scholarly journals Hyperoxia Exacerbates Postnatal Inflammation-Induced Lung Injury in Neonatal BRP-39 Null Mutant Mice Promoting the M1 Macrophage Phenotype

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Mansoor A. Syed ◽  
Vineet Bhandari
Keyword(s):  
Lung Injury ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Continuous Exposure ◽  
Macrophage Phenotype ◽  
Cell Counts ◽  
M1 Macrophage ◽  
Neonatal Lung ◽  
Neonatal Lung Injury ◽  
Anti Inflammatory

Rationale. Hyperoxia exposure to developing lungs—critical in the pathogenesis of bronchopulmonary dysplasia—may augment lung inflammation by inhibiting anti-inflammatory mediators in alveolar macrophages.Objective. We sought to determine the O2-induced effects on the polarization of macrophages and the role of anti-inflammatory BRP-39 in macrophage phenotype and neonatal lung injury.Methods. We used RAW264.7, peritoneal, and bone marrow derived macrophages for polarization (M1/M2) studies. Forin vivostudies, wild-type (WT) and BRP-39−/−mice received continuous exposure to 21% O2(control mice) or 100% O2from postnatal (PN) 1 to PN7 days, along with intranasal lipopolysaccharide (LPS) administered on alternate days (PN2, -4, and -6). Lung histology, bronchoalveolar lavage (BAL) cell counts, BAL protein, and cytokines measurements were performed.Measurements and Main Results. Hyperoxia differentially contributed to macrophage polarization by enhancing LPS induced M1 and inhibiting interleukin-4 induced M2 phenotype. BRP-39 absence led to further enhancement of the hyperoxia and LPS induced M1 phenotype. In addition, BRP-39−/−mice were significantly more sensitive to LPS plus hyperoxia induced lung injury and mortality compared to WT mice.Conclusions. These findings collectively indicate that BRP-39 is involved in repressing the M1 proinflammatory phenotype in hyperoxia, thereby deactivating inflammatory responses in macrophages and preventing neonatal lung injury.

Abstract 17035: Inhibition of DNMT and HDAC6 Together Regulates Macrophage Polarization by FoxO1-HIF2α Signaling and Protects Endotoxemia-Induced Inflammation

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Saheli Samanta ◽  
Zhigang Zhou ◽  
Sheeja Rajasingh ◽  
Kyley K Burkey ◽  
Rajasingh Johnson
Keyword(s):  
Signaling Pathway ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Combined Treatment ◽  
Cell Polarization ◽  
M2 Macrophage ◽  
Macrophage Phenotype ◽  
Therapeutic Drugs ◽  
Protein Expressions ◽  
Anti Inflammatory

Introduction: Acute lung injury (ALI) is a common pulmonary disease caused by bacterial infection leading to an imbalance between pro-inflammatory and anti-inflammatory immune responses. Studies have shown that macrophage polarization (M1 and M2) during ALI plays a key role in regulating these responses. Hypothesis: We hypothesized that combined treatment with 5-Aza 2-deoxycytidine (Aza) + tubastatin A (TBA) would reduce inflammation and promote an anti-inflammatory M2 macrophage phenotype by regulating the HIF2α signaling pathway. Methods: To show the effect of Aza+TBA, lipopolysaccharide (LPS)-induced macrophages (RAW 264.7) were treated with either Aza (50nM), TBA n(750nM), or together (Aza+TBA) for 24 hours. The mRNA and protein expressions of FoxO1, HIF2α, NOS2 (M1), and CD206 (M2) were measured by qRT-PCR and Western analyses in lung tissue and macrophages. Results: Our results revealed that LPS induced macrophages showed an increased expression of NOS2 (M1) and decreased expression of Fizz-1 (M2) whereas the LPS-induced macrophages were treated with Aza+TBA showed decreased NOS2 (Fig. A) and increased Fizz-1 mRNA (Fig. B) and protein expressions. Furthermore, the LPS significantly decreased the mRNA and protein expressions of FoxO1 and HIF2α in macrophages. These expressions were significantly increased when the LPS-induced macrophages were treated with Aza +TBA (Fig. C) . These results suggest that Aza+TBA treatment together generates more M2 macrophages there by reducing the LPS-induced inflammatory responses. Conclusions: Overall, these data show the first time that the combinatorial treatment with Aza+TBA regulates macrophage cell polarization and abrogates LPS-induced inflammation through FoxO1-HIF2α signaling pathway. Thus, epigenetic modifiers may be potential therapeutic drugs for ALI. <!--EndFragment-->

