scholarly journals Mesenchymal Stem Cells Attenuate Acute Lung Injury in Mice Partly by Suppressing Alveolar Macrophage Activation in a PGE2-dependent Manner

2021 ◽  
Author(s):  
Gaojian Wang ◽  
Yaping Zhang ◽  
Nianqiang Hu ◽  
Qinxue Liu ◽  
Fengjie Ma ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Macrophage Activation ◽  
Rna Seq ◽  
Ep4 Receptor ◽  
Pge2 Receptor ◽  
Cox2 Inhibitor

Abstract Background: Mesenchymal stem cell have shown therapeutic effect on acute lung injury, MSC could be activated when added to inflammatory environment and in turn suppress inflammation, yet the mechanism is complex and not understood. Methods: To determine the effect of MSC on ALI and alveolar macrophage activation, MSCs were administered to ALI mice and co-cultured with activated MH-S cells (alveolar macrophage cell line). To find the genes critical for MSC’s immunosuppressive effects, rest and activated MSCs induced by inflammatory MH-S cells were harvested for RNA-seq. To prove that PGE2 participates in the immunosuppressive effects of MSC, COX2 inhibitor and PGE2 receptor antagonist were added to the co-culture system and administrated to ALI mice. Results: The intratracheal administration of MSCs attenuated ALI and suppressed alveolar macrophages activation in vivo, the activation of MH-S cells was also significantly reduced after co-culturing with MSCs in vitro. The RNA-seq data of rest and activated MSCs suggested that the Ptgs2 gene may play an important role in MSC exerting immunosuppressive effects. Correspondingly, we found that the COX2 protein and PGE2 released by activated MSCs were increased dramatically after co-culturing with MH-S. The use of COX2 inhibitor NS-398 restrained the secretion of PGE2 and reversed the suppressive effect on macrophages activation of MSCs in vitro. Furthermore, GW627368X, a selective antagonist of PGE2 receptor (EP4 receptor), also reversed the inhibitory effects of MSCs on alveolar macrophages and their protective effects on ALI mice.Conclusions: MSC attenuate ALI partly through suppressing alveolar macrophage activation via PGE2 binding to EP4 receptor.

Geranylgeranyl diphosphate synthase deficiency hyperactivates macrophages and aggravates lipopolysaccharide-induced acute lung injury

2021 ◽  
Author(s):  
Jiajia Jin ◽  
Hong Qian ◽  
Bing Wan ◽  
Li Zhou ◽  
Cen Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Macrophage Activation ◽  
Nuclear Translocation ◽  
Inflammatory Responses ◽  
Alveolar Epithelium ◽  
Geranylgeranyl Diphosphate Synthase ◽  
Geranylgeranyl Diphosphate

Macrophage activation is a key contributing factor for excessive inflammatory responses of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Geranylgeranyl diphosphate synthase (GGPPS) plays a key role in the development of inflammatory diseases. Our group previously showed that GGPPS in alveolar epithelium have deleterious effects on acute lung injury induced by LPS or mechanical ventilation. Herein, we examined the role of GGPPS in modulating macrophage activation in ALI/ARDS. We found significant increased GGPPS expression in alveolar macrophages in ARDS patients compared to healthy volunteers and in ALI mice induced by LPS. GGPPS-floxed control (GGPPSfl/fl) and myeloid-selective knockout (GGPPSfl/flLysMcre) mice were then generated. Interestingly, using a LPS-induced ALI mouse model, we showed that myeloid-specific GGPPS knockout significantly increased mortality, aggravated lung injury, and increased the accumulation of inflammatory cells, total protein, and inflammatory cytokines in BALF. In vitro, GGPPS deficiency up-regulated the production of LPS-induced IL-6, IL-1β, and TNF-α in alveolar macrophages, bone marrow-derived macrophages (BMDMs), and THP-1 cells. Mechanistically, GGPPS knockout increased phosphorylation and nuclear translocation of NF-κB p65 induced by LPS. In addition, GGPPS deficiency increased the level of GTP-Rac1, which was responsible for NF-κB activation. In conclusion, decreased expression of GGPPS in macrophages aggravates lung injury and inflammation in ARDS, at least partly by regulating Rac1-dependent NF-κB signaling. GGPPS in macrophages may represent a novel therapeutic target in ARDS.

