hMSCs suppress neutrophil-dominant airway inflammation in a murine model of asthma

Hong, Gyong Hwa; Kwon, Hyouk‐Soo; Lee, Kyoung Young; Ha, Eun Hee; Moon, Keun‐Ai; Kim, Seong Who; Oh, Wonil; Kim, Tae‐Bum; Moon, Hee‐Bom; Cho, You Sook

doi:10.1038/emm.2016.135

Cited by 26 publications

(28 citation statements)

References 46 publications

(50 reference statements)

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“…In previous studies, a single dose of MSCs administered prophylactically or therapeutically reduced lung influx of inflammatory cells, airway hyperresponsiveness, and mucus hypersecretion in models of ovalbumin-induced allergic asthma. 3,7,8,22,23 In HDM-induced allergic asthma, a single dose of MSCs administered prophylactically also prevented inflammation by modulating epithelial cell activation. 24 However, effects on the inflammatory process were only marginal, with no improvements in lung function and remodeling when MSCs were administered therapeutically.…”

Section: Discussionmentioning

confidence: 99%

“…Mesenchymal stromal cell (MSC) therapy has demonstrated promising results in several lung disease models, but its impact on airway remodeling has been sometimes controversial . In models of ovalbumin‐ and Aspergillus hyphal extract‐induced allergic asthma, a single dose of MSCs administered either locally or systemically resulted in reduction of both lung inflammation and remodeling . Conversely, in house dust mite extract (HDM)‐induced allergic asthma, a single dose of MSCs reduced some inflammatory parameters but was unable to ameliorate lung function or remodeling .…”

Section: Introductionmentioning

confidence: 99%

“…[3][4][5][6] In models of ovalbuminand Aspergillus hyphal extract-induced allergic asthma, a single dose of MSCs administered either locally or systemically resulted in reduction of both lung inflammation and remodeling. 3,[7][8][9][10] Conversely, in house dust mite extract (HDM)-induced allergic asthma, a single dose of MSCs reduced some inflammatory parameters but was unable to ameliorate lung function or remodeling. 4,5 Some reports have indicated that repeated cell-based therapy yielded better therapeutic effects, either by preventing disease progression or by further reducing inflammation and remodeling, in experimental silicosis and elastase-induced emphysema.…”

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confidence: 99%

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Multiple doses of adipose tissue-derived mesenchymal stromal cells induce immunosuppression in experimental asthma

Castro

Kitoko

Xisto

et al. 2019

Stem Cells Translational Medicine

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In experimental house dust mite (HDM)-induced allergic asthma, therapeutic administration of a single dose of adipose tissue-derived mesenchymal stromal cells (MSCs) ameliorates lung inflammation but is unable to reverse remodeling. We hypothesized that multiple doses of MSCs might exert better therapeutic effects by reducing lung inflammation and remodeling but might also result in immunosuppressive effects in experimental asthma. HDM was administered intranasally in C57BL/6 mice. After the last HDM challenge, mice received two or three doses of MSCs (10 5 cells per day) or salineintravenously. An additional cohort of mice received dexamethasone as a positive control for immunosuppression. Two and three doses of MSCs reduced lung inflammation; levels of interleukin (IL)-4, IL-13, and eotaxin; total leukocyte, CD4 + T-cell, and eosinophil counts in bronchoalveolar lavage fluid; and total leukocyte counts in bone marrow, spleen, and mediastinal lymph nodes. Two and three doses of MSCs also reduced collagen fiber content and transforming growth factor-β levels in lung tissue; however, the three-dose regimen was more effective, and it reduced these parameters to control levels, while also decreasing α-actin content in lung tissue. Two and three doses of MSCs improved lung mechanics. Dexamethasone and two and three doses of MSCs similarly increased galectin levels, but only the three-dose regimen increased CD39 levels in the thymus. Dexamethasone and the three-dose, but not the two-dose, regimen also increased the levels of programmed death receptor-1 and IL-10, while reducing CD4 + CD8 low cell percentage in the thymus. In conclusion, multiple doses of MSCs reduced lung inflammation and remodeling while causing immunosuppression in HDM-induced allergic asthma. K E Y W O R D Sadipose stem cells, cellular therapy, immunosuppression, lung, mesenchymal stromal cells

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Multiple doses of adipose tissue-derived mesenchymal stromal cells induce immunosuppression in experimental asthma

Castro

Kitoko

Xisto

et al. 2019

Stem Cells Translational Medicine

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“…Neutrophil infiltration into the airways and lung parenchyma is a hallmark event in acute pulmonary inflammation, and typifies a wide range of human lung diseases, including asthma, chronic obstructive lung disease, and pneumonia [29] , [30] . In the present work, the involvement of (bi)sulfite-induced free radicals in LPS-induced lung inflammation was evaluated in mice.…”

