, 2012). Fibrocytes stimulated with IL-4 and CH5424802 cost IL-13 produce high levels of collagen and non-collagen components of the extracellular matrix (Bellini et al., 2011), and the balance between

levels of these cytokines is related to recruitment of eosinophils to the lung parenchyma (Rothenberg et al., 2011). Therefore, the reduction in IL-4 and IL-13 promoted by BMDMC therapy may be associated with a decrease in the number of PMNs and collagen fibre content. Similarly, both BMDMC administration routes were able to reduce TGF-β and VEGF levels, contributing to airway repair and curtailing the remodelling process. In this context, TGF-β, the major mediator of EMT (Alipio et al., 2011), may impair airway epithelial sheet migration over matrix-coated plates due to enhancement of cell adhesion

(Spurzem et al., 1993). It may also play a key role in bronchial angiogenesis and vascular remodelling in asthma via VEGF, an important angiogenic molecule (Willems-Widyastuti et al., 2011). In this line, a recent see more study has reported that VEGF receptor inhibition led to a significant reduction in inflammation and remodelling in experimental asthma (Lee et al., 2006). Future studies should be conducted to address the role of pathways involved in chemokine and growth factor production in the context of BMDMC L-NAME HCl therapy. Our study has some limitations: (1) BMDMCs were injected 24 h before the first ovalbumin challenge, before the remodelling process was established. Thus, more studies should be performed to assess whether these routes of administration could promote similar effects in a remodelled airway; (2) we cannot ascertain whether the role of cytokines and growth factors is related to engraftment. To clarify this issue, specific gene-deficient animals should be used;

(3) even though the amount of GFP was quantified in lung tissue, we did not analyze whether these engrafted cells transdifferentiated into any type of lung cell; and (4) we were unable to ascertain the role of MSCs in our bone marrow fraction, even though they accounted for approximately 4% of cells in this fraction (a proportion higher than the average reported in the recent literature). In conclusion, bone marrow-derived mononuclear cells were effective as a pre-treatment protocol in the murine model of allergic asthma used herein, leading to a reduction in inflammatory and remodelling processes and improving airway epithelial repair and lung mechanics regardless of administration route. These improvements were not affected by the higher pulmonary engraftment observed after intratracheal instillation compared to intravenous administration, suggesting an important role of BMDMCs in modulating immune response.