scholarly journals Liposomal delivery of azithromycin enhances its immunotherapeutic efficacy and reduces toxicity in myocardial infarction

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Ahmed Al-Darraji ◽  
Renée R. Donahue ◽  
Himi Tripathi ◽  
Hsuan Peng ◽  
Bryana M. Levitan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Significant Shift ◽  
Inflammatory Genes ◽  
Cardiac Recovery ◽  
Inflammatory Monocytes ◽  
Acute Myocardial Injury ◽  
Anti Inflammatory ◽  
Target Effects

Abstract A growing body of evidence shows that altering the inflammatory response by alternative macrophage polarization is protective against complications related to acute myocardial infarction (MI). We have previously shown that oral azithromycin (AZM), initiated prior to MI, reduces inflammation and its negative sequelae on the myocardium. Here, we investigated the immunomodulatory role of a liposomal AZM formulation (L-AZM) in a clinically relevant model to enhance its therapeutic potency and avoid off-target effects. L-AZM (40 or 10 mg/kg, IV) was administered immediately post-MI and compared to free AZM (F-AZM). L-AZM reduced cardiac toxicity and associated mortality by 50% in mice. We observed a significant shift favoring reparatory/anti-inflammatory macrophages with L-AZM formulation. L-AZM use resulted in a remarkable decrease in cardiac inflammatory neutrophils and the infiltration of inflammatory monocytes. Immune cell modulation was associated with the downregulation of pro-inflammatory genes and the upregulation of anti-inflammatory genes. The immunomodulatory effects of L-AZM were associated with a reduction in cardiac cell death and scar size as well as enhanced angiogenesis. Overall, L-AZM use enhanced cardiac recovery and survival after MI. Importantly, L-AZM was protective from F-AZM cardiac off-target effects. We demonstrate that the liposomal formulation of AZM enhances the drug’s efficacy and safety in an animal model of acute myocardial injury. This is the first study to establish the immunomodulatory properties of liposomal AZM formulations. Our findings strongly support clinical trials using L-AZM as a novel and clinically relevant therapeutic target to improve cardiac recovery and reduce heart failure post-MI in humans.

scholarly journals Colchicine-Containing Nanoparticles Attenuates Acute Myocardial Infarction Injury by Inhibiting Inflammation

2021 ◽  
Author(s):  
Li Wang ◽  
Yun-fan Peng ◽  
Li-jun Song ◽  
Da-sheng Xia ◽  
Chao Li ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Calcium Carbonate ◽  
Rat Model ◽  
Myocardial Infarct ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
Myocardial Infarct Size ◽  
Anti Inflammatory

Abstract Purpose Anti-inflammatory therapy is important for reducing myocardial injury after acute myocardial infarction (MI). New anti-inflammatory drugs and their mechanism are necessary to be explored to improve the clinical efficacy. We aimed to improve the efficacy of colchicine on attenuating MI injury by nano-drug delivery systems, and to investigate the mechanism of anti-inflammatory. Methods Colchicine-containing delivery system based on calcium carbonate nanoparticles (ColCaNPs) was synthesized. The protection against MI by ColCaNPs was evaluated using an in vivo rat model established by ligating the left anterior descending coronary artery. Macrophage polarization and the levels of inflammatory cytokines were determined using immunohistochemistry, western blot and ELISA analysis. Results ColCaNPs treatment showed about a 45% reduction in myocardial infarct size and attenuating myocardial fibrosis compared with groups without drug intervention after MI. Furthmore, ColCaNPs significantly decreased the levels of CRP, TNF-α and IL-1β in serum and the expression of proinflammatory cytokine in myocardial tissues after MI (p < 0.05). We also found that ColCaNPs notably restrained pyroptosis, and inhibited inflammatory response by modulating on M1/M2 macrophage polarization and suppressing TLR4/NFκB/NLRP3 signal pathway. Conculsion Colchicine-containing nanoparticles can protect against MI injury in a clinically relevant rat model by reducing inflammation. In addition, calcium carbonate nanoparticles can increase the cardioprotective effects of colchicine.

scholarly journals Phenylbutyrate facilitates homeostasis of non-resolving inflammatory macrophages

2019 ◽  
Vol 26 (1) ◽  
pp. 62-72 ◽  
Author(s):  
Allison Rahtes ◽  
Kisha Pradhan ◽  
Mimosa Sarma ◽  
David Xie ◽  
Chang Lu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Low Dose ◽  
Inflammatory Diseases ◽  
Macrophage Polarization ◽  
Related Factor ◽  
Inflammatory Monocytes ◽  
Inflammatory Protein ◽  
Anti Inflammatory ◽  
Inflammation Resolution ◽  
Ccl2 Gene

