Mesenchymal Stem Cell-Based Therapy of Inflammatory Lung Diseases: Current Understanding and Future Perspectives

Abstract

During acute or chronic lung injury, inappropriate immune response and/or aberrant repair process causes irreversible damage in lung tissue and most usually results in the development of fibrosis followed by decline in lung function. Inhaled corticosteroids and other anti-inflammatory drugs are very effective in patients with inflammatory lung disorders, but their long-term use is associated with severe side effects. Accordingly, new therapeutic agents that will attenuate ongoing inflammation and, at the same time, promote regeneration of injured alveolar epithelial cells are urgently needed. Mesenchymal stem cells (MSCs) are able to modulate proliferation, activation, and effector function of all immune cells that play an important role in the pathogenesis of acute and chronic inflammatory lung diseases. In addition to the suppression of lung-infiltrated immune cells, MSCs have potential to differentiate into alveolar epithelial cells in vitro and, accordingly, represent new players in cell-based therapy of inflammatory lung disorders. In this review article, we described molecular mechanisms involved in MSC-based therapy of acute and chronic pulmonary diseases and emphasized current knowledge and future perspectives related to the therapeutic application of MSCs in patients suffering from acute respiratory distress syndrome, pneumonia, asthma, chronic obstructive pulmonary diseases, and idiopathic pulmonary fibrosis.

The role of Interleukin 1 receptor antagonist in mesenchymal stem cell‐based tissue repair and regeneration

“…In addition to its potential to suppress acute inflammation in the lungs, IL‐1Ra was also responsible for the beneficial effects of MSCs in the treatment of chronic airway inflammation . As suggested by Duong and coworkers, MSC‐derived IL‐1Ra was crucially important for the attenuation of house dust mite (HDM)‐induced chronic allergic inflammatory response in mice .…”

“…For that purpose, through the secretion of IL‐1Ra, MSCs in an autocrine manner, upregulate expression of TLR‐4 that has crucially important role in bacterial clearance . Lipopolysaccharide, released from the cell wall of Gram‐negative bacteria, binds to TLR‐4 in MSCs and induces enhanced secretion of lipocalin‐2 that, in turn, binds bacterial ferric siderophores, reduces the uptake of iron, and suppresses bacterial growth . On the other hand, upon the elimination of bacterial pathogens and under the influence of high concentration of released inflammatory cytokines, MSCs obtain anti‐inflammatory phenotype and, through the production of immunosuppressive factors (IL‐1Ra, IL‐10, and PGE2) inhibit production of proinflammatory cytokines (IL‐1β, TNF‐α) in alveolar macrophages and attenuate ongoing inflammation in the lungs (Figure ) …”

“…Importantly, as revealed by Xu and colleagues, MSC‐derived IL‐1Ra creates “positive autocrine loop” in population of lung‐infiltrated MSCs by promoting their expansion and capacity for neovascularization, bacterial clearance, and immunosuppression . Under the influence of IL‐1Ra, MSCs upregulate the expression of vascular endothelial growth factor (VEGF) that prevents the apoptosis of endothelial cells, induces neovascularization, and promotes regeneration of injured alveolar Type II epithelial cells . IL‐1Ra regulates TLR‐4 signaling pathway in MSCs, leucocytes, and nonimmune cells, having important role in the modulation of immune response against bacterial antigens and allergens in the lungs .…”

“…53,55 Under the influence of IL-1Ra, MSCs upregulate the expression of vascular endothelial growth factor (VEGF) that prevents the apoptosis of endothelial cells, induces neovascularization, and promotes regeneration of injured alveolar Type II epithelial cells. 53,58 IL-1Ra regulates TLR-4 signaling pathway in MSCs, leucocytes, and nonimmune cells, having important role in the modulation of immune response against bacterial antigens and allergens in the lungs. 21,58,59 The effects of MSC-derived IL-1Ra on TLR-4 axis depend on the role that TLR-4-expressing cells play in the immune response to the inhaled antigens.…”

“…53,58 IL-1Ra regulates TLR-4 signaling pathway in MSCs, leucocytes, and nonimmune cells, having important role in the modulation of immune response against bacterial antigens and allergens in the lungs. 21,58,59 The effects of MSC-derived IL-1Ra on TLR-4 axis depend on the role that TLR-4-expressing cells play in the immune response to the inhaled antigens. 12,21 During the onset of bacterial pneumonia, under the influence of low concentration of inflammatory cytokines, MSCs obtain proinflammatory phenotype and cooperate with lung resident immune cells (macrophages, DCs) in the elimination of bacterial pathogens.…”