Section: Discussionmentioning

confidence: 99%

Sulfite-induced protein radical formation in LPS aerosol-challenged mice: Implications for sulfite sensitivity in human lung disease

et al. 2018

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Exposure to (bi)sulfite (HSO3–) and sulfite (SO32–) has been shown to induce a wide range of adverse reactions in sensitive individuals. Studies have shown that peroxidase-catalyzed oxidation of (bi)sulfite leads to formation of several reactive free radicals, such as sulfur trioxide anion (.SO3–), peroxymonosulfate (–O3SOO.), and especially the sulfate (SO4. –) anion radicals. One such peroxidase in neutrophils is myeloperoxidase (MPO), which has been shown to form protein radicals. Although formation of (bi)sulfite-derived protein radicals is documented in isolated neutrophils, its involvement and role in in vivo inflammatory processes, has not been demonstrated. Therefore, we aimed to investigate (bi)sulfite-derived protein radical formation and its mechanism in LPS aerosol-challenged mice, a model of non-atopic asthma. Using immuno-spin trapping to detect protein radical formation, we show that, in the presence of (bi)sulfite, neutrophils present in bronchoalveolar lavage and in the lung parenchyma exhibit, MPO-catalyzed oxidation of MPO to a protein radical. The absence of radical formation in LPS-challenged MPO- or NADPH oxidase-knockout mice indicates that sulfite-derived radical formation is dependent on both MPO and NADPH oxidase activity. In addition to its oxidation by the MPO-catalyzed pathway, (bi)sulfite is efficiently detoxified to sulfate by the sulfite oxidase (SOX) pathway, which forms sulfate in a two-electron oxidation reaction. Since SOX activity in rodents is much higher than in humans, to better model sulfite toxicity in humans, we induced SOX deficiency in mice by feeding them a low molybdenum diet with tungstate. We found that mice treated with the SOX deficiency diet prior to exposure to (bi)sulfite had much higher protein radical formation than mice with normal SOX activity. Altogether, these results demonstrate the role of MPO and NADPH oxidase in (bi)sulfite-derived protein radical formation and show the involvement of protein radicals in a mouse model of human lung disease.

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“… 11 It is widely accepted that transcriptional regulation plays a pivotal role in IL-10 gene expression. 11 , 26 Indeed, ERK-dependent transcription activity mechanisms in IL-10 production have been demonstrated. 27 A number of studies have reported that IL-33 activates MAPKs, but to the best of our knowledge, no study has explored the relationship between IL-33-induced MAPK activation and IL-10 expression.…”

Section: Discussionmentioning

confidence: 99%

IL-33 promotes IL-10 production in macrophages: a role for IL-33 in macrophage foam cell formation

Zhang

Lin

et al. 2017

Exp Mol Med

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We evaluated the role of IL-10- in IL-33-mediated cholesterol reduction in macrophage-derived foam cells (MFCs) and the mechanism by which IL-33 upregulates IL-10. Serum IL-33 and IL-10 levels in coronary artery disease patients were measured. The effects of IL-33 on intra-MFC cholesterol level, IL-10, ABCA1 and CD36 expression, ERK 1/2, Sp1, STAT3 and STAT4 activation, and IL-10 promoter activity were determined. Core sequences were identified using bioinformatic analysis and site-specific mutagenesis. The serum IL-33 levels positively correlated with those of IL-10. IL-33 decreased cellular cholesterol level and upregulated IL-10 and ABCA1 but had no effect on CD36 expression. siRNA-IL-10 partially abolished cellular cholesterol reduction and ABCA1 elevation by IL-33 but did not reverse the decreased CD36 levels. IL-33 increased IL-10 mRNA production but had little effect on its stability. IL-33 induced ERK 1/2 phosphorylation and increased the luciferase expression driven by the IL-10 promoter, with the highest extent within the −2000 to −1752 bp segment of the 5′-flank of the transcription start site; these effects were counteracted by U0126. IL-33 activated Sp1, STAT3 and STAT4, but only the STAT3 binding site was predicted in the above segment. Site-directed mutagenesis of the predicted STAT3-binding sites (CTGCTTCCTGGCAGCAGAA→CTGCCTGGCAGCAGAA) reduced luciferase activity, and a STAT3 inhibitor blocked the regulatory effects of IL-33 on IL-10 expression. Chromatin immunoprecipitation (CHIP) confirmed the STAT3-binding sequences within the −1997 to −1700 and −1091 to −811 bp locus regions. IL-33 increased IL-10 expression in MFCs via activating ERK 1/2 and STAT3, which subsequently promoted IL-10 transcription and thus contributed to the beneficial effects of IL-33 on MFCs.

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hMSCs suppress neutrophil-dominant airway inflammation in a murine model of asthma

Cited by 26 publications

References 46 publications

Multiple doses of adipose tissue-derived mesenchymal stromal cells induce immunosuppression in experimental asthma

Multiple doses of adipose tissue-derived mesenchymal stromal cells induce immunosuppression in experimental asthma

Sulfite-induced protein radical formation in LPS aerosol-challenged mice: Implications for sulfite sensitivity in human lung disease

IL-33 promotes IL-10 production in macrophages: a role for IL-33 in macrophage foam cell formation

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