Expanded endothelial progenitor cells mitigate lung injury in septic mice

Submitted by sandra infurna ([email protected]) on 2016-03-22T16:54:16Z No. of bitstreams: 1 tataina_gutierrez_etal_IOC_2015.pdf: 942633 bytes, checksum: 816a2181c5a43c3038245cde47196e7a (MD5)Approved for entry into archive by sandra infurna ([email protected]) on 2016-03-22T17:10:21Z (GMT) No. of bitstreams: 1 tataina_gutierrez_etal_IOC_2015.pdf: 942633 bytes, checksum: 816a2181c5a43c3038245cde47196e7a (MD5)Made available in DSpace on 2016-03-22T17:10:21Z (GMT). No. of bitstreams: 1 tataina_gutierrez_etal_IOC_2015.pdf: 942633 bytes, checksum: 816a2181c5a43c3038245cde47196e7a (MD5) Previous issue date: 2015Technische Universität Dresden. University Hospital Dresden. Department of Anesthesiology and Intensive Care Medicine. Dredesm Germany / Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho (IBCCF). Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho (IBCCF). Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho (IBCCF). Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, BrasilUniversidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho (IBCCF). Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, BrasilPontifícia Universidade Católica do Paraná. Centro de Tecnologia Celular. Curitiba, PR, Brasil.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho (IBCCF). Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, BrasilUniversidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho (IBCCF). Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, BrasilPontifícia Universidade Católica do Paraná. Centro de Tecnologia Celular. Curitiba, PR, Brasil.Technische Universität Dresden. University Hospital Dresden. Department of Anesthesiology and Intensive Care Medicine. Dredesm Germany.Universidade Federal do Rio de Janeiro. Centro de Ciências da Saúde. Instituto de Biofísica Carlos Chagas Filho (IBCCF). Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Endothelial progenitor cells (EPCs) improve survival and reduce organ failure in cecal ligation and puncture-induced sepsis; however, expanded EPCs may represent an even better approach for vascular repair. To date, no study has compared the effects of non-expanded EPCs (EPC-NEXP) with those of expanded EPCs (EPC-EXP) and mesenchymal stromal cells of human (MSC-HUMAN) and mouse (MSC-MICE) origin in experimental sepsis. One day after cecal ligation and puncture sepsis induction, BALB/c mice were randomized to receive saline, EPC-EXP, EPC-NEXP, MSC-HUMAN or MSC-MICE (1 × 105 ) intravenously. EPC-EXP, EPC-NEXP, MSC-HUMAN, and MSC-MICE displayed differences in phenotypic characterization. On days 1 and 3, cecal ligation and puncture mice showed decreased survival rate, and increased elastance, diffuse alveolar damage, and levels of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor-α, vascular endothelial growth factor, and platelet-derived growth factor in lung tissue. EPC-EXP and MSC-HUMAN had reduced elastance, diffuse alveolar damage, and platelet-derived growth factor compared to no-cell treatment. Tumor necrosis factor-α levels decreased in the EPC-EXP, MSC-HUMAN, and MSC-MICE groups. IL-1β levels decreased in the EPC-EXP group, while IL-10 decreased in the MSC-MICE. IL-6 levels decreased both in the EPC-EXP and MSC-MICE groups. Vascular endothelial growth factor levels were reduced regardless of therapy. In conclusion, EPC-EXP and MSC-HUMAN yielded better lung function and reduced histologic damage in septic mice

Insult-dependent effect of bone marrow cell therapy on inflammatory response in a murine model of extrapulmonary acute respiratory distress syndrome

