Glucocorticoid attenuates acute lung injury through induction of type 2 macrophage

Tu, Guo-Wei; Shi, Yi; Zheng, Yijun; Ju, Minghe; He, Hong; Ma, Genshan; Hao, Guang-Wei; Luo, Zhe

doi:10.1186/s12967-017-1284-7

Cited by 108 publications

(101 citation statements)

References 35 publications

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“…In addition, it was important to exclude the nonsigni cantly changed genes by applying an FDR (false discovery rate) of 0.05. This study supports the rising interest in macrophages that shift their polarisation state and function from pro-in ammatory to anti-in ammatory phenotype, thus contributing to resolving in ammation and improvement of tissue repair after injury [32]. Furthermore, it is known that dysregulation of macrophage polarisation contributes to the development of various in ammatory diseases [33].…”

Section: Discussionsupporting

confidence: 82%

Transcriptional Analysis Reveals Alteration of Lung Macrophages Following Mesenchymal Stem Cell Therapy in Neonatal Mice With Hyperoxia-Induced Injury

Al-Rubaie

DeMatteo

Sozo

et al. 2020

Preprint

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Background Lung immaturity is one of the most serious consequences of growth restriction and premature birth. Preterm babies often require mechanical ventilation to survive, but exposure to high levels of oxygen can permanently damage the lungs and interrupts normal development. As lung macrophages play an important role in hyperoxic lung injury and repair, our objective was to use next generation sequencing (NGS) to identify changes in the macrophage transcriptome following neonatal hyperoxia, with and without treatment with human mesenchymal stem cells (hMSCs). We provide the first report of RNA-sequencing of lung macrophages following neonatal hyperoxia and hMSCs therapy. Methods Neonatal mice exposed to normoxia (21%O2) or hyperoxia (90% O2) from birth to postnatal day 4 were randomized to receive either hMSCs or vehicle via intratracheal delivery on postnatal day 4. Mouse lungs from normoxia and hyperoxia groups with and without hMSCs therapy were examined at day 14. RNA-sequencing was performed on flow-cytometric CD45+CD11b+CD11c+ sorted lung macrophages. Purified total RNA was used to construct barcoded multiplex-compatible sequencing libraries using: 1) Illumina Stranded mRNA Sample Preparation chemistry (for transcriptomics) and 2) Bio Scientific NEXTFlex Small RNA chemistry (for small RNA). Results Sorted CD45+CD11b+CD11c+ lung macrophages from hyperoxia-exposed neonatal mice showed differentially expressed macrophage genes and miRNA compared to mice exposed to normoxia or hyperoxia+hMSCs. The administration of hMSCs was found to differentially upregulate 421 genes and downregulate 651 genes in CD45+CD11b+CD11c+ lung macrophages from neonatal mice exposed to hyperoxia, compared to normoxia. Integrity pathway analysis (IPA) analysis of macrophage-specific gene pathways revealed the effectiveness of hMSCs in altering macrophage function towards an anti-inflammatory ‘M2’ phenotype. Small-RNA sequencing provided further evidence on the effects of hMSCs, where 1,098 small RNAs transcriptomes were expressed as either significantly up- or down-regulated in response to hMSCs therapy following hyperoxia-induced lung damage. Conclusions Pathway analysis of the predicted mRNA targets of differentially expressed genes provides insight into miRNAs that preferentially target several important pathways. These miRNAs will be functionally relevant for lung macrophages, and will provide a greater understanding of the interaction between macrophage genotype and the associated phenotypes in the setting of inflammation or tissue repair.

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Section: Discussionsupporting

confidence: 82%

Transcriptional Analysis Reveals Alteration of Lung Macrophages Following Mesenchymal Stem Cell Therapy in Neonatal Mice With Hyperoxia-Induced Injury

Al-Rubaie

DeMatteo

Sozo

et al. 2020

Preprint

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“…This is especially true for MΦ-IL10, which can be polarised by administration of GC. Recent publications reported an increase in M2-MΦ after GC treatment and an improved outcome in acute lung injury 15 . Patients with therapeutically polarised MΦ-IL10 recovered with a better outcome from asthma 16 .…”

