Abstract
BackgroundA single administration of mesenchymal stromal cells (MSCs) has been shown to reduce lung inflammation in experimental elastase-induced emphysema; however, effects were limited in terms of lung-tissue repair and cardiac function improvement. We hypothesized that two doses of MSCs could induce further lung and cardiovascular repair by mitigating inflammation and remodeling in a model of emphysema induced by multiple elastase instillations. We aimed to comparatively investigate the effects of one versus two doses of MSCs, administered 1 week apart, in a murine model of elastase-induced emphysema.MethodsC57BL/6 mice were randomly divided into control (CTRL) and emphysema (E) groups. Mice in the E group received porcine pancreatic elastase (0.2 IU, 50 μL) intratracheally once weekly for four consecutive weeks; the CTRL animals received sterile saline (50 μL) using the same protocol. Three hours after the last instillation, the E group was further randomized to receive either saline (SAL) or murine MSCs (105 cells) intratracheally, in one or two doses (1 week apart). Fourteen days later, mice were euthanized, and all data analyzed.ResultsBoth one and two doses of MSCs improved lung mechanics, reducing keratinocyte-derived chemokine and transforming growth factor-β levels in lung homogenates, total cell and macrophage counts in bronchoalveolar lavage fluid (BALF), and collagen fiber content in airways and blood vessels, as well as increasing vascular endothelial growth factor in lung homogenates and elastic fiber content in lung parenchyma. However, only the two-dose group exhibited reductions in tumor necrosis factor-α in lung tissue, BALF neutrophil and lymphocyte count, thymus weight, and total cellularity, as well as CD8+ cell counts and cervical lymph node CD4+ and CD8+ T cell counts, as well as further increased elastic fiber content in the lung parenchyma and reduced severity of pulmonary arterial hypertension.ConclusionsTwo doses of MSCs enhanced lung repair and improvement in cardiac function, while inducing T cell immunosuppression, mainly of CD8+ cells, in elastase-induced emphysema.
Highlights
A single administration of mesenchymal stromal cells (MSCs) has been shown to reduce lung inflammation in experimental elastase-induced emphysema; effects were limited in terms of lungtissue repair and cardiac function improvement
In a previous study conducted by our group, MSCs mitigated lung damage and improved cardiac function in experimental emphysema induced by multiple instillations of elastase; the effects were only modest in terms of lung-tissue repair [10]
Administration of one and two doses of MSCs modulated protein levels of mediators, but a two-dose regimen further mitigated inflammation and morphological changes in the lungs Initially, we investigated the impact of one vs. two doses of MSC-based therapy on inflammation in the lung, as it is the primary tissue injured in emphysema [3, 5, 10]
Summary
A single administration of mesenchymal stromal cells (MSCs) has been shown to reduce lung inflammation in experimental elastase-induced emphysema; effects were limited in terms of lungtissue repair and cardiac function improvement. We hypothesized that two doses of MSCs could induce further lung and cardiovascular repair by mitigating inflammation and remodeling in a model of emphysema induced by multiple elastase instillations. Several studies have demonstrated that mesenchymal stromal cells (MSCs) secrete paracrine factors that can modulate inflammation and remodeling in different experimental models of emphysema [5,6,7,8,9]. In a previous study conducted by our group, MSCs mitigated lung damage and improved cardiac function in experimental emphysema induced by multiple instillations of elastase; the effects were only modest in terms of lung-tissue repair [10]. A single dose of MSCs has been shown to reduce lung inflammation and fibrosis in experimental emphysema [6, 8, 10], more than one dose of MSCs may be required to induce efficient repair of lung and heart damage
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