scholarly journals Phagocytosis of microparticles by alveolar macrophages during acute lung injury requires MerTK

2018 ◽  
Vol 314 (1) ◽  
pp. L69-L82 ◽  
Author(s):  
Michael P. Mohning ◽  
Stacey M. Thomas ◽  
Lea Barthel ◽  
Kara J. Mould ◽  
Alexandria L. McCubbrey ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Primary Objective ◽  
Cytochalasin D ◽  
Inflammatory Signaling ◽  
Macrophage Population ◽  
Bronchoalveolar Fluid

Microparticles are a newly recognized class of mediators in the pathophysiology of lung inflammation and injury, but little is known about the factors that regulate their accumulation and clearance. The primary objective of our study was to determine whether alveolar macrophages engulf microparticles and to elucidate the mechanisms by which this occurs. Alveolar microparticles were quantified in bronchoalveolar fluid of mice with lung injury induced by LPS and hydrochloric acid. Microparticle numbers were greatest at the peak of inflammation and declined as inflammation resolved. Isolated, fluorescently labeled particles were placed in culture with macrophages to evaluate ingestion in the presence of endocytosis inhibitors. Ingestion was blocked with cytochalasin D and wortmannin, consistent with a phagocytic process. In separate experiments, mice were treated intratracheally with labeled microparticles, and their uptake was assessed though microscopy and flow cytometry. Resident alveolar macrophages, not recruited macrophages, were the primary cell-ingesting microparticles in the alveolus during lung injury. In vitro, microparticles promoted inflammatory signaling in LPS primed epithelial cells, signifying the importance of microparticle clearance in resolving lung injury. Microparticles were found to have phosphatidylserine exposed on their surfaces. Accordingly, we measured expression of phosphatidylserine receptors on macrophages and found high expression of MerTK and Axl in the resident macrophage population. Endocytosis of microparticles was markedly reduced in MerTK-deficient macrophages in vitro and in vivo. In conclusion, microparticles are released during acute lung injury and peak in number at the height of inflammation. Resident alveolar macrophages efficiently clear these microparticles through MerTK-mediated phagocytosis.

Alveolar macrophages contribute to alveolar barrier dysfunction in ventilator-induced lung injury

2006 ◽  
Vol 291 (6) ◽  
pp. L1191-L1198 ◽  
Author(s):  
James A. Frank ◽  
Charlie M. Wray ◽  
Danny F. McAuley ◽  
Reto Schwendener ◽  
Michael A. Matthay
Keyword(s):  
Mechanical Ventilation ◽  
Epithelial Cell ◽  
Lung Injury ◽  
Tidal Volume ◽  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Macrophage Activation ◽  
Alveolar Epithelial Cell ◽  
Alveolar Epithelial ◽  
Ventilator Induced Lung Injury

In patients requiring mechanical ventilation for acute lung injury or acute respiratory distress syndrome (ARDS), tidal volume reduction decreases mortality, but the mechanisms of the protective effect have not been fully explored. To test the hypothesis that alveolar macrophage activation is an early and critical event in the initiation of ventilator-induced lung injury (VILI), rats were ventilated with high tidal volume (HVT) for 10 min to 4 h. Alveolar macrophage counts in bronchoalveolar lavage (BAL) fluid decreased 45% by 20 min of HVT( P < 0.05) consistent with activation-associated adhesion. Depletion of alveolar macrophages in vivo with liposomal clodronate significantly decreased permeability and pulmonary edema following 4 h of HVT( P < 0.05). BAL fluid from rats exposed to 20 min of HVTincreased nitric oxide synthase activity nearly threefold in naïve primary alveolar macrophages ( P < 0.05) indicating that soluble factors present in the air spaces contribute to macrophage activation in VILI. Media from cocultures of alveolar epithelial cell monolayers and alveolar macrophages exposed to 30 min of stretch in vitro also significantly increased nitrite production in naïve macrophages ( P < 0.05), but media from stretched alveolar epithelial cells or primary alveolar macrophages alone did not, suggesting alveolar epithelial cell-macrophage interaction was required for the subsequent macrophage activation observed. These data demonstrate that injurious mechanical ventilation rapidly activates alveolar macrophages and that alveolar macrophages play an important role in the initial pathogenesis of VILI.

scholarly journals Negative Effects of SIGIRR on TRAF6 Ubiquitination in Acute Lung Injury In Vitro