Non-resolving inflammatory monocytes/macrophages are critically involved in the pathogenesis of chronic inflammatory diseases. However, mechanisms of macrophage polarization are not well understood, thus hindering the development of effective strategies to promote inflammation resolution. In this study, we report that macrophages polarized by subclinical super-low dose LPS preferentially expressed pro-inflammatory mediators such as ccl2 (which encodes the protein monocyte chemo attractant protein-1) with reduced expression of anti-inflammatory/homeostatic mediators such as slc40a1 (which encodes the protein ferroportin-1). We observed significantly elevated levels of the autophagy-associated and pro-inflammatory protein p62 in polarized macrophages, closely correlated with the inflammatory activation of ccl2 gene expression. In contrast, we noted a significant increase of ubiquitinated/inactive nuclear-erythroid-related factor 2 (NRF2), consistent with reduced slc40a1 gene expression in polarized macrophages. Addition of the homeostatic restorative agent phenylbutyrate (4-PBA) effectively reduced cellular levels of p62 as well as ccl2 gene induction by super-low dose LPS. On the other hand, application of 4-PBA also blocked the accumulation of ubiquitinated NRF2 and restored anti-inflammatory slc40a1 gene expression in macrophages. Together, our study provides novel insights with regard to macrophage polarization and reveals 4-PBA as a promising molecule in restoring macrophage homeostasis.

scholarly journals Anti-Inflammatory Effect of Curcumin on the Mouse Model of Myocardial Infarction through Regulating Macrophage Polarization

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Shaoxi Yan ◽  
Mo Zhou ◽  
Xiaoyun Zheng ◽  
Yuanyuan Xing ◽  
Juan Dong ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Ventricular Remodeling ◽  
Macrophage Polarization ◽  
M2 Macrophage ◽  
M1 Macrophages ◽  
Macrophage Marker ◽  
M1 Macrophage ◽  
Anti Inflammatory

Inflammation causes tissue damage and promotes ventricular remodeling after myocardial infarction (MI), and the infiltration and polarization of macrophages play an important role in regulating inflammation post-MI. Here, we investigated the anti-inflammatory function of curcumin after MI and studied its relationship with macrophage polarization. In vivo, curcumin not only attenuated ventricular remodeling 3 months after MI but also suppressed inflammation during the first 7 days post-MI. Importantly, the results of qPCR and immunochemistry showed that curcumin decreased M1 (iNOS, CCL2, and CD86) but increased M2 macrophage (Arg1, CD163, and CD206) marker expression in the myocardium of MI mice during the first 7 days post-MI. And flow cytometry analysis indicated that curcumin suppressed M1 (CD45+Gr-1-CD11b+iNOS+ cells) but enhanced M2 macrophage (CD45+Gr-1-CD11b+Arg+ cells) expansion in the myocardium of MI mice during the first 7 days post-MI. In vitro, curcumin decreased LPS/IFNγ-elevated M1 macrophage marker (iNOS and CD86) expression and the proportion of M1 macrophages (iNOS+F4/80+ cells) but increased LPS/IFNγ-suppressed M2 macrophage marker (Arg1 and CD206) expression and the proportion of M2 macrophages (Arg1+F4/80+ cells). In addition, curcumin modulates M1/M2 macrophage polarization partly via AMPK. In conclusion, curcumin suppressed the MI-induced inflammation by modulating macrophage polarization partly via the AMPK pathway.

scholarly journals Sodium Lactate Accelerates M2 Macrophage Polarization and Improves Cardiac Function after Myocardial Infarction in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Jialiang Zhang ◽  
Fangyang Huang ◽  
Li Chen ◽  
Guoyong Li ◽  
Wenhua Lei ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Cardiac Fibrosis ◽  
Macrophage Polarization ◽  
Flow Cytometric Analysis ◽  
Sodium Lactate ◽  
M2 Macrophage ◽  
Mrna Levels ◽  
M2 Macrophage Polarization ◽  
Anti Inflammatory