scholarly journals Role of microRNA-21 and Its Underlying Mechanisms in Inflammatory Responses in Diabetic Wounds

2020 ◽  
Vol 21 (9) ◽  
pp. 3328 ◽  
Author(s):  
Cole Liechty ◽  
Junyi Hu ◽  
Liping Zhang ◽  
Kenneth W. Liechty ◽  
Junwang Xu
Keyword(s):  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Regulation Of Gene Expression ◽  
Mouse Skin ◽  
M2 Macrophage ◽  
Central Feature ◽  
Macrophage Phenotype ◽  
Macrophage Cells ◽  
M1 Macrophage ◽  
Diabetic Wounds

A central feature of diabetic wounds is the persistence of chronic inflammation, which is partly due to the prolonged presence of pro-inflammatory (M1) macrophages in diabetic wounds. Persistence of the M1 macrophage phenotype and failure to transition to the regenerative or pro-remodeling (M2) macrophage phenotype plays an indispensable role in diabetic wound impairment; however, the mechanism underlying this relationship remains unclear. Recently, microRNAs have been shown to provide an additional layer of regulation of gene expression. In particular, microRNA-21 (miR-21) is essential for an inflammatory immune response. We hypothesize that miR-21 plays a role in regulating inflammation by promoting M1 macrophage polarization and the production of reactive oxygen species (ROS). To test our hypothesis, we employed an in vivo mouse skin wound model in conjunction with an in vitro mouse model to assess miR-21 expression and macrophage polarization. First, we found that miR-21 exhibits a distinct expression pattern in each phase of healing in diabetic wounds. MiR-21 abundance was higher during early and late phases of wound repair in diabetic wounds, while it was significantly lower in the middle phase of wounding (at days 3 and 7 following wounding). In macrophage cells, M1 polarized macrophages exhibited an upregulation of miR-21, as well as the M1 and pro-inflammatory markers IL-1b, TNFa, iNos, IL-6, and IL-8. Overexpression of miR-21 in macrophage cells resulted in an upregulation of miR-21 and also increased expression of the M1 markers IL-1b, TNFa, iNos, and IL-6. Furthermore, hyperglycemia induced NOX2 expression and ROS production through the HG/miR-21/PI3K/NOX2/ROS signaling cascade. These findings provide evidence that miR-21 is involved in the regulation of inflammation. Dysregulation of miR-21 may explain the abnormal inflammation and persistent M1 macrophage polarization seen in diabetic wounds.

scholarly journals Neutrophil-derived extracellular vesicles: proinflammatory trails and anti-inflammatory microvesicles

2019 ◽  
Author(s):  
Young-Jin Youn ◽  
Sanjeeb Shrestha ◽  
Jun-Kyu Kim ◽  
Yu-Bin Lee ◽  
Jee Hyun Lee ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Inflammatory Responses ◽  
Macrophage Polarization ◽  
Pi3k Pathway ◽  
M2 Macrophage ◽  
List Type ◽  
Protective Effects ◽  
M1 Macrophage ◽  
M2 Macrophage Polarization ◽  
Anti Inflammatory

