 5) and control (n = 5)] and fed with a diet containing 2.0% cholesterol and 20% lard throughout the study. Balloon injury was created in 40 coronary segments two weeks after starting the oral administration of pemafibrate or placebo. Necropsy was conducted 8 weeks later. Coronary artery sections were reviewed to evaluate lesion progression and the mRNA expression levels for C-Jun, NFκ B, CCL2, CCR7, CD163 and MMP9 determined using real-time RT-PCR. LDL cholesterol at baseline was about 700 mg/dL. The mean ratio of macrophages to plaque area was significantly lower in pemafibrate group compared with control one (7.63±1.16 vs 14.04±4.51, P = 0.02) whereas no differences were observed in intimal area between groups. The mRNA levels of C-Jun, NFκB and MMP9 were significantly decreased in pemafibrate group. Conclusions Pemafibrate was associated with inhibition of inflammatory responses in coronary artery atherosclerosis model using LDLR-KO swine with balloon injury.

scholarly journals PPARγ activation normalizes resolution of acute sterile inflammation in murine chronic granulomatous disease

Blood ◽  
2010 ◽  
Vol 116 (22) ◽  
pp. 4512-4522 ◽  
Author(s):  
Ruby Fernandez-Boyanapalli ◽  
S. Courtney Frasch ◽  
David W. H. Riches ◽  
R. William Vandivier ◽  
Peter M. Henson ◽  
...  
Keyword(s):  
Chronic Granulomatous Disease ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Sterile Inflammation ◽  
Peroxisome Proliferator ◽  
Granulomatous Disease ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Inflammatory Conditions ◽  
Pparγ Agonist ◽  
Pparγ Expression

Absence of a functional nicotinamide adenine dinucleotide phosphate (NADPH) oxidase predisposes chronic granulomatous disease (CGD) patients to infection, and also to unexplained, exaggerated inflammation. The impaired recognition and removal (efferocytosis) of apoptotic neutrophils by CGD macrophages may contribute to this effect. We hypothesized that peroxisome proliferator-activated receptor γ (PPARγ) activation during CGD inflammation is deficient, leading to altered macrophage programming and decreased efferocytosis, and that PPARγ agonism would enhance resolution. using the gp91phox−/− murine model of X-linked CGD in a well-characterized model of sterile, zymosan-induced peritonitis, it was demonstrated that PPARγ expression and activation in CGD macrophages were significantly deficient at baseline, and acquisition was delayed over the course of inflammation relative to that of wild-type. Efferocytosis by macrophages reflected PPARγ activation during peritonitis and was impaired in CGD mice (versus wild-type), leading to accumulation of apoptotic neutrophils. Importantly, provision of the PPARγ agonist, pioglitazone, either prophylactically or during inflammation, significantly enhanced macrophage PPARγ-mediated programming and efferocytosis, reduced accumulation of apoptotic neutrophils, and normalized the course of peritonitis in CGD mice. As such, PPARγ may be a therapeutic target for CGD, and possibly other inflammatory conditions where aberrant macrophage programming and impaired efferocytosis delay resolution of inflammation.

scholarly journals BST204 Protects Dexamethasone-Induced Myotube Atrophy through the Upregulation of Myotube Formation and Mitochondrial Function

2021 ◽  
Vol 18 (5) ◽  
pp. 2367
Author(s):  
Ryuni Kim ◽  
Hyebeen Kim ◽  
Minju Im ◽  
Sun Kyu Park ◽  
Hae Jung Han ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Inflammatory Responses ◽  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dry Extract ◽  
Myotube Formation ◽  
Species Production

BST204 is a purified ginseng dry extract that has an inhibitory effect on lipopolysaccharide-induced inflammatory responses, but its effect on muscle atrophy is yet to be investigated. In this study, C2C12 myoblasts were induced to differentiate for three days followed by the treatment of dexamethasone (DEX), a corticosteroid drug, with vehicle or BST204 for one day and subjected to immunoblotting, immunocytochemistry, qRT-PCR and biochemical analysis for mitochondrial function. BST204 alleviates the myotube atrophic effect mediated by DEX via the activation of protein kinase B/mammalian target of rapamycin (Akt/mTOR) signaling. Through this pathway, BST204 suppresses the expression of muscle-specific E3 ubiquitin ligases contributing to the enhanced myotube formation and enlarged myotube diameter in DEX-treated myotubes. In addition, BST204 treatment significantly decreases the mitochondrial reactive oxygen species production in DEX-treated myotubes. Furthermore, BST204 improves mitochondrial function by upregulating the expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) in DEX-induced myotube atrophy. This study provides a mechanistic insight into the effect of BST204 on DEX-induced myotube atrophy, suggesting that BST204 has protective effects against the toxicity of a corticosteroid drug in muscle and promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.

scholarly journals Adverse Adipose Phenotype and Hyperinsulinemia in Gravid Mice Deficient in Placental Growth Factor

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2176-2183 ◽  
Author(s):  
Bianca Hemmeryckx ◽  
Rita van Bree ◽  
Berthe Van Hoef ◽  
Lisbeth Vercruysse ◽  
H. Roger Lijnen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Adrenergic Receptors ◽  
Growth Factor Receptor ◽  
Placental Growth Factor ◽  
Peroxisome Proliferator ◽  
Vascular Endothelial ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Adipocyte Hypertrophy ◽  
Endothelial Growth Factor