Made available in DSpace on 2015-09-21T17:25:45Z (GMT). No. of bitstreams: 2 license.txt: 1914 bytes, checksum: 7d48279ffeed55da8dfe2f8e81f3b81f (MD5) edson_assis_etal_IOC_2013.pdf: 2494283 bytes, checksum: e24e1c4238c815ae4471a81396a32fda (MD5) Previous issue date: 2013Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Laboratório de Fisiologia Molecular e Celular. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Li Ka Shing Knowledge Institute of St. Michael's Hospital. The Keenan Research Centre; Toronto, Ontario, Canada / University of Toronto. St. Michael’s Hospital. Interdepartmental Division of Critical Care. Toronto, Ontario, Canada.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Fisiologia Molecular e Celular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Introduction: Administration of bone marrow-derived cells produces beneficial effects in experimental extrapulmonary acute respiratory distress syndrome (ARDS). However, there are controversies regarding the effects of timing of cell administration and initial insult severity on inflammatory response. We evaluated the effects of bone marrow-derived mononuclear cells (BMDMC) in two models of extrapulmonary ARDS once lung morphofunctional changes had already been installed. Methods: BALB/c mice received lipopolysaccharide (LPS) intraperitoneally (5 mg/kg in 0.5 ml saline) or underwent cecal ligation and puncture (CLP). Control mice received saline intraperitoneally (0.5 ml) or underwent sham surgery. At 24 hours, groups were further randomized to receive saline or BMDMC (2 × 106) intravenously. Lung mechanics, histology, and humoral and cellular parameters of lung inflammation and remodeling were analyzed 1, 3 and 7 days after ARDS induction. Results: BMDMC therapy led to improved survival in the CLP group, reduced lung elastance, alveolar collapse, tissue and bronchoalveolar lavage fluid cellularity, collagen fiber content, and interleukin-1β and increased chemokine (keratinocyte-derived chemokine and monocyte chemotactic protein-1) expression in lung tissue regardless of the experimental ARDS model. Intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression in lung tissue increased after cell therapy depending on the insult (LPS or CLP). Conclusions: BMDMC therapy at day 1 successfully reduced lung inflammation and remodeling, thus contributing to improvement of lung mechanics in both extrapulmonary ARDS models. Nevertheless, the different inflammatory responses induced by LPS and CLP resulted in distinct effects of BMDMC therapy. These data may be useful in the clinical setting, as they suggest that the type of initial insult plays a key role in the outcome of treatment

Human adipose tissue mesenchymal stromal cells and their extracellular vesicles act differentially on lung mechanics and inflammation in experimental allergic asthma

Abstract Background Asthma is a chronic inflammatory disease that can be difficult to treat due to its complex pathophysiology. Most current drugs focus on controlling the inflammatory process, but are unable to revert the changes of tissue remodeling. Human mesenchymal stromal cells (MSCs) are effective at reducing inflammation and tissue remodeling; nevertheless, no study has evaluated the therapeutic effects of extracellular vesicles (EVs) obtained from human adipose tissue-derived MSCs (AD-MSC) on established airway remodeling in experimental allergic asthma. Methods C57BL/6 female mice were sensitized and challenged with ovalbumin (OVA). Control (CTRL) animals received saline solution using the same protocol. One day after the last challenge, each group received saline, 105 human AD-MSCs, or EVs (released by 105 AD-MSCs). Seven days after treatment, animals were anesthetized for lung function assessment and subsequently euthanized. Bronchoalveolar lavage fluid (BALF), lungs, thymus, and mediastinal lymph nodes were harvested for analysis of inflammation. Collagen fiber content of airways and lung parenchyma were also evaluated. Results In OVA animals, AD-MSCs and EVs acted differently on static lung elastance and on BALF regulatory T cells, CD3+CD4+ T cells, and pro-inflammatory mediators (interleukin [IL]-4, IL-5, IL-13, and eotaxin), but similarly reduced eosinophils in lung tissue, collagen fiber content in airways and lung parenchyma, levels of transforming growth factor-β in lung tissue, and CD3+CD4+ T cell counts in the thymus. No significant changes were observed in total cell count or percentage of CD3+CD4+ T cells in the mediastinal lymph nodes. Conclusions In this immunocompetent mouse model of allergic asthma, human AD-MSCs and EVs effectively reduced eosinophil counts in lung tissue and BALF and modulated airway remodeling, but their effects on T cells differed in lung and thymus. EVs may hold promise for asthma; however, further studies are required to elucidate the different mechanisms of action of AD-MSCs versus their EVs

Eicosapentaenoic Acid Enhances the Effects of Mesenchymal Stromal Cell Therapy in Experimental Allergic Asthma

Submitted by Sandra Infurna ([email protected]) on 2018-09-13T14:47:56Z No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2018.pdf: 1164827 bytes, checksum: 7df1542cb297a8e9b5dbb67dfca081b1 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-09-13T15:12:40Z (GMT) No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2018.pdf: 1164827 bytes, checksum: 7df1542cb297a8e9b5dbb67dfca081b1 (MD5)Made available in DSpace on 2018-09-13T15:12:40Z (GMT). No. of bitstreams: 1 cassiano_albuquerque_etal_IOC_2018.pdf: 1164827 bytes, checksum: 7df1542cb297a8e9b5dbb67dfca081b1 (MD5) Previous issue date: 2018Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil / University of Vermont. College of Medicine. Department of Medicine. Burlington, VT, USA.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil / / Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de InvestigaçRio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Fisiologia Molecular e Celular. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Escola de Farmácia. Laboratório de Bacteriologia Clínica e Imunológica. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil.Universidade Federal do Estado do Rio de Janeiro. Instituto Biomédico. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Imunofarmacologia. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Escola de Farmácia. Laboratório de Bacteriologia Clínica e Imunologia. Rio de Janeiro, RJ, Brasil.University of Vermont. College of Medicine. Department of Medicine. Burlington, VT, USA.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Fisiologia Molecular e Celular. Rio de Janeiro, RJ, Brasil / Instituto Nacional de Ciência e Tecnologia para Medicina Regenerativa. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Inflamação. Rio de Janeiro, RJ, Brasil.Universidade Federal do Rio de Janeiro. Instituto de Biofísica Carlos Chagas Filho. Laboratório de Investigação Pulmonar. Rio de Janeiro, RJ, Brasil / Instituto Nacional de Ciência e Tecnologia para Medicina Regenerativa. Rio de Janeiro, RJ, Brasil.Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC)-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA) potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM) extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF), thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D1 (RvD1), prostaglandin E2 (PGE2), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated in vitro. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes), and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD1, PGE2, IL-10, and TGF-β), modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel strategy to potentiate MSCs effects

