Therapeutic effects of bone marrow-derived mononuclear cells from healthy or silicotic donors on recipient silicosis mice

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Abstract

Background

Administration of bone marrow mononuclear cells (BMMCs) modulates lung inflammation and fibrosis in experimental silicosis. However, no studies have evaluated whether silicosis affects the efficacy of autologous BMMCs treatment. We hypothesized that BMMCs obtained from healthy or silicotic mice may improve lung function, but they might affect the inflammatory and fibrotic processes differently in experimental silicosis.

Methods

C57BL/6 mice were randomly divided into control (C) and silicosis (SIL) groups. Mice in the SIL group were instilled with silica particles intratracheally; the C animals received saline using the same protocol. On day 15, the animals were treated with saline (Sal) or BMMCs (2 × 10 ⁶ cells) from healthy (BMMC-healthy) and silicotic (BMMC-sil) donors. Lung mechanics were measured, and lungs were collected for histology and molecular biology analysis.

Results

BMMCs obtained from healthy and silicotic donors presented similar percentages of cell populations. ^99mTc-BMMCs tracking revealed preferential migration of cells to the liver, and only a few GFP ⁺ BMMCs were observed in lung tissue 24 h after treatment, regardless of donor type. Both the SIL-BMMC-healthy and SIL-BMMC-sil groups showed improvement in lung function, a reduction in the fractional area of granuloma, and a decrease in the number of mononuclear and apoptotic cells in lung parenchyma. In addition, the number of F4/80 ⁺ macrophages, the levels of interleukin-1 beta and transforming growth factor beta, and collagen fiber content in granuloma were reduced in SIL-BMMC-healthy mice, whereas mRNA expression of MMP-9 and procollagen I and III was reduced in the SIL-BMMC-sil group.

Conclusions

Administration of BMMCs from healthy and silicotic donors reduced lung inflammation and fibrosis, thus improving lung function. In addition, BMMC-healthy exhibited a greater improvement in lung morpho-functional changes in murine model of silicosis.

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Most cited references 35

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Silica binding and toxicity in alveolar macrophages.

Tejender S. Thakur, Andrij Holian, Raymond Hamilton (2008)

Inhalation of the crystalline form of silica is associated with a variety of pathologies, from acute lung inflammation to silicosis, in addition to autoimmune disorders and cancer. Basic science investigators looking at the mechanisms involved with the earliest initiators of disease are focused on how the alveolar macrophage interacts with the inhaled silica particle and the consequences of silica-induced toxicity on the cellular level. Based on experimental results, several rationales have been developed for exactly how crystalline silica particles are toxic to the macrophage cell that is functionally responsible for clearance of the foreign particle. For example, silica is capable of producing reactive oxygen species (ROS) either directly (on the particle surface) or indirectly (produced by the cell as a response to silica), triggering cell-signaling pathways initiating cytokine release and apoptosis. With murine macrophages, reactive nitrogen species are produced in the initial respiratory burst in addition to ROS. An alternative explanation for silica toxicity includes lysosomal permeability, by which silica disrupts the normal internalization process leading to cytokine release and cell death. Still other research has focused on the cell surface receptors (collectively known as scavenger receptors) involved in silica binding and internalization. The silica-induced cytokine release and apoptosis are described as the function of receptor-mediated signaling rather than free radical damage. Current research ideas on silica toxicity and binding in the alveolar macrophage are reviewed and discussed.

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Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression.