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Feng Tian ◽  
Qiang Lu ◽  
Jie Lei ◽  
Yunfeng Ni ◽  
Nianlin Xie ◽  
...  
Keyword(s):  
Immune Response ◽  
Acute Lung Injury ◽  
Epithelial Cells ◽  
Lung Injury ◽  
Alveolar Macrophage ◽  
Signaling Pathway ◽  
Alveolar Epithelial Cells ◽  
Alveolar Epithelial ◽  
Macrophage Cells

In this study, the effects of single immunoglobin IL-1 receptor-related protein (SIGIRR) on tumor necrosis factor- (TNF-) receptor-associated factor 6 (TRAF6) ubiquitination in acute lung injury (ALI) were evaluated in both alveolar epithelial cells and alveolar macrophage cells in vitro. Our results found that SIGIRR negatively regulated TRAF6 ubiquitination and such SIGIRR inhibition could enhance the TRAF6 expression in both alveolar epithelial cells (AECs) and alveolar macrophage cells (AMCs). SIGIRR knockdown may increase NF-κB activity via TRAF6 regulation by the classical but not the nonclassical NF-κB signaling pathway. Such modulation between TRAF6 and SIGIRR could affect cytokine secretion and exacerbate the immune response; the IL-8, NFKB1, and NFKBIA mRNA levels were reduced after SIGIRR overexpression. The current study reveals the molecular mechanisms of the negative regulatory roles of SIGIRR on the innate immune response related to the LPS/TLR-4 signaling pathway and provides evidence for strategies to clinically treat inflammatory diseases.

scholarly journals Ghrelin attenuates sepsis-induced acute lung injury by inhibiting the NF-κB, iNOS, and Akt signaling in alveolar macrophages

2019 ◽  
Vol 317 (3) ◽  
pp. L381-L391 ◽  
Author(s):  
Haichong Zheng ◽  
Wenjie Liang ◽  
Wanmei He ◽  
Chunrong Huang ◽  
Qingui Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Inflammatory Responses ◽  
Pulmonary Inflammation ◽  
Cecal Ligation ◽  
Protective Role ◽  
Akt Signaling ◽  
Cytokines And Chemokines

Ghrelin has proven to be protective against sepsis-induced acute lung injury (ALI) via anti-inflammatory effects. However, its mechanisms remain poorly understood. Alveolar macrophages (AMs) play a key role in mediating inflammatory responses during sepsis-induced ALI by secretion of cytokines and chemokines. This study was undertaken to investigate whether ghrelin suppresses inflammatory effects of AMs and therefore may help to attenuate sepsis-induced ALI. A sepsis model in rats was achieved using cecal ligation and puncture. Ghrelin treatment markedly improved histopathological changes in the lungs and reduced pulmonary inflammation in septic rats. NF-κB translocation and p-Akt and inducible nitric oxide synthase (iNOS) activities in AMs from septic rats were suppressed by ghrelin. In vitro data indicated that ghrelin decreased the levels of LPS-induced IL-1β, TNF-α, and IL-6, NF-κB translocation, and iNOS and Akt activities of AMs. Furthermore, the NF-κB/iNOS pathway or Akt signaling was positively correlated with LPS-induced inflammatory production of AMs in vitro. In conclusion, ghrelin exerts a protective role against sepsis-induced ALI probably by reducing the production of inflammatory cytokines from AMs via inhibition of the NF-κB/iNOS pathway or Akt signaling.

ROLE OF PULMONARY ALVEOLAR MACROPHAGE ACTIVATION IN ACUTE LUNG INJURY AFTER BURNS AND SMOKE INHALATION

The Lancet ◽  
1988 ◽  
Vol 332 (8616) ◽  
pp. 872-874 ◽  
Author(s):  
C.J. Clark ◽  
W.H. Reid ◽  
A.J. Pollock ◽  
D. Campbell ◽  
C. Gemmell
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophage ◽  
Macrophage Activation ◽  
Smoke Inhalation ◽  
Pulmonary Alveolar Macrophage

scholarly journals MK2 mediates macrophage activation and acute lung injury by regulating let-7e miRNA

