Abstract
We sought to assess whether the effects of mesenchymal stromal cells (MSC) on lung inflammation and remodeling in experimental emphysema would differ according to MSC source and administration route. Emphysema was induced in C57BL/6 mice by intratracheal (IT) administration of porcine pancreatic elastase (0.1 UI) weekly for 1 month. After the last elastase instillation, saline or MSCs (1×105), isolated from either mouse bone marrow (BM), adipose tissue (AD) or lung tissue (L), were administered intravenously (IV) or IT. After 1 week, mice were euthanized. Regardless of administration route, MSCs from each source yielded: 1) decreased mean linear intercept, neutrophil infiltration, and cell apoptosis; 2) increased elastic fiber content; 3) reduced alveolar epithelial and endothelial cell damage; and 4) decreased keratinocyte-derived chemokine (KC, a mouse analog of interleukin-8) and transforming growth factor-β levels in lung tissue. In contrast with IV, IT MSC administration further reduced alveolar hyperinflation (BM-MSC) and collagen fiber content (BM-MSC and L-MSC). Intravenous administration of BM- and AD-MSCs reduced the number of M1 macrophages and pulmonary hypertension on echocardiography, while increasing vascular endothelial growth factor. Only BM-MSCs (IV > IT) increased the number of M2 macrophages. In conclusion, different MSC sources and administration routes variably reduced elastase-induced lung damage, but IV administration of BM-MSCs resulted in better cardiovascular function and change of the macrophage phenotype from M1 to M2.
Highlights
Emphysema, a key feature of chronic obstructive pulmonary disease (COPD), is characterized by the enlargement of air spaces accompanied by destruction of parenchymal structure and impaired pulmonary regeneration [1]
The aims of the present study were to: (a) comparatively assess the extent to which different sources of mesenchymal stem cells (MSC) are able to decrease inflammation and promote alveolar epithelium and endothelium repair, thereby improving lung function in elastase-induced emphysema in mice, (b) investigate whether IV versus IT administration of MSCs influences their effectiveness on lung inflammation and remodeling, and (c) evaluate the effects of IV versus IT delivery of the aforementioned different sources of MSCs on elastase-induced changes in cardiac function
Whenever gross remnants persisted after collagenase digestion were allowed to settle for 1 to 3 minutes, and the supernatant was transferred to a new tube containing fresh medium and centrifuged at 400 g for 10 minutes at room temperature (RT)
Summary
A key feature of chronic obstructive pulmonary disease (COPD), is characterized by the enlargement of air spaces accompanied by destruction of parenchymal structure and impaired pulmonary regeneration [1]. One potential therapeutic approach for emphysema has focused on inducing lung repair and regeneration and/or decreasing chronic inflammation by administering mesenchymal stem (stromal). While IV injection of MSCs is generally utilized in preclinical studies of experimental emphysema, due to ease of administration and subsequent wide biodistribution [4,6,11,12], intratracheal (IT) administration of MSCs attenuates lung damage [13,14]. No definite conclusion has been reached regarding the optimal administration route of MSCs in experimental emphysema. The aims of the present study were to: (a) comparatively assess the extent to which different sources (bone marrow, adipose, or lung tissue) of MSCs are able to decrease inflammation and promote alveolar epithelium and endothelium repair, thereby improving lung function in elastase-induced emphysema in mice, (b) investigate whether IV versus IT administration of MSCs influences their effectiveness on lung inflammation and remodeling, and (c) evaluate the effects of IV versus IT delivery of the aforementioned different sources of MSCs on elastase (emphysema)-induced changes in cardiac function
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