Repeated Administration of Bone Marrow-Derived Cells Prevents Disease Progression in Experimental Silicosis

Lopes‐Pacheco, Miquéias; Xisto, Débora G.; Ornellas, Felipe M.; Antunes, Mariana A.; Abreu, Soraia C.; Rocco, Patricia R. M.; Takiya, Christina Maeda; Morales, Marcelo M.

doi:10.1159/000356603

Cited by 31 publications

(33 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the murine model used in the present study, silicosis was induced by a single exposure to crystalline silica, which, after 15 days, led to lung mechanical and histological changes that resembled those of human silicosis (Faffe et al, 2001; Maron-Gutierrez et al, 2011; Lopes-Pacheco et al, 2013). In addition, we have decided to use a C57BL/6 mouse strain, which is a prototypical Th1-type mouse strain.…”

Section: Discussionmentioning

confidence: 88%

“…Mice exposed to silica exhibited higher Est,L and ΔP2,L values, which were associated with the presence of silicotic granulomas, alveolar collapse, thickening of alveolar septa, infiltration of inflammatory cells in lung parenchyma, and collagen fiber deposition. The increase in airway resistive pressure (ΔP1,L) may have been due to the greater number of cells in the bronchi associated with areas of lumen obstruction (Faffe et al, 2001; Borges et al, 2002; Maron-Gutierrez et al, 2011; Lopes-Pacheco et al, 2013; Cruz et al, 2016). Bosutinib decreased both Est,L and ΔP2,L likely due to reduction in alveolar collapse, interstitial edema, thickening of alveolar septa, cell infiltration and collagen fiber content, whereas Δ P 1,L did not change after therapy which may be attributed to the presence of the silica particle adhere to the airway and airway hyperreactivity (Ferreira et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, points falling on collapsed or normal pulmonary areas were counted and divided by the total number of points in each microscopic field (Weibel, 1990). Additionally, the fraction area of granuloma was determined in 20 random non-coincident microscopic fields, at 400× magnification (Maron-Gutierrez et al, 2011; Lopes-Pacheco et al, 2013). Total cells and mononuclear and polymorphonuclear cell subpopulations in the alveolar septa and granuloma tissue were evaluated at 1,000× magnification in 10 random microscopic fields.…”

Section: Methodsmentioning

confidence: 99%

“…Sample size calculation for testing the primary hypothesis (static lung elastance increased in the SIL group) was based on previous measurements (Lopes-Pacheco et al, 2013; Cruz et al, 2016) and on pilot studies. A sample size of 8 animals per group (considering one animal as dropout) was deemed to provide the appropriate power (1–β = 0.8) to identify significant (α = 0.05) differences in static lung elastance between SIL animals and those treated with BOS, with an effect size d = 1.9, a two-sided test, and a sample size ratio = 1 (G * Power 3.1.9.2, University of Düsseldorf, Germany).…”