Background. After myocardial infarction, anti-inflammatory macrophages perform key homeostatic functions that facilitate cardiac recovery and remodeling. Several studies have shown that lactate may serve as a modifier that influences phenotype of macrophage. However, the therapeutic role of sodium lactate in myocardial infarction (MI) is unclear. Methods. MI was established by permanent ligation of the left anterior descending coronary artery followed by injection of saline or sodium lactate. Cardiac function was assessed by echocardiography. The cardiac fibrosis area was assessed by Masson trichrome staining. Macrophage phenotype was detected via qPCR, flow cytometry, and immunofluorescence. Signaling proteins were measured by Western blotting. Results. Sodium lactate treatment following MI improved cardiac performance, enhanced anti-inflammatory macrophage proportion, reduced cardiac myocytes apoptosis, and increased neovascularization. Flow-cytometric analysis results reported that sodium lactate repressed the number of the IL-6+, IL-12+, and TNF-α+ macrophages among LPS-stimulated bone marrow-derived macrophages (BMDMs) and increased the mRNA levels of Arg-1, YM1, TGF-β, and IL-10. Mechanistic studies revealed that sodium lactate enhanced the expression of P-STAT3. Furthermore, a STAT3 inhibitor eliminated sodium lactate-mediated promotion macrophage polarization. Conclusion. Sodium lactate facilitates anti-inflammatory M2 macrophage polarization and protects against MI by regulating P-STAT3.

scholarly journals ST36 Acupuncture Alleviates the Inflammation of Adjuvant-Induced Arthritic Rats by Targeting Monocyte/Macrophage Modulation

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Fuming Yang ◽  
Yinan Gong ◽  
Nannan Yu ◽  
Lin Yao ◽  
Xue Zhao ◽  
...  
Keyword(s):  
Communication Networks ◽  
Immune Cell ◽  
Macrophage Polarization ◽  
Cell Communication ◽  
Bone Destruction ◽  
Systematic Research ◽  
Ankle Joints ◽  
M1 Phenotype ◽  
Anti Inflammatory ◽  
Inflammatory Action

Background. Rheumatoid arthritis (RA) is a chronic systemic chronic autoimmune disease characterized by the aggregation of immune cells and secretion of cytokines in the joint synovium, causing hyperblastosis and even bone destruction. Acupuncture has been proven effective in RA treatment. This study aimed to investigate the anti-inflammatory action of acupuncture, specifically, in relation to immune cell interactions and key mediators. Methods. Rats with adjuvant-induced arthritics (AIA) were treated with manual acupuncture (MA) at Zusanli (ST36). Joint edema and paw withdrawal latency were monitored to observe the effects on inflammation. The levels of 24 cytokines, chemokines, and growth factors in ankle joints during the treatment (on days 1, 7, 15, and 21) were detected by multiplex immunoassay. A bioinformatics analysis based on a directed weighted mathematical model was used to construct cell communication network diagrams and identify the key cells through calculation. The monocyte/macrophage polarization in inflamed joints was investigated by detecting M1- and M2-phenotypic populations and their related cytokines. Results. ST36 MA alleviated paw edema and upregulated the nociceptive threshold of AIA rats. Several innate and adaptive immune cytokines were dynamically regulated by MA, and MA-treated rats showed a significant improvement in symptoms compared with AIA rats by day 21. The immune cell-cell communication networks were intensified with the development of RA but were significantly reduced after treatment with MA. MA was found to specifically regulate monocytes/macrophages in inflamed ankle joints ST36 MA also inhibited M1-phenotype macrophages accompanied by decreased levels of IL-1β. Conclusions. ST36 MA showed anti-inflammatory and analgesic effects as well as inhibition of immune cell communication networks in inflamed joints of AIA rats. Inhibiting the polarization of macrophages to the M1-phenotype in inflamed joints may be one of the key mechanisms of MA anti-inflammatory action. This research highlighted a systematic research paradigm for investigating mechanisms of acupuncture action.

scholarly journals The Apolipoprotein A-I Mimetic L-4F Attenuates Monocyte Activation and Adverse Cardiac Remodeling after Myocardial Infarction

2020 ◽  
Vol 21 (10) ◽  
pp. 3519
Author(s):  
Tariq Hamid ◽  
Mohamed Ameen Ismahil ◽  
Shyam S. Bansal ◽  
Bindiya Patel ◽  
Mehak Goel ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Immune Cell ◽  
Left Ventricular ◽  
Beneficial Effects ◽  
Glycolytic Gene ◽  
Inflammatory Monocytes ◽  
Apolipoprotein A ◽  
Lv Remodeling ◽  
Monocytes And Macrophages

