Acetylated Diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol in Autoimmune Arthritis and Interstitial Lung Disease in SKG Mice

Acetylated diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) is a lipid molecule from the antlers of sika deer that might reduce inflammation by effectively controlling neutrophil infiltration, endothelial permeability and inflammatory chemokine production. Therefore, we evaluated the modulatory effect of PLAG on arthritis and interstitial lung disease (ILD) in an autoimmune arthritis model. We injected curdlan into SKG mice and PLAG was orally administered every day from 3 weeks to 20 weeks after the curdlan injection. The arthritis score was measured every week after the curdlan injection. At 20 weeks post-injection, the lung specimens were evaluated with H&E, Masson’s trichrome and multiplexed immunofluorescent staining. Serum cytokines were also analyzed using a Luminex multiple cytokine assay. PLAG administration decreased the arthritis score until 8 weeks after the curdlan injection. However, the effect was not sustained thereafter. A lung histology revealed severe inflammation and fibrosis in the curdlan-induced SKG mice, which was attenuated in the PLAG-treated mice. Furthermore, immunofluorescent staining of the lung tissue showed a GM-CSF+ neutrophil accumulation and a decreased citrullinated histone 3 expression after PLAG treatment. PLAG also downregulated the levels of IL-6 and TNF-α and upregulated the level of sIL-7Rα, an anti-fibrotic molecule. Our results indicate that PLAG might have a preventative effect on ILD development through the resolution of NETosis in the lung.

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SAT0009 ROLE OF EC-18 IN AUTOIMMUNE ARTHRITIS AND INTERSTITIAL LUNG DISEASE IN CURDLAN-ADMINISTERED SKG MICE

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4157 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 934.2-935

Author(s):

E. J. Lee ◽

D. H. Kim ◽

J. H. Lee ◽

S. J. Choi ◽

S. H. Nam ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Murine Model ◽

Histological Analysis ◽

Immunofluorescent Staining ◽

Autoimmune Arthritis ◽

Post Injection ◽

Arthritis Score ◽

Neutrophil Accumulation ◽

Peripheral Arthritis

Background:Although the mortality of patients with rheumatoid arthritis (RA), for which interstitial lung disease (ILD) is one of the major contributors, has still not decreased, new target therapies for RA have shown good response in peripheral arthritis. EC-18 (acetylated diacylglycerol 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol) is a mono-acetyl-diglyceride that has been isolated from the antlers of sika deer and can be chemically synthesized from glycerol, palmitic acid, and linoleic acid. Research using LPS-induced acute lung injury murine model has reported that EC-18 stimulates a more rapid resolution of LPS-induced lung Inflammation. In addition, it has been reported that in a murine model of collagen-induced arthritis, EC-18 treatment ameliorated arthritis, with down-regulation of IL-6 level by regulating the activity of STAT3 in the synovium. Curdlan-administered SKG mice develop ILD spontaneously followed by peripheral arthritis, which resembles RA-ILD.Objectives:We evaluated the modulatory effect of the EC-18 on arthritis and ILD in autoimmune arthritis animal model.Methods:Male SKG mice were obtained from Dr. S. Sakaguchi. We injected curdlan (3 mg/mice) in 8-week-old SKG mice and identified the presence of ILD by histological analysis at 20 weeks post-injection. Arthritis score was measured every week for up to 20 weeks. EC-18 (250 mg/kg body weight/day, Enzychem Lifesciences Co., Daejeon, Korea) was administered every day orally. At 20 weeks post-injection, lung sections were stained with H&E and Masson’s trichrome. Using the Opal method, multiplexed immunofluorescent staining of lung tissue was performed. According to the scale by Ashcroft et al., fibrosis severity of lung sections was assessed by a system of eight grades. Analysis of serum cytokines by the luminex multiplex cytokine assay was performed at 20 weeks post-injection.Results:Oral administration of EC-18 decreased arthritis score significantly until 8 weeks post-injection and remained unchanged thereafter. At 20 weeks post-injection, histological analysis showed severe pulmonary destruction, including bronchial alveolar tissue damage and massive leukocyte infiltration, and fibrosis in the curdlan-administered mice, which was attenuated in EC-18 treated mice. In particular, 67% of curdlan-administered mice showed ILD-like phenotype, whereas the incidence rate in EC-18-treated mice was 17%. Furthermore, immunofluorescent-staining showed both IL-17A and neutrophil accumulation in lung in curdlan-administered mice; these were decreased in EC-18-treated mice. Interestingly, at 20weeks post-injection, EC-18 treatment down-regulated serum levels of IL-6 and TNF-α and up-regulated sIL-7Rα (anti-fibrotic molecule).Conclusion:Taken together, EC-18 exerts an anti-arthritic effect in early phase, but a long-term effect was not indicated. We emphasize the effect on ILD prevention of EC-18 via up-regulation of sIL-7Rα and inhibition of neutrophil accumulation, suggesting a therapeutic agent potentially for RA-ILD.Disclosure of Interests:None declared

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THU0089 Il-17a+gm-csf+ neutrophils are the major infiltrating cells in interstitial lung disease in an autoimmune arthritis model

10.1136/annrheumdis-2018-eular.3399 ◽

2018 ◽

Author(s):

O.C. Kwon ◽

E.-J. Lee ◽

E.-J. Chang ◽

W.J. Seo ◽

J.S. Oh ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Autoimmune Arthritis ◽

Arthritis Model ◽

Gm Csf ◽

Infiltrating Cells

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IL-17A+GM-CSF+ Neutrophils Are the Major Infiltrating Cells in Interstitial Lung Disease in an Autoimmune Arthritis Model

Frontiers in Immunology ◽

10.3389/fimmu.2018.01544 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 8

Author(s):

Oh Chan Kwon ◽

Eun-Ju Lee ◽

Eun-Ju Chang ◽

Jeehee Youn ◽

Byeongzu Ghang ◽

...

