Abstract
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.
Highlights
Allergic asthma is a chronic inflammatory disease characterized by airflow obstruction and airway hyperresponsiveness driven by immune responses to allergens [1]
The present study aimed to investigate whether exposure of Mesenchymal stromal cell (MSC) to eicosapentaenoic acid (EPA) could potentiate their effects in experimental allergic asthma by enabling them to further reduce inflammation and airway remodeling
EPA-stimulated MSCs produced increased levels of IL-10 and transforming growth factor (TGF)-β compared to unstimulated MSCs (14- and 1.56-fold increase, respectively) (Figures 1E,F)
Summary
Allergic asthma is a chronic inflammatory disease characterized by airflow obstruction and airway hyperresponsiveness driven by immune responses to allergens [1]. Systemic or intratracheal administration of MSCs derived from bone marrow, adipose, and other tissues has been shown to significantly reduce inflammation and improve airway hyperresponsiveness in different models of allergic asthma [6, 9,10,11]. Their ability to reverse airways remodeling is only marginal [7, 12, 13]. Recent studies have tried to potentiate the therapeutic effects of MSCs by using physical, biological, and/or chemical pre-stimulation to enhance cell survival and regenerative properties [14,15,16,17]
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