Predicted effects of observed changes in the mRNA and microRNA transcriptome of lung neutrophils during S. pneumoniae pneumonia in mice

Gomez, John C.; Dang, Hong; Kanke, Matthew; Hagan, Robert S.; Mock, Jason R.; Kelada, Samir N. P.; Sethupathy, Praveen; Doerschuk, Claire M.

doi:10.1038/s41598-017-11638-7

Cited by 18 publications

(16 citation statements)

References 69 publications

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“…Mice given ALI induced by Streptococcus pneumoniae ( Sp ) were studied 6 days after infection, a time point during resolution when infected mice have regained much of their weight loss (Gomez et al, ; Matute‐Bello et al, ) Mice lacking IFN‐γ had a similar weight loss and return to baseline weight by 6 days post‐ Sp , compared to WT mice (Figure a). In prior reports, similar inocula of Sp did not demonstrate a difference in bacterial clearance between genotypes (Yamada et al, ).…”

Section: Resultsmentioning

confidence: 99%

“…By day 7 post‐injury, resolution is underway; type II epithelial cell (AT2) proliferation is high, lymphocyte numbers are increasing, and neutrophils and inflammatory macrophages are decreased. Two other stimuli that are important common causes of lung injury ( S. pneumoniae and H1N1 influenza) were also studied to identify and compare the effects of IFN‐γ deficiency at a time point during resolution when mice have regained much of their weight loss (Arpaia et al, ; Gomez et al, ; Matute‐Bello, Frevert, & Martin, ). These studies identified the contribution of IFN‐γ both to lung injury and to changes in immune cell kinetics during resolution from lung injury.…”

Section: Introductionmentioning

confidence: 99%

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Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

et al. 2020

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The immunologic responses that occur early in the acute respiratory distress syndrome (ARDS) elicit immune‐mediated damage. The mechanisms underlying the resolution of ARDS, particularly the role of signaling molecules in regulating immune cell kinetics, remain important questions. Th1‐mediated responses can contribute to the pathogenesis of acute lung injury (ALI). Interferon‐gamma (IFN‐γ) orchestrates early inflammatory events, enhancing immune‐mediated damage. The current study investigated IFN‐γ during resolution in several experimental models of ALI. The absence of IFN‐γ resulted in altered kinetics of lymphocyte and macrophage responses, suggesting that IFN‐γ present in this microenvironment is influential in ALI resolution. Genetic deficiency of IFN‐γ or administering neutralizing IFN‐γ antibodies accelerated the pace of resolution. Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased alveolar macrophage numbers during resolution. Our results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution. Identifying and elucidating the mechanisms critical to ALI resolution will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the response to injury.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

et al. 2020

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“…Specifically, the expression of mmu-miR-21a-5p, mmu-miR-147-3p, mmu-miR-449a-5p, and mmu-miR-703 was deregulated in the lungs of mice exposed to multi-walled carbon nanotubes [24] and mmu-miR-342-3p in mice exposed to nano-TiO2 particles [25]. The deregulation of the miRNAs observed in our study was further found in the lungs of mice after cigarette smoke exposure (mmu-miR-21a-5p, mmu-miR-135b-5p, mmu-miR-146a-5p, mmu-miR-146b-5p, mmu-miR-155-5p, mmu-miR-342-3p, mmu-miR-449a-5p, mmu-miR-489-3p, and mmu-miR-672-5p) [26], in mice with cigarette smoke induced atherosclerosis (mmu-miR-21a-5p and mmu-miR-155-5p) [27], in the lungs of mice after radon inhalation (mmu-miR-21a-3p, mmu-miR-135b-5p, mmu-miR-146b-5p, mmu-miR-1298-5p, mmu-miR-6972-5p, and mmu-miR-703) [28], in mice with lung tumors (mmu-miR-135b-5p, mmu-miR-146b-5p, mmu-miR-223-3p, and mmu-miR-1298-5p) [29][30][31], in an ovalbumin-induced asthma mouse model (mmu-miR-21a-5p, mmu-miR-135b-5p, mmu-miR-146a-5p, mmu-miR-155-5p, mmu-miR-223-3p, and mmu-miR-451a) [32], and in mice with pneumonia and influenza infections (mmu-miR-21a-5p, mmu-miR-144-5p, mmu-miR-155-5p, and mmu-miR-223-3p) [33][34][35]. This overall suggests that the inhalation of CuO NPs induces a similar response as the above-mentioned adverse conditions and therefore likely has negative effects on the organism.…”