SUMMARYExtracellular vesicles (EVs) are membrane-derived vesicles that mediate intercellular communications. Neutrophils produce different subtypes of EVs during inflammatory responses. Neutrophil-derived trails (NDTRs) are generated by neutrophils migrating toward inflammatory foci, whereas neutrophil-derived microvesicles (NDMVs) are thought to be generated by neutrophils that have arrived at the inflammatory foci. However, the physical and functional characteristics of neutrophil-derived EVs are incompletely understood. In this study, we investigated the similarities and differences between neutrophil-derived EV subtypes. Neutrophil-derived EVs shared similar characteristics regarding stimulators, generation mechanisms, and surface marker expression. Both neutrophil-derived EV subtypes exhibited similar functions, such as direct bactericidal activity and induction of monocyte chemotaxis via MCP-1. However, NDTR generation was dependent on the integrin signaling, while NDMV generation was dependent on the PI3K pathway. The CD16 expression level differentiated the neutrophil-derived EV subtypes. Interestingly, both subtypes showed different patterns of miRNA expression and were easily phagocytosed by monocytes. NDTRs induced M1 macrophage polarization, whereas NDMVs induced M2 macrophage polarization. Moreover, NDTRs but not NDMVs exerted protective effects against sepsis-induced lethality in a murine sepsis model and pathological changes in a murine chronic colitis model. These results suggest a new insight into neutrophil-derived EV subtypes: proinflammatory NDTRs and anti-inflammatory NDMVs.Key pointsNeutrophil-derived trails are proinflammatory extracellular vesicles that induce M1 macrophage polarization and protect against inflammationNeutrophil-derived microvesicles are anti-inflammatory extracellular vesicles that induce M2 macrophage polarization

scholarly journals Inflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Keizo Kohno ◽  
Satomi Koya-Miyata ◽  
Akira Harashima ◽  
Takahiko Tsukuda ◽  
Masataka Katakami ◽  
...  
Keyword(s):  
Wound Healing ◽  
Chronic Wounds ◽  
Macrophage Polarization ◽  
Phenotypic Switching ◽  
Apoptotic Cells ◽  
Phenotypic Switch ◽  
Inflammatory Phase ◽  
M1 Macrophage ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Background NK-4 has been used to promote wound healing since the early-1950s; however, the mechanism of action of NK-4 is unknown. In this study, we examined whether NK-4 exerts a regulatory effect on macrophages, which play multiple roles during wound healing from the initial inflammatory phase until the tissue regeneration phase. Results NK-4 treatment of THP-1 macrophages induced morphological features characteristic of classically-activated M1 macrophages, an inflammatory cytokine profile, and increased expression of the M1 macrophage-associated molecules CD38 and CD86. Interestingly, NK-4 augmented TNF-α production by THP-1 macrophages in combination with LPS, Pam3CSK4, or poly(I:C). Furthermore, NK-4 treatment enhanced THP-1 macrophage phagocytosis of latex beads. These results indicate that NK-4 drives macrophage polarization toward an inflammatory M1-like phenotype with increased phagocytic activity. Efferocytosis is a crucial event for resolution of the inflammatory phase in wound healing. NK-4-treated THP-1 macrophages co-cultured with apoptotic Jurkat E6.1 (Apo-J) cells switched from an M1-like phenotype to an M2-like phenotype, as seen in the inverted ratio of TNF-α to IL-10 produced in response to LPS. We identified two separate mechanisms that are involved in this phenotypic switch. First, recognition of phosphatidylserine molecules on Apo-J cells by THP-1 macrophages downregulates TNF-α production. Second, phagocytosis of Apo-J cells by THP-1 macrophages and activation of PI3K/Akt signaling pathway upregulates IL-10 production. Conclusion It is postulated that the phenotypic switch from a proinflammatory M1-like phenotype to an anti-inflammatory M2-like phenotype is dysregulated due to impaired efferocytosis of apoptotic neutrophils at the wound site. Our results demonstrate that NK-4 improves phagocytosis of apoptotic cells, suggesting its potential as a therapeutic strategy to resolve sustained inflammation in chronic wounds.