Eicosapentaenoic Acid Enhances the Effects of Mesenchymal Stromal Cell Therapy in Experimental Allergic Asthma

Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC)-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA) potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM) extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF), thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D1 (RvD1), prostaglandin E2 (PGE2), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated in vitro. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes), and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD1, PGE2, IL-10, and TGF-β), modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel strategy to potentiate MSCs effects

Image_1_Eicosapentaenoic Acid Enhances the Effects of Mesenchymal Stromal Cell Therapy in Experimental Allergic Asthma.PDF

<p>Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC)-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA) potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM) extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF), thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D₁ (RvD₁), prostaglandin E₂ (PGE₂), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated in vitro. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes), and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD₁, PGE₂, IL-10, and TGF-β), modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel strategy to potentiate MSCs effects.</p

Image_5_Eicosapentaenoic Acid Enhances the Effects of Mesenchymal Stromal Cell Therapy in Experimental Allergic Asthma.PDF

<p>Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC)-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA) potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM) extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF), thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D₁ (RvD₁), prostaglandin E₂ (PGE₂), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated in vitro. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes), and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD₁, PGE₂, IL-10, and TGF-β), modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel strategy to potentiate MSCs effects.</p

Image_3_Eicosapentaenoic Acid Enhances the Effects of Mesenchymal Stromal Cell Therapy in Experimental Allergic Asthma.PDF

<p>Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC)-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA) potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM) extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF), thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D₁ (RvD₁), prostaglandin E₂ (PGE₂), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated in vitro. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes), and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD₁, PGE₂, IL-10, and TGF-β), modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel strategy to potentiate MSCs effects.</p

Image_2_Eicosapentaenoic Acid Enhances the Effects of Mesenchymal Stromal Cell Therapy in Experimental Allergic Asthma.PDF

<p>Asthma is characterized by chronic lung inflammation and airway hyperresponsiveness. Despite recent advances in the understanding of its pathophysiology, asthma remains a major public health problem and, at present, there are no effective interventions capable of reversing airway remodeling. Mesenchymal stromal cell (MSC)-based therapy mitigates lung inflammation in experimental allergic asthma; however, its ability to reduce airway remodeling is limited. We aimed to investigate whether pre-treatment with eicosapentaenoic acid (EPA) potentiates the therapeutic properties of MSCs in experimental allergic asthma. Seventy-two C57BL/6 mice were used. House dust mite (HDM) extract was intranasally administered to induce severe allergic asthma in mice. Unstimulated or EPA-stimulated MSCs were administered intratracheally 24 h after final HDM challenge. Lung mechanics, histology, protein levels of biomarkers, and cellularity in bronchoalveolar lavage fluid (BALF), thymus, lymph nodes, and bone marrow were analyzed. Furthermore, the effects of EPA on lipid body formation and secretion of resolvin-D₁ (RvD₁), prostaglandin E₂ (PGE₂), interleukin (IL)-10, and transforming growth factor (TGF)-β1 by MSCs were evaluated in vitro. EPA-stimulated MSCs, compared to unstimulated MSCs, yielded greater therapeutic effects by further reducing bronchoconstriction, alveolar collapse, total cell counts (in BALF, bone marrow, and lymph nodes), and collagen fiber content in airways, while increasing IL-10 levels in BALF and M2 macrophage counts in lungs. In conclusion, EPA potentiated MSC-based therapy in experimental allergic asthma, leading to increased secretion of pro-resolution and anti-inflammatory mediators (RvD₁, PGE₂, IL-10, and TGF-β), modulation of macrophages toward an anti-inflammatory phenotype, and reduction in the remodeling process. Taken together, these modifications may explain the greater improvement in lung mechanics obtained. This may be a promising novel strategy to potentiate MSCs effects.</p