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

et al. 2017

View full text Add to dashboard Cite

Silicosis is an occupational lung disease for which no effective therapy exists. We hypothesized that bosutinib, a tyrosine kinase inhibitor, might ameliorate inflammatory responses, attenuate pulmonary fibrosis, and thus improve lung function in experimental silicosis. For this purpose, we investigated the potential efficacy of bosutinib in the treatment of experimental silicosis induced in C57BL/6 mice by intratracheal administration of silica particles. After 15 days, once disease was established, animals were randomly assigned to receive DMSO or bosutinib (1 mg/kg/dose in 0.1 mL 1% DMSO) by oral gavage, twice daily for 14 days. On day 30, lung mechanics and morphometry, total and differential cell count in alveolar septa and granuloma, levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-4, transforming growth factor (TGF)-β, and vascular endothelial growth factor in lung homogenate, M1 and M2 macrophages, total leukocytes, and T cells in BALF, lymph nodes, and thymus, and collagen fiber content in alveolar septa and granuloma were analyzed. In a separate in vitro experiment, RAW264.7 macrophages were exposed to silica particles in the presence or absence of bosutinib. After 24 h, gene expressions of arginase-1, IL-10, IL-12, inducible nitric oxide synthase (iNOS), metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase (TIMP)-1, and caspase-3 were evaluated. In vivo, in silicotic animals, bosutinib, compared to DMSO, decreased: (1) fraction area of collapsed alveoli, (2) size and number of granulomas, and mononuclear cell granuloma infiltration; (3) IL-1β, TNF-α, IFN-γ, and TGF-β levels in lung homogenates, (4) collagen fiber content in lung parenchyma, and (5) viscoelastic pressure and static lung elastance. Bosutinib also reduced M1 cell counts while increasing M2 macrophage population in both lung parenchyma and granulomas. Total leukocyte, regulatory T, CD4+, and CD8+ cell counts in the lung-draining lymph nodes also decreased with bosutinib therapy without affecting thymus cellularity. In vitro, bosutinib led to a decrease in IL-12 and iNOS and increase in IL-10, arginase-1, MMP-9, and TIMP-1. In conclusion, in the current model of silicosis, bosutinib therapy yielded beneficial effects on lung inflammation and remodeling, therefore resulting in lung mechanics improvement. Bosutinib may hold promise for silicosis; however, further studies are required.

show abstract

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

et al. 2017

View full text Add to dashboard Cite

show abstract

“…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 . 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 . However, the impact of multiple‐dose cell therapy regimens in experimental allergic asthma remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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

Castro

Kitoko

Xisto

et al. 2019

Stem Cells Translational Medicine

Self Cite

View full text Add to dashboard Cite

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

show abstract

Trimetazidine, a metabolic modulator, attenuates silica‐induced pulmonary fibrosis and decreases lactate levels and LDH activity in rats

Abdelrahman

Shawky

2022

J Biochem & Molecular Tox

View full text Add to dashboard Cite

Pulmonary fibrosis has been recently linked to metabolic dysregulation. Silicainduced pulmonary fibrosis in rats was employed by the current study to explore the effects of trimetazidine (a metabolic modulator-antianginal drug; TMZ) on silicainduced pulmonary fibrosis. Pulmonary fibrosis was induced by intranasal instillation of silica (50 mg/100 µl/rat) in TMZ versus vehicle-treated rats. Body weights of rats, weights of lungs, and wet-to-dry lung weights were determined. Various parameters were also measured in serum, bronchoalveolar lavage fluid (BALF) in addition to lung tissue homogenates. Moreover, histopathological examination of sectioned lungs for lesion score and distribution and histochemical detection of myeloperoxidase (MPO) in lung tissues were also performed. No significant differences were observed in body weight gains, lung coefficients, lung weights, and wet-to-dry lung weight in silica versus control rats. Elevated lactate levels in serum and lung homogenates were significantly attenuated by TMZ. In addition, lactate dehydrogenase activity, transforming growth factor-β, and total proteins in BALF were significantly normalized with TMZ. Moreover, TMZ significantly increased reduced glutathione and adenosine triphosphate levels and decreased nitrate/nitrite and hydroxyproline content in lungs of silica-treated rats. Histopathological examination of lungs revealed more than 56% reduction in lesion score and distribution by TMZ. MPO expression in lungs of silica-treated rats was also significantly attenuated by TMZ.TMZ attenuates silica-induced pulmonary fibrosis, an effect that could be mediated by suppressing anaerobic glycolysis-induced excessive lactate production. Regulation of oxidative stress could also play a role in TMZ-promoted protective effects.

show abstract

Repeated Administration of Bone Marrow-Derived Cells Prevents Disease Progression in Experimental Silicosis

Cited by 31 publications

References 34 publications

Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

Bosutinib Therapy Ameliorates Lung Inflammation and Fibrosis in Experimental Silicosis

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

Trimetazidine, a metabolic modulator, attenuates silica‐induced pulmonary fibrosis and decreases lactate levels and LDH activity in rats

Contact Info

Product

Resources

About