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Macrophage migration inhibitory factor (MIF) is an inflammatory mediator that contributes to asthmatic airway remodeling; however, little is known regarding the effects of MIF on airway smooth muscle cells (ASMCs). In the present study, we found that an enhanced expression of MIF promoted ASMC proliferation, increased the population of cells in the S/G2 phase, downregulated P21 expression, and upregulated cyclin D1, cyclin D3, and Cdk6 expression. In addition, the apoptosis of ASMCs was significantly decreased in response to MIF overexpression, compared with the negative control. Moreover, MIF facilitated the migration of ASMCs by upregulating the expression of matrix metalloproteinase (MMP)-2. Finally, we showed that MIF increased the phosphorylation of extracellular regulated protein kinases (ERK) 1/2 and focal adhesion kinase (FAK), which are associated with proliferation and migration. In conclusion, this study demonstrated that MIF overexpression promotes the proliferation and migration of ASMCs by upregulating the activity of the ERK1/2 and FAK signaling pathways in these cells, further indicating that inhibition of MIF may prove to be an effective strategy for treating asthma patients with airway remodeling.

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-β 1 (TGF-β1), 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-β1, 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-β1-TAK1-p38MAPK pathway activity.

Asthma remains a common chronic inflammatory disease whose incidence has markedly increased over the past two decades. In addition, the chronic inflammation associated with a given patient is often linked with the remodeling of airway structure that may impair lung function [1, 2]. These changes include peribronchial fibrosis, fibroblast proliferation and conversion to myofibroblasts, and smooth muscle hypertrophy [3]. Although these features are well recognized, the mechanisms leading to remodeling and the effect of therapy on preventing or reversing these changes are largely unknown. A variety of cells, cytokines, chemokines, and growth factors that are released from inflammatory and structural cells in the airway have been implicated in promoting airway inflammation and, in turn, remodeling events. Furthermore, the cross-talk between epithelium and the underlying mesenchyme appears to be critical for driving remodeling responses in asthma. Findings from long-term patient studies, which have been ongoing for more than a decade, have indicated that transforming growth factor-β1 (TGF-β1) may be an important mediator of allergic inflammation and airway remodeling. TGF-β1 is produced by various cell types in the lung, such as airway epithelial cells and leukocytes comprising the pulmonary pro-inflammatory cell infiltrate [4, 5], and more recent studies suggested that this pulmonary TGF-β1 contributes to subepithelial fibrosis and airway smooth muscle remodeling linked with many asthma patients [6, 7]. An important positive regulator of many growth factor signaling pathways, including TGF-β, is the protein tyrosine phosphatase SHP2. SHP2 is a cytoplasmic phosphotyrosine phosphatase with two SH2 domains (N-SHP2 and C-SHP2) that is widely expressed in the airway epithelium [8]. Studies of allergic respiratory inflammation have also identified SHP2 as both a positive and negative regulator of key pulmonary immune signaling pathways. These SHP2 functions include fine-tuning of cellular response to cytokines [9–12], effects on inhibitory receptor signaling [13–15], and mediating T-cell development and function [16–18]. In the present study, the role of SHP2 expression in airway epithelial cells was defined further using a mouse model of chronic allergen exposure that is accompanied by characteristic airway remodeling events. These studies avoid the early embryonic lethality associated with homozygous shp2 knockout mice [19, 20] and instead exploit an inducible shp2 knockout strategy to specifically delete the expression in the mouse airway epithelia. Airway epithelial cell shp2 expression was linked with the airway remodeling events following chronic allergen exposure. Subsequent cell culture studies with BEAS-2B airway epithelial cells showed that the shp2-mediated airway remodeling occurring in mice may be mediated by the regulation of airway epithelial TGF-β1 production. These data suggest that shp2 may be a key regulator of airway remodeling events and thus a previously underappreciated therapeutic target.