Sphingosine kinase 1 regulates lysyl oxidase through STAT3 in hyperoxia-mediated neonatal lung injury

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2020-216469
Author(s):  
Alison W Ha ◽  
Tao Bai ◽  
David L Ebenezer ◽  
Tanvi Sethi ◽  
Tara Sudhadevi ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lysyl Oxidase ◽  
Critical Role ◽  
Sphingosine Kinase ◽  
In Vivo Studies ◽  
Sphingosine Kinase 1 ◽  
Neonatal Lung ◽  
Neonatal Lung Injury

IntroductionNeonatal lung injury as a consequence of hyperoxia (HO) therapy and ventilator care contribute to the development of bronchopulmonary dysplasia (BPD). Increased expression and activity of lysyl oxidase (LOX), a key enzyme that cross-links collagen, was associated with increased sphingosine kinase 1 (SPHK1) in human BPD. We, therefore, examined closely the link between LOX and SPHK1 in BPD.MethodThe enzyme expression of SPHK1 and LOX were assessed in lung tissues of human BPD using immunohistochemistry and quantified (Halo). In vivo studies were based on Sphk1−/− and matched wild type (WT) neonatal mice exposed to HO while treated with PF543, an inhibitor of SPHK1. In vitro mechanistic studies used human lung microvascular endothelial cells (HLMVECs).ResultsBoth SPHK1 and LOX expressions were increased in lungs of patients with BPD. Tracheal aspirates from patients with BPD had increased LOX, correlating with sphingosine-1-phosphate (S1P) levels. HO-induced increase of LOX in lungs were attenuated in both Sphk1−/− and PF543-treated WT mice, accompanied by reduced collagen staining (sirius red). PF543 reduced LOX activity in both bronchoalveolar lavage fluid and supernatant of HLMVECs following HO. In silico analysis revealed STAT3 as a potential transcriptional regulator of LOX. In HLMVECs, following HO, ChIP assay confirmed increased STAT3 binding to LOX promoter. SPHK1 inhibition reduced phosphorylation of STAT3. Antibody to S1P and siRNA against SPNS2, S1P receptor 1 (S1P1) and STAT3 reduced LOX expression.ConclusionHO-induced SPHK1/S1P signalling axis plays a critical role in transcriptional regulation of LOX expression via SPNS2, S1P1 and STAT3 in lung endothelium.

scholarly journals IL-6/STAT3/miR-34a protects against neonatal lung injury patients

2017 ◽  
Vol 16 (4) ◽  
pp. 4355-4361 ◽  
Author(s):  
Huajun Liu ◽  
Wenbin Liu ◽  
Xueqing Tang ◽  
Taisen Wang ◽  
Xianlin Sun ◽  
...  
Keyword(s):  
Lung Injury ◽  
Neonatal Lung ◽  
Neonatal Lung Injury

scholarly journals The effect of coal-derived humic substances and their silver-containing bionanocomposites on arginine balance in peritoneal macrophages of intact mice

2022 ◽  
Vol 20 (4) ◽  
pp. 71-78
Author(s):  
E. S. Trofimova ◽  
M. V. Zykova ◽  
M. G. Danilets ◽  
A. A. Ligacheva ◽  
E. Yu. Sherstoboev ◽  
...  
Keyword(s):  
Humic Substances ◽  
Chronic Wounds ◽  
Macrophage Polarization ◽  
Antigen Presenting Cells ◽  
Peritoneal Macrophages ◽  
Research Area ◽  
The Body ◽  
M1 Macrophage ◽  
Anti Inflammatory ◽  
Antigen Presenting