C. Ramos, M. Montano, J. Garcia-Alvarez … (2001)

Idiopathic pulmonary fibrosis (IPF) is a chronic lung disorder characterized by fibroblast proliferation and extracellular matrix accumulation. However, studies on fibroblast growth rate and collagen synthesis have given contradictory results. Here we analyzed fibroblast growth rate by a formazan-based chromogenic assay; fibroblast apoptosis by in situ end labeling (ISEL) and propidium iodide staining; percent of alpha-smooth muscle actin (alpha-SMA) positive cells by fluorescence-activated cell sorter; and alpha1-(I) collagen, transforming growth factor (TGF)-beta1, collagenase-1, gelatinases A and B, and tissue inhibitor of metalloproteinase (TIMP)-1, -2, -3, and -4 expression by reverse transcriptase/polymerase chain reaction in fibroblasts derived from IPF and control lungs. Growth rate was significantly lower in IPF fibroblasts compared with controls (13.3 +/- 38.5% versus 294.6 +/- 57%, P < 0.0001 at 13 d). Conversely, a significantly higher percentage of apoptotic cells was observed in IPF-derived fibroblasts (ISEL: 31.9 +/- 7.0% versus 15.5 +/- 7.6% from controls; P < 0.008). alpha-SMA analysis revealed a significantly higher percentage of myofibroblasts in IPF samples (62.8 +/- 25.2% versus 14.8 +/- 11.7% from controls; P < 0.01). IPF fibroblasts were characterized by an increase in pro-alpha1-(I) collagen, TGF-beta1, gelatinase B, and all TIMPs' gene expression, whereas collagenase-1 and gelatinase A expression showed no differences. These results suggest that fibroblasts from IPF exhibit a profibrotic secretory phenotype, with lower growth rate and increased spontaneous apoptosis.

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Silicosis: a review.

Michael Greenberg, Javier Waksman, John Curtis (2007)

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Author and article information

Contributors

Helena D’Anunciação de Oliveira: hdanunciacao@gmail.com

Elga Bernardo Bandeira de Melo: elgabandeira@gmail.com

Johnatas Dutra Silva: johnatasdutra@gmail.com

Jamil Zola Kitoko: jamilkitoko@hotmail.com

Bianca Gutfilen: bianca.gutfilen@gmail.com

Thiago Barboza: drthiagobarboza@gmail.com

Sergio Augusto Lopes de Souza: sergioalsouza@gmail.com

Christina Maeda Takiya: cmtakiya@gmail.com

Patricia Rieken Macedo Rocco: prmrocco@biof.ufrj.br

Miquéias Lopes-Pacheco: mlopes0811@gmail.com

Marcelo Marcos Morales: mmorales@biof.ufrj.br

Journal

Journal ID (nlm-ta): Stem Cell Res Ther

Journal ID (iso-abbrev): Stem Cell Res Ther

Title: Stem Cell Research & Therapy

Publisher: BioMed Central (London )

ISSN (Electronic): 1757-6512

Publication date (Electronic): 10 November 2017

Publication date PMC-release: 10 November 2017

Publication date Collection: 2017

Volume: 8

Electronic Location Identifier: 259

Affiliations

[1 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Laboratory of Cellular and Molecular Physiology, Carlos Chagas Filho Institute of Biophysics, , Federal University of Rio de Janeiro, ; Rio de Janeiro, Brazil

[2 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Laboratory of Pulmonary Investigation, Carlos Chagas Filho Institute of Biophysics, , Federal University of Rio de Janeiro, ; Rio de Janeiro, Brazil

[3 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Department of Radiology, School of Medicine, , Federal University of Rio de Janeiro, ; Rio de Janeiro, Brazil

[4 ]ISNI 0000 0001 2294 473X, GRID grid.8536.8, Laboratory of Cellular Pathology, Carlos Chagas Filho Institute of Biophysics, , Federal University of Rio de Janeiro, ; Rio de Janeiro, Brazil

Article

Publisher ID: 699

DOI: 10.1186/s13287-017-0699-7

PMC ID: 5681761

PubMed ID: 29126438

SO-VID: ebadd6a4-044d-4156-99d5-4a2d0210e979

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 13 June 2017

Date revision received : 27 September 2017

Date accepted : 16 October 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100003593, Conselho Nacional de Desenvolvimento Científico e Tecnológico;

Funded by: Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (BR)

Funded by: FundRef http://dx.doi.org/10.13039/501100002322, Coordenação de Aperfeiçoamento de Pessoal de Nível Superior;

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ScienceOpen disciplines: Molecular medicine

Keywords: silicosis,cell therapy,bone marrow mononuclear cells,lung fibrosis,inflammation

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ScienceOpen disciplines: Molecular medicine

Keywords: silicosis, cell therapy, bone marrow mononuclear cells, lung fibrosis, inflammation

Therapeutic effects of bone marrow-derived mononuclear cells from healthy or silicotic donors on recipient silicosis mice

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Abstract

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Conclusions

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Biomarkers for Inflammatory Lung Disease

Most cited references 35

Silica binding and toxicity in alveolar macrophages.

Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate, apoptosis, and tissue inhibitor of metalloproteinases expression.

Silicosis: a review.

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