Keyword(s):

Interstitial Lung Disease ◽

Lung Disease ◽

Autoimmune Arthritis ◽

Arthritis Model ◽

Gm Csf ◽

Infiltrating Cells

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Monocyte chemoattractant protein-1 influences trauma-hemorrhage-induced distal organ damage via regulation of keratinocyte-derived chemokine production

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00650.2006 ◽

2007 ◽

Vol 292 (3) ◽

pp. R1110-R1116 ◽

Cited By ~ 26

Author(s):

Michael Frink ◽

Ailing Lu ◽

Bjoern M. Thobe ◽

Ya-Ching Hsieh ◽

Mashkoor A. Choudhry ◽

...

Keyword(s):

Neutrophil Infiltration ◽

Organ Damage ◽

Sham Operation ◽

Neutrophil Accumulation ◽

Edema Formation ◽

Chemokine Production ◽

Monocyte Chemoattractant Protein 1 ◽

Monocyte Chemoattractant ◽

Monocyte Chemoattractant Protein ◽

Control Serum

Leukocyte infiltration, mediated by chemokines, is a key step in the development of organ dysfunction. Lung and liver neutrophil infiltration following trauma-hemorrhage is associated with upregulation of monocyte chemoattractant protein-1 (MCP-1). Because MCP-1 is not a major attractant for neutrophils, we hypothesized that MCP-1 influences neutrophil infiltration via regulation of keratinocyte-derived chemokines (KC). To study this, male C3H/HeN mice were pretreated with MCP-1 antiserum or control serum and subjected to trauma-hemorrhage or sham operation. Animals were killed 4 h after resuscitation. One group of trauma-hemorrhage mice receiving MCP-1 antiserum was also treated with murine KC during resuscitation. Plasma levels and tissue content of MCP-1 and KC were determined by cytometric bead arrays. Immunohistochemistry was performed to determine neutrophil infiltration; organ damage was assessed by edema formation. Treatment with MCP-1 antiserum significantly decreased systemic, lung, and liver levels of MCP-1 and KC following trauma-hemorrhage. This decrease in MCP-1 levels was associated with decreased neutrophil infiltration and edema formation in lung and liver following trauma-hemorrhage. Restitution of KC in mice treated with MCP-1 antiserum restored tissue neutrophil infiltration and edema. These results lead us to conclude that increased levels of MCP-1 cause neutrophil accumulation and distant organ damage by regulating KC production during the postinjury inflammatory response.

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Anti-inflammatory effect of fibrate protects from cisplatin-induced ARF

AJP Renal Physiology ◽

10.1152/ajprenal.00038.2005 ◽

2005 ◽

Vol 289 (2) ◽

pp. F469-F480 ◽

Cited By ~ 91

Author(s):

Shenyang Li ◽

Neriman Gokden ◽

Mark D. Okusa ◽

Renu Bhatt ◽

Didier Portilla

Keyword(s):

Inflammatory Responses ◽

Kidney Tissue ◽

Neutrophil Infiltration ◽

Binding Activity ◽

Peroxisome Proliferator ◽

Wild Type ◽

Neutrophil Accumulation ◽

Chemokine Production ◽

Anti Inflammatory ◽

Inflammatory Effect

Recently, we demonstrated that peroxisome proliferator-activated receptor-α (PPARα) ligand ameliorates cisplatin-induced acute renal failure (ARF) by preventing inhibition of substrate oxidation, and also by preventing apoptosis and necrosis of the proximal tubule (Li S, Bhatt R, Megyesi J, Gokden N, Shah SV, and Portilla D. Am J Physiol Renal Physiol 287: F990–F998, 2004). In the following studies, we examined the protective effect of PPARα ligand on cisplatin-induced inflammatory responses during ARF. Mice subjected to a single intraperitoneal injection of cisplatin developed ARF at day 3. Cisplatin increased mRNA and protein expression of TNF-α, RANTES, and also upregulated endothelial adhesion molecules ICAM-1/VCAM-1 and chemokine receptors CCR1/CCR5. Cisplatin also led to neutrophil infiltration in the corticomedullary region. Pretreatment of wild-type mice with WY-14,643, a fibrate class of PPARα ligands, before cisplatin significantly suppressed cisplatin-induced upregulation of cytokine/chemokine expression, prevented neutrophil accumulation, and ameliorated renal dysfunction. In contrast, treatment with PPARα ligand before cisplatin did not prevent cytokine/chemokine production, neutrophil accumulation, and did not protect kidney function in PPARα null mice. In addition, we observed that cisplatin-induced NF-κB binding activity in nuclear extracts from wild-type mice was markedly reduced by treatment with PPARα ligand. These results demonstrate that PPARα exerts an anti-inflammatory effect in kidney tissue by a mechanism that includes inhibition of NF-κB DNA binding activity, and this effect results in inhibition of neutrophil infiltration, cytokine/chemokine release, and amelioration of cisplatin-induced ARF.

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