Pregnancy-induced metabolic changes are regulated by signals from an expanded adipose organ. Placental growth factor (PlGF), acting through vascular endothelial growth factor receptor-1, may be among those signals. There is a steep rise in circulating PlGF during normal pregnancy, which is repressed in gravidas who develop preeclampsia. PlGF-deficiency in mice impairs adipose vascularization and development. Here we studied young-adult PlGF-deficient (PlGF−/−) and wild-type mice on a high-fat diet in the nongravid state and at embryonic day (E) 13.5 or E18.5 of gestation. Litter size and weight were normal, but E18.5 placentas were smaller in PlGF−/− pregnancies. PlGF−/− mice showed altered intraadipose dynamics, with the following: 1) less blood vessels and fewer brown, uncoupling protein (UCP)-1-positive, adipocytes in white sc and perigonadal fat compartments and 2) white adipocyte hypertrophy. The mRNA expression of β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1 was decreased accordingly. Moreover, PlGF−/− mice showed hyperinsulinemia. Pregnancy-associated changes were largely comparable in PlGF−/− and wild-type dams. They included expanded sc fat compartments and adipocyte hypertrophy, whereas adipose expression of key angiogenesis/adipogenesis (vascular endothelial growth factor receptor-1, peroxisome proliferator-activated receptor-γ2) and thermogenesis (β3-adrenergic receptors, peroxisome proliferator-activated receptor-γ coactivator-1α, and UCP-1) genes was down-regulated; circulating insulin levels gradually increased during pregnancy. In conclusion, reduced adipose vascularization in PlGF−/− mice impairs adaptive thermogenesis in favor of energy storage, thereby promoting insulin resistance and hyperinsulinemia. Pregnancy adds to these changes by PlGF-independent mechanisms. Disturbed intraadipose dynamics is a novel mechanism to explain metabolic changes in late pregnancy in general and preeclamptic pregnancy in particular.

scholarly journals Conjugated Linoleic Acid and Brain Metabolism: A Possible Anti-Neuroinflammatory Role Mediated by PPARα Activation

2021 ◽  
Vol 11 ◽  
Author(s):  
Elisabetta Murru ◽  
Gianfranca Carta ◽  
Claudia Manca ◽  
Valeria Sogos ◽  
Marco Pistis ◽  
...  
Keyword(s):  
Linoleic Acid ◽  
Conjugated Linoleic Acid ◽  
Inflammatory Responses ◽  
Feedback Mechanism ◽  
Bioactive Metabolites ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Beneficial Effects ◽  
Cellular Effects ◽  
Positive Feedback Mechanism

Fatty acids play a crucial role in the brain as specific receptor ligands and as precursors of bioactive metabolites. Conjugated linoleic acid (CLA), a group of positional and geometric isomers of linoleic acid (LA, 18:2 n-6) present in meat and dairy products of ruminants and synthesized endogenously in non-ruminants and humans, has been shown to possess different nutritional properties associated with health benefits. Its ability to bind to peroxisome proliferator-activated receptor (PPAR) α, a nuclear receptor key regulator of fatty acid metabolism and inflammatory responses, partly mediates these beneficial effects. CLA is incorporated and metabolized into brain tissue where induces the biosynthesis of endogenous PPARα ligands palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), likely through a positive feedback mechanism where PPARα activation sustains its own cellular effects through ligand biosynthesis. In addition to PPARα, PEA and OEA may as well bind to other receptors such as TRPV1, further extending CLA own anti-neuroinflammatory actions. Future studies are needed to investigate whether dietary CLA may exert anti-inflammatory activity, particularly in the setting of neurodegenerative diseases and neuropsychiatric disorders with a neuroinflammatory basis.

scholarly journals CD36-Mediated Lipid Accumulation and Activation of NLRP3 Inflammasome Lead to Podocyte Injury in Obesity-Related Glomerulopathy

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Jing Zhao ◽  
Hong-liang Rui ◽  
Min Yang ◽  
Li-jun Sun ◽  
Hong-rui Dong ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Lipid Accumulation ◽  
Inflammatory Responses ◽  
Regulatory Element ◽  
Animal Experiments ◽  
Receptor Protein ◽  
Peroxisome Proliferator ◽  
Podocyte Injury ◽  
Peroxisome Proliferator Activated Receptor

Podocyte injury critically contributes to the pathogenesis of obesity-related glomerulopathy (ORG). Recently, lipid accumulation and inflammatory responses have been found to be involved in podocyte injury. This study is to explore their role and relationship in podocyte injury of ORG. In animal experiments, the ORG mice developed proteinuria, podocyte injury, and hypertriglyceridemia, accompanied with deregulated lipid metabolism, renal ectopic lipid deposition, activation of NOD-like receptor protein 3 (NLRP3) inflammasome, and secretion of IL-1β of the kidney. The expression of adipose differentiation-related protein (ADRP), CD36, sterol regulatory element-binding protein 1 (SREBP-1), and peroxisome proliferator-activated receptor α (PPARα) in renal tissue were increased. In in vitro cell experiments, after cultured podocytes were stimulated with leptin, similar to ORG mice, we found aggravated podocyte injury, formatted lipid droplet, increased expression of ADRP and CD36, activated NLRP3 inflammasome, and released IL-1β. In addition, after blocking CD36 with inhibitor sulfo-N-succinimidyl oleate (SSO) or CD36 siRNA, activation of NLRP3 inflammasome and release of IL-1β are downregulated, and podocyte injury was alleviated. However, after blocking NLRP3 with MCC950, although podocyte injury was alleviated and release of IL-1β was decreased, there was no change in the expression of CD36, ADRP, and intracellular lipid droplets. Taken together, our study suggests that CD36-mediated lipid accumulation and activation of NLRP3 inflammasome may be one of the potential pathogeneses of ORG podocyte injury.

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