2018 ◽  
Vol 315 (3) ◽  
pp. L371-L381 ◽  
Author(s):  
Yaxian Wu ◽  
Huiqiong He ◽  
Yunhe Ding ◽  
Sirui Liu ◽  
Depeng Zhang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Macrophage Activation ◽  
Critical Role ◽  
Protein A ◽  
Cytokine Expression ◽  
Conditional Knockout ◽  
Lps Challenge ◽  
Tnf Α

MAPK-activated protein kinase 2 (MK2) plays a critical role in the development of inflammation. However, the modulatory mechanisms in macrophage activation and acute lung injury (ALI) have not been completely defined. Here, we reported that MK2-deficient mice (MK2−/−) protected against sepsis-induced ALI. In response to lipopolysaccharide (LPS) challenge, MK2−/− mice and myeloid cell-specific MK2 conditional knockout mice (MK2Lyz2-KO) exhibited attenuated inflammatory response, especially producing fewer amounts of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and macrophage inflammatory protein 2 (MIP-2). LPS treatment in vitro resulted in reduced cytokine expression in MK2−/− bone marrow-derived macrophages (BMDMs). Furthermore, we found that LPS-induced microRNA lethal-7e ( let-7e) expression was significantly increased in MK2−/− macrophages. Transfection of let-7e antagomirs into MK2−/− BMDM rescued LPS-induced expression of TNF-α, IL-6, and MIP-2. In contrast, transfection of let-7e mimics into MK2+/+BMDM decreased cytokine expression. Meanwhile, LPS-induced phosphorylation of cAMP response element-binding (CREB) protein, a substrate of MK2, was downregulated in MK2−/− BMDMs. Lin28, an inhibitory molecule of let-7, was significantly reduced in MK2−/− macrophages. Our results suggested that MK2 boosts LPS-induced macrophage activation and ALI via increasing activation of CREB and consequently, the expression of Lin28 and downregulation of let-7e.

scholarly journals BMSC-Derived Exosomes Ameliorate LPS-Induced Acute Lung Injury by miR-384-5p-Controlled Alveolar Macrophage Autophagy

2021 ◽  
Vol 2021 ◽  
pp. 1-23
Author(s):  
Xuan Liu ◽  
Chengjin Gao ◽  
Yang Wang ◽  
Lei Niu ◽  
Shaowei Jiang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophage ◽  
Vascular Permeability ◽  
Alveolar Macrophages ◽  
Weight Ratio ◽  
Beclin 1 ◽  
Cell Counting ◽  
Pulmonary Vascular Permeability ◽  
Therapeutic Mechanism

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common critical diseases. Bone marrow mesenchymal stem cell (BMSC) transplantation is previously shown to effectively rescue injured lung tissues. The therapeutic mechanism of BMSC-derived exosomes is not fully understood. Here, we investigated the BMSC-derived exosomal microRNAs (miRNAs) on effecting lipopolysaccharide- (LPS-) induced ALI and its mechanism. In vitro, rat alveolar macrophages were treated with or without exosomes in the presence of 10 μg/ml LPS for 24 h. Cell viability was determined with Cell Counting Kit-8 assay. Apoptotic ratio was determined with TUNEL and Annexin V-FITC/PI double staining. The levels of miR-384-5p and autophagy-associated genes were measured by RT-qPCR and western blot. Autophagy was observed by TEM and assessed by means of the mRFP-GFP-LC3 adenovirus transfection assay. In vivo, we constructed LPS-induced ALI rat models. Exosomes were injected into rats via the caudal vein or trachea 4 h later after LPS treatment. The lung histological pathology was determined by H&E staining. Pulmonary vascular permeability was assessed by wet-to-dry weight ratio and Evans blue dye leakage assay, and inflammatory cytokines in serum and BALF were measured by ELISA. Furthermore, the therapeutic mechanism involved in miR-384-5p and Beclin-1 was determined. The results showed that BMSC-derived exosomes were taken up by the alveolar macrophages and attenuated LPS-induced alveolar macrophage viability loss and apoptosis. Exosomes effectively improved the survival rate of ALI rats within 7 days, which was associated with alleviating lung pathological changes and pulmonary vascular permeability and attenuating inflammatory response. Furthermore, this study for the first time found that miR-384-5p was enriched in BMSC-derived exosomes, and exosomal miR-384-5p resulted in relieving LPS-injured autophagy disorder in alveolar macrophages by targeting Beclin-1. Therefore, exosomal miR-384-5p could be demonstrated as a promising therapeutic strategy for ALI/ARDS.

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