Background. Antigen-presenting cells (APCs), especially macrophages, play an important role in the body defense against various pathogens. Their dysfunction and polarization are associated with most inflammatory and autoimmune diseases. The inflammatory process is regulated by activation and / or inhibition of genes differentially expressed by macrophages. Successful correction of inflammation leads firstly to elimination of inflammatory stimuli and then to remodeling and restoration of tissues and organs. It was experimentally confirmed that silvercontaining bionanocomposites based on natural humic substances (HS) obtained from coal of different origin, as well as initial matrices of these HS, are capable of activating pro- and anti-inflammatory properties of macrophages.Aim. To study cytotoxic, pyrogenic, and immunomodulatory properties (arginine balance) of initial HS samples and samples of silver nanoparticles ultradispersed in these HS matrices (HS-AgNPs) in the cell culture of peritoneal macrophages, as well as their effect on pro- and anti-inflammatory properties of APCs.Materials and methods. Cultural and biochemical methods were used in the study.Results. The study showed that the samples CHE-K, CHE-AgNPs, CHS-K, and CHP-K increased M1 macrophage polarization due to stimulation of the NO-synthase activity and inhibition of arginase. The samples CHI-K, CHIAgNPs, CHP-AgNPs, and CHS-AgNPs modulated an alternative M2 or M2-like state of macrophage activation. At the same time, HS are not cytotoxic at effective concentrations, and three out of four studied samples did not contain pyrogenic impurities.Conclusion. The use of HS and their silver-containing bionanocomposites, which have the ability to greatly affect the polarization of antigen-presenting cells, is a promising research area in correction of the inflammatory response for solving an important social and medical problem of treating chronic wounds. 

scholarly journals Curcumin augments lung maturation, preventing neonatal lung injury by inhibiting TGF-β signaling

2011 ◽  
Vol 301 (5) ◽  
pp. L721-L730 ◽  
Author(s):  
Reiko Sakurai ◽  
Yishi Li ◽  
John S. Torday ◽  
Virender K. Rehan
Keyword(s):  
Lung Injury ◽  
Intraperitoneal Administration ◽  
Lung Fibroblasts ◽  
Related Protein ◽  
Lung Maturation ◽  
Injury Repair ◽  
Parathyroid Hormone Related Protein ◽  
Neonatal Lung ◽  
Neonatal Lung Injury ◽  
Pthrp Receptor

There is no effective intervention to prevent or treat bronchopulmonary dysplasia (BPD). Curcumin has potent antioxidant and anti-inflammatory properties, and it modulates signaling of peroxisome proliferator-activated receptor-γ (PPARγ), an important molecule in the pathobiology of BPD. However, its role in the prevention of BPD is not known. We determined 1) if curcumin enhances neonatal lung maturation, 2) if curcumin protects against hyperoxia-induced neonatal lung injury, and 3) if this protection is mediated by blocking TGF-β. Embryonic day 19 fetal rat lung fibroblasts were exposed to 21% or 95% O2 for 24 h following 1 h of treatment with curcumin. Curcumin dose dependently accelerated e19 fibroblast differentiation [increased parathyroid hormone-related protein (PTHrP) receptor, PPARγ, and adipocyte differentiation-related protein (ADRP) levels and triolein uptake] and proliferation (increased thymidine incorporation). Pretreatment with curcumin blocked the hyperoxia-induced decrease (PPARγ and ADRP) and increase (α-smooth muscle actin and fibronectin) in markers of lung injury/repair, as well as the activation of TGF-β signaling. In a separate set of experiments, neonatal Sprague-Dawley rat pups were exposed to 21% or 95% O2 for 7 days with or without intraperitoneal administration of curcumin. Analysis for markers of lung injury/repair [PTHrP receptor, PPARγ, ADRP, fibronectin, TGF-β receptor (activin receptor-like kinase 5), and Smad3] and lung morphology (radial alveolar count) demonstrated that curcumin effectively blocks TGF-β activation and hyperoxia-induced lung injury. Therefore, curcumin accelerates lung maturation by stimulating key alveolar epithelial-mesenchymal interactions and prevents hyperoxia-induced neonatal lung injury, possibly by blocking TGF-β activation, suggesting that it is a potential intervention against BPD.

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