Excessive inflammation after myocardial infarction (MI) can promote infarct expansion and adverse left ventricular (LV) remodeling. L-4F, a mimetic peptide of apolipoprotein A-I (apoA-I), exhibits anti-inflammatory and anti-atherogenic properties; however, whether L-4F imparts beneficial effects after myocardial infarction (MI) is unknown. Here we demonstrate that L-4F suppresses the expansion of blood, splenic, and myocardial pro-inflammatory monocytes and macrophages in a mouse model of reperfused MI. Changes in immune cell profiles were accompanied by alleviation of post-MI LV remodeling and dysfunction. In vitro, L-4F also inhibited pro-inflammatory and glycolytic gene expression in macrophages. In summary, L-4F treatment prevents prolonged and excessive inflammation after MI, in part through modulation of pro-inflammatory monocytes and macrophages, and improves post-MI LV remodeling. These data suggest that L-4F could be a used as a therapeutic adjunct in humans with MI to limit inflammation and alleviate the progression to heart failure.

scholarly journals Recombinant Human Proteoglycan 4 Regulates Phagocytic Activation of Monocytes and Reduces IL-1β Secretion by Urate Crystal Stimulated Gout PBMCs

2021 ◽  
Vol 12 ◽  
Author(s):  
Sandy ElSayed ◽  
Gregory D. Jay ◽  
Ralph Cabezas ◽  
Marwa Qadri ◽  
Tannin A. Schmidt ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Immune Cell ◽  
Ros Generation ◽  
Acute Gout ◽  
Caspase 1 ◽  
Inflammatory Monocytes ◽  
Proteoglycan 4 ◽  
Anti Inflammatory ◽  
The Impact ◽  
Deficient Mice

ObjectivesTo compare phagocytic activities of monocytes in peripheral blood mononuclear cells (PBMCs) from acute gout patients and normal subjects, examine monosodium urate monohydrate (MSU) crystal-induced IL-1β secretion ± recombinant human proteoglycan 4 (rhPRG4) or interleukin-1 receptor antagonist (IL-1RA), and study the anti-inflammatory mechanism of rhPRG4 in MSU stimulated monocytes.MethodsAcute gout PBMCs were collected from patients in the Emergency Department and normal PBMCs were obtained from a commercial source. Monocytes in PBMCs were identified by flow cytometry. PBMCs were primed with Pam3CSK4 (1μg/mL) for 24h and phagocytic activation of monocytes was determined using fluorescently labeled latex beads. MSU (200μg/mL) stimulated IL-1β secretion was determined by ELISA. Reactive oxygen species (ROS) generation in monocytes was determined fluorometrically. PBMCs were incubated with IL-1RA (250ng/mL) or rhPRG4 (200μg/mL) and bead phagocytosis by monocytes was determined. THP-1 monocytes were treated with MSU crystals ± rhPRG4 and cellular levels of NLRP3 protein, pro-IL-1β, secreted IL-1β, and activities of caspase-1 and protein phosphatase-2A (PP2A) were quantified. The peritoneal influx of inflammatory and anti-inflammatory monocytes and neutrophils in Prg4 deficient mice was studied and the impact of rhPRG4 on immune cell trafficking was assessed.ResultsEnhanced phagocytic activation of gout monocytes under basal conditions (p&lt;0.001) was associated with ROS generation and MSU stimulated IL-1β secretion (p&lt;0.05). rhPRG4 reduced bead phagocytosis by normal and gout monocytes compared to IL-1RA and both treatments were efficacious in reducing IL-1β secretion (p&lt;0.05). rhPRG4 reduced pro-IL-1β content, caspase-1 activity, conversion of pro-IL-1β to mature IL-1β and restored PP2A activity in monocytes (p&lt;0.05). PP2A inhibition reversed rhPRG4’s effects on pro-IL-1β and mature IL-1β in MSU stimulated monocytes. Neutrophils accumulated in peritoneal cavities of Prg4 deficient mice (p&lt;0.01) and rhPRG4 treatment reduced neutrophil accumulation and enhanced anti-inflammatory monocyte influx (p&lt;0.05).ConclusionsMSU phagocytosis was higher in gout monocytes resulting in higher ROS and IL-1β secretion. rhPRG4 reduced monocyte phagocytic activation to a greater extent than IL-1RA and reduced IL-1β secretion. The anti-inflammatory activity of rhPRG4 in monocytes is partially mediated by PP2A, and in vivo, PRG4 plays a role in regulating the trafficking of immune cells into the site of a gout flare.

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