Section: Discussionmentioning

confidence: 99%

Gene Expression and Epigenetic Changes in Mice Following Inhalation of Copper(II) Oxide Nanoparticles

et al. 2020

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We investigated the transcriptomic response and epigenetic changes in the lungs of mice exposed to inhalation of copper(II) oxide nanoparticles (CuO NPs) (8 × 10 5 NPs/m 3 ) for periods of 3 days, 2 weeks, 6 weeks, and 3 months. A whole genome transcriptome and miRNA analysis was performed using next generation sequencing. Global DNA methylation was assessed by ELISA. The inhalation resulted in the deregulation of mRNA transcripts: we detected 170, 590, 534, and 1551 differentially expressed transcripts after 3 days, 2 weeks, 6 weeks, and 3 months of inhalation, respectively. Biological processes and pathways affected by inhalation, differed between 3 days exposure (collagen formation) and longer treatments (immune response). Periods of two weeks exposure further induced apoptotic processes, 6 weeks of inhalation affected the cell cycle, and 3 months of treatment impacted the processes related to cell adhesion. The expression of miRNA was not affected by 3 days of inhalation. Prolonged exposure periods modified miRNA levels, although the numbers were relatively low (17, 18, and 38 miRNAs, for periods of 2 weeks, 6 weeks, and 3 months, respectively). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analysis based on miRNA-mRNA interactions, revealed the deregulation of processes implicated in the immune response and carcinogenesis. Global DNA methylation was not significantly affected in any of the exposure periods. In summary, the inhalation of CuO NPs impacted on both mRNA and miRNA expression. A significant transcriptomic response was already observed after 3 days of exposure. The affected biological processes and pathways indicated the negative impacts on the immune system and potential role in carcinogenesis.

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“…Following BAL collection, a single cell digest was generated from the right lung of each mouse using enzymatic digestion and mechanical disruption, as previously described [39–41]. After lysis to remove red blood cells, the single cell digest was stained to identify neutrophils using CD45 and Ly6G.…”

Section: Methodsmentioning

confidence: 99%

Dynamic changes in lung responses after single and repeated exposures to cigarette smoke in mice

et al. 2019

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Cigarette smoke is well recognized to cause injury to the airways and the alveolar walls over time. This injury usually requires many years of exposure, suggesting that the lungs may rapidly develop responses that initially protect it from this repetitive injury. Our studies tested the hypotheses that smoke induces an inflammatory response and changes in mRNA profiles that are dependent on sex and the health status of the lung, and that the response of the lungs to smoke differs after 1 day compared to 5 days of exposure. Male and female wildtype (WT) and Scnn1b -transgenic (βENaC) mice, which have chronic bronchitis and emphysematous changes due to dehydrated mucus, were exposed to cigarette smoke or sham air conditions for 1 or 5 days. The inflammatory response and gene expression profiles were analyzed in lung tissue. Overall, the inflammatory response to cigarette smoke was mild, and changes in mediators were more numerous after 1 than 5 days. βENaC mice had more airspace leukocytes than WT mice, and smoke exposure resulted in additional significant alterations. Many genes and gene sets responded similarly at 1 and 5 days: genes involved in oxidative stress responses were upregulated while immune response genes were downregulated. However, certain genes and biological processes were regulated differently after 1 compared to 5 days. Extracellular matrix biology genes and gene sets were upregulated after 1 day but downregulated by 5 days of smoke compared to sham exposure. There was no difference in the transcriptional response to smoke between WT and βENaC mice or between male and female mice at either 1 or 5 days. Taken together, these studies suggest that the lungs rapidly alter gene expression after only one exposure to cigarette smoke, with few additional changes after four additional days of repeated exposure. These changes may contribute to preventing lung damage.

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Predicted effects of observed changes in the mRNA and microRNA transcriptome of lung neutrophils during S. pneumoniae pneumonia in mice

Cited by 18 publications

References 69 publications

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

Effects of IFN‐γ on immune cell kinetics during the resolution of acute lung injury

Gene Expression and Epigenetic Changes in Mice Following Inhalation of Copper(II) Oxide Nanoparticles

Dynamic changes in lung responses after single and repeated exposures to cigarette smoke in mice

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