EPO modified MSCs can inhibit asthmatic airway remodeling in an animal model.

There was no effective measures can be obtained at present to reverse or prevent airway remodeling. We investigated the therapeutic effect of Erythropoietin (EPO) gene modified mesenchymal stem cells (MSCs) on asthmatic airway remodeling and the possible underlied molecular mechanisms. EPO gene was transfected into MSCs via lentivirus vector. The transfected cells (EPO-MSCs) were identified by flow cytometry and the EPO secreting function was detected by PCR and Western blot. MSCs or EPO-MSCs were administrated to albumin (OVA)-induced chronic asthmatic mouse model via tail veins. The asthmatic phenotype was analyzed. Number of cells in bronchoalveolar lavage fluid (BALF) was counted using a hemocytometer. Histological findings of airways were evaluated by microscopic examination. The concentrations of interleukin 4(IL-4), interleukin 5(IL-5), and interleukin 13(IL-13) in lung homogenate were determined by ELISA. The activation state of transforming growth factor-ß 1 (TGF-ß1), Transforming growth factor beta-activated kinase 1 (TAK1), and p38 Mitogen Activated Protein Kinase (p38MAPK) signaling was detected by Real-Time PCR and Western blotting. EPO-MSCs were successfully constructed. EPO-MSCs showed a more potently suppressive effect on local asthmatic airway inflammation and the level of IL-4, IL-5, and IL-13 in lung tissue than MSCs. Moreover, the numbers of goblet cells, the thicknesses of smooth muscle layer, collagen density, percentage of proliferating cell nuclear antigen positive (PCNA+ ) mesenchymal cells, and von Willebrand factor positive(vWF+ ) vessels were also significantly inhibited by EPO-MSCs. Furthermore, EPO-MSCs could downregulate the expression of TGF-ß1, TAK1, and p38MAPK in lung tissue both in mRNA level and in protein level. EPO gene modified MSCs may more efficiently attenuate asthmatic airway remodeling, which maybe related with the downregulation of TGF-ß1-TAK1-p38MAPK pathway activity.

The role of bone marrow-derived adult stem cells in a transgenic mouse model of allergic asthma.

BACKGROUND: Asthmatic airway remodeling is an abnormal injury/repair process of the small airways caused by chronic inflammation in which the quantities of multiple cells increase dramatically. However, the origin of these proliferative cells is still undetermined. OBJECTIVE: The aim of this study was to examine whether bone marrow (BM)-derived adult stem cells are responsible for the proliferative cells in asthmatic airway remodeling. METHODS: Adult mice were durably engrafted with BM isolated from green fluorescent protein (GFP) transgenic mice. Using GFP BM chimera mice, an ovalbumin (OVA)-induced chronic asthma mouse model was established. The distribution of BM-derived GFP+ cells in the lungs of chronic asthma mice was detected by fluorescence microscopy. The phenotype of BM-derived GFP+ cells in the lung tissues of chronic asthma mice was analyzed by flow cytometry. RESULTS: BM chimera mice were successfully generated, with no detectable radioactive inflammation observed. Using BM chimera mice, we established a mouse model of chronic asthma characterized by a significant increase in the thickness of the airway subepithelial basement membrane and smooth muscle layers. OVA treatment caused many GFP+ cells to appear at sites of small airway inflammation. The extravascular localization of some GFP+ cells and their morphology were not consistent with leukocytes. Flow cytometric analysis of lung cells revealed a significant increase in type I collagen (Col I)+GFP+ cells and α-smooth muscle actin (α-SMA)+GFP+ cells in OVA-treated GFP BM chimera mice. CONCLUSIONS: Considerable numbers of Col I- and α-SMA-producing cells originated from BM in the lung tissues of mice with OVA-induced chronic asthma.

Therapeutic efficacy of a co-blockade of IL-13 and IL-25 on airway inflammation and remodeling in a mouse model of asthma.

Repeated airway inflammation and unremitting remodeling provoke irreversible pulmonary dysfunction and resistance to current drugs in patients with chronic bronchial asthma. Interleukin (IL)-13 and IL-25 play an important role in airway inflammation and remodeling in asthma. We aimed to investigate whether co-inhibiting IL-13 and IL-25 can effectively down-regulate allergen-induced airway inflammation and remodeling in mice. Mice with asthma induced by chronic exposure to ovalbumin (OVA) were given soluble IL-13 receptor α2 (sIL-13R) or soluble IL-25 receptor (sIL-25R) protein alone and in combination to neutralize the bioactivity of IL-13 and IL-25, and relevant airway inflammation and remodeling experiments were performed. We found that the co-blockade of IL-13 and IL-25 with sIL-13R and sIL-25R was more effective than either agent alone at decreasing inflammatory cell infiltration, airway hyperresponsiveness (AhR) and airway remodeling including mucus production, extracellular collagen deposition, smooth muscle cell hyperplasia and angiogenesis in mice exposed to OVA. These results suggest that the combined inhibition of IL-13 and IL-25 may provide a novel therapeutic strategy for asthma, especially for patients who are resistant to current treatments.