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

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.

Serum from Asthmatic Mice Potentiates the Therapeutic Effects of Mesenchymal Stromal Cells in Experimental Allergic Asthma

“…Alternatively, HDM affects ∼85% of humans with asthma worldwide, and the HDM model resembles crucial features of chronic human asthma, such as local sensitization in the lungs and activation of complex inflammatory pathways, which involve the structural cells of the lung . Another advantage of the model used herein is that only 3 weeks are needed to observe both the inflammation and remodeling characteristic of chronic asthma . MSCs were extracted from bone marrow, since these cells exerted greater immunomodulatory responses compared with MSCs from other sources in previous studies by our group .…”

“…Prophylactic administration of MSCs also mitigated the inflammatory process in asthma models using clinically relevant allergens, including ragweed, Aspergillus hyphal extract, and HDM extract . However, repair of injured tissue and reversal of the remodeling process, especially in the airways, were limited when MSCs were administered after lung function had been impaired and inflammation and remodeling had already been established . One potential explanation is that the lung inflammatory environment after antigen challenge in sensitized mice somehow alters MSCs activity.…”

“…Mice were randomly assigned into two groups. In the HDM group, mice were challenged by intranasal instillation of 25 μg of protein (25 μl) presented in HDM extract ( Dermatophagoides pteronyssinus ; Greer Laboratories, Lenoir, NC), 3 days weekly for 3 consecutive weeks . In the control group (CTRL), the vehicle (phosphate‐buffered saline [PBS] 1×) was administered using the same protocol.…”

“…BALF and bone marrow cells were pelleted onto glass slides by cytocentrifugation and stained by the May–Grünwald–Giemsa method. Differential cell counts were performed as described elsewhere .…”

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

“…For quantification of α‐smooth muscle actin (α‐actin), immunohistochemistry was performed using a monoclonal antibody (α‐actin; Dako, Carpinteria, California) at a 1:500 dilution. Analysis was performed by applying the point‐counting technique . Using a 121‐point grid, the volume proportion of α‐actin was calculated as a ratio of points falling on actin‐stained vs non‐stained tissue.…”