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confidence: 97%

Impaired functional capacity of polarised neonatal macrophages

Dreschers

Ohl

Schulte

et al. 2020

Sci Rep

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neonatal sepsis is accompanied by impaired apoptotic depletion of monocytes and macrophages (MΦ), aberrant cytokine production, impaired cell metabolism, and sustained inflammation. Macrophage-colony stimulating factor (M-CSF) triggers the differentiation from monocytes into MΦ (MΦ-0). Interleukin-10 (IL10) and Interferon-gamma (IFNy) further differentiate MΦ subpopulations, the anti-inflammatory MΦ-IL10 and the pro-inflammatory MΦ-ifny subtype. We previously have shown significant differences between adult (PBMΦ) and cord blood (CBMΦ) in the metabolism of all subtypes. To test the hypothesis whether the competence to differentiate monocytes into MΦ-0 and to polarise into MΦ-ifny and MΦ-IL10 was diminished in CBMΦ as compared to PBMΦ, we polarised monocytes by cultivation with M-CSF for 72 h, followed by stimulation with IFNy or IL10, for 48 h. After flow cytometry based immunotyping, we tested four functions: Phagocytosis of GFP-E. coli, uptake of erythrocytes, t-cell proliferation, induction of regulatory t-cells as well as phosphorylation analysis of AKT and STAT1/STAT3. Phosphorylation of STAT-1 and STAT-3, obligatory to differentiate into MΦifnγ, MΦ-0 and MΦ-IL10, was found to be aberrant in CBMΦ. Whereas infected MΦ-0 showed identical phagocytic indices and intracellular degradation, TLR4-expression, NFkB up-regulation, IL10-, IL6-, and tnfα production of CBMΦ-0 were reduced. In addition, the capacity to bind aged erythrocytes and the consecutive IL10 production was lower in CBMΦ-IL10. Polarised PBMΦ-IFNy and PBMΦ-IL10 expressed higher levels of co-stimulatory receptors (CD80, CD86), had a higher capacity to stimulate T-cells and induced higher amounts of regulatory t-cells (all p < 0.05 vs. corresponding CBMΦ). Hypoxia-induciblefactor-1α (HIF-1α) was stronger expressed in CBMΦ-IFNy and upregulated in infected CBMΦ-0, whereas heme-oxygenase 1 (HO-1) expression was similar to adult PBMΦ. neonatal MΦ-0, MΦ-ifny and MΦ-IL10 polarisation is impaired with respect to phenotype and functions tested which may contribute to sustained inflammation in neonatal sepsis. Macrophages (MФ) have an extremely broad spectrum of functions in both the induction and resolution of inflammation due to their heterogeneity and plasticity. They are involved in a range of processes, including tissue homeostasis, clearance or pulmonary surfactant as well as inflammation. Deriving from monocytes, they develop into different populations of circulating inflammatory or resident macrophages (MФ) recruited to various tissues. These processes occur in response to inflammation or infection but also in homeostasis in order to replace apoptotic (MФ) 1. The migration of monocytes to the site of infection is crucial 2. After infiltrating the infected tissue they polarise into functional distinguishable MФ. The term "polarisation" instead of differentiation became accepted, since this process depends on the local cytokine milieu and specific microenvironmental cues, and therefore is reversible 3,4. By analogy to T helper cell (Th) nomenclature, MФ ...

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“…[42,43] Animal experiments in recent years have provided evidence for the use of glucocorticoids to reduce inflammation, the attenuation of acute lung injury, and reduction in mortality during the acute phase of severe disease. [44,45] However, other studies have suggested that glucocorticoid therapy in ARDS is not necessary, and may even aggravate the clinical picture. The use of hydrocortisone improves lung function in sepsis-associated ARDS, but no significant survival benefit has been observed in these patients.…”

Section: Discussionmentioning

confidence: 99%

Effectiveness of glucocorticoid therapy in patients with severe coronavirus disease 2019: protocol of a randomized controlled trial

Qin

Zhou

et al. 2020

Chinese Medical Journal

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Background: At the end of 2019, a novel coronavirus outbreak emerged in Wuhan, China, and its causative organism has been subsequently designated the 2019 novel coronavirus (2019-nCoV). The effectiveness of adjunctive glucocorticoid therapy in the management of 2019-nCoV-infected patients with severe lower respiratory tract infections is not clear, and warrants further investigation. Methods: The present study will be conducted as an open-labeled, randomized, controlled trial. We will enrol 48 subjects from Chongqing Public Health Medical Center. Each eligible subject will be assigned to an intervention group (methylprednisolone via intravenous injection at a dose of 1-2 mg/kg/day for 3 days) or a control group (no glucocorticoid use) randomly, at a 1:1 ratio. Subjects in both groups will be invited for 28 days of follow-up which will be scheduled at four consecutive visit points. We will use the clinical improvement rate as our primary endpoint. Secondary endpoints include the timing of clinical improvement after intervention, duration of mechanical ventilation, duration of hospitalization, overall incidence of adverse events, as well as rate of adverse events at each visit, and mortality at 2 and 4 weeks. Discussion: The present coronavirus outbreak is the third serious global coronavirus outbreak in the past two decades. Oral and parenteral glucocorticoids have been used in the management of severe respiratory symptoms in coronavirus-infected patients in the past. However, there remains no definitive evidence in the literature for or against the utilization of systemic glucocorticoids in seriously ill patients with coronavirus-related severe respiratory disease, or indeed in other types of severe respiratory disease. In this study, we hope to discover evidence either supporting or opposing the systemic therapeutic administration of glucocorticoids in patients with severe coronavirus disease 2019. Trial registration: ClinicalTrials.gov, ChiCTR2000029386, http://www.chictr.org.cn/showproj.aspx?proj=48777.

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Glucocorticoid attenuates acute lung injury through induction of type 2 macrophage

Cited by 108 publications

References 35 publications

Transcriptional Analysis Reveals Alteration of Lung Macrophages Following Mesenchymal Stem Cell Therapy in Neonatal Mice With Hyperoxia-Induced Injury

Transcriptional Analysis Reveals Alteration of Lung Macrophages Following Mesenchymal Stem Cell Therapy in Neonatal Mice With Hyperoxia-Induced Injury

Impaired functional capacity of polarised neonatal macrophages

Effectiveness of glucocorticoid therapy in patients with severe coronavirus disease 2019: protocol of a randomized controlled trial

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