Modulation of cytokine and nitric oxide by mesenchymal stem cell transfer in lung injury/fibrosis

Abstract

BackgroundNo effective treatment for acute lung injury and fibrosis currently exists. Aim of this study was to investigate the time-dependent effect of bone marrow-derived mesenchymal stem cells (BMDMSCs) on bleomycin (BLM)-induced acute lung injury and fibrosis and nitric oxide metabolites and inflammatory cytokine production.MethodsBMDMSCs were transferred 4 days after BLM inhalation. Wet/dry ratio, bronchoalveolar lavage cell profiles, histologic changes and deposition of collagen were analyzed.ResultsNitrite, nitrate and cytokines were measured weekly through day 28. At day 7, the wet/dry ratio, neutrophilic inflammation, and amount of collagen were elevated in BLM-treated rats compared to sham rats (p = 0.05-0.002). Levels nitrite, nitrate, IL-1β, IL-6, TNF-α, TGF-β and VEGF were also higher at day 7 (p < 0.05). Degree of lymphocyte and macrophage infiltration increased steadily over time. BMDMSC transfer significantly reduced the BLM-induced increase in wet/dry ratio, degree of neutrophilic infiltration, collagen deposition, and levels of the cytokines, nitrite, and nitrate to those in sham-treated rats (p < 0.05). Fluorescence in situ hybridization localized the engrafted cells to areas of lung injury.ConclusionSystemic transfer of BMDMSCs effectively reduced the BLM-induced lung injury and fibrosis through the down-regulation of nitric oxide metabolites, and proinflammatory and angiogenic cytokines.

Differentiation of Mouse Induced Pluripotent Stem Cells Into Alveolar Epithelial Cells In Vitro for Use In Vivo

“…Although some studies have demonstrated the therapeutic potential of bone marrow-derived stem cells in rodent lung injury models [23,[26][27][28], there is no evidence of a role for these stem cells in populating the lung alveolar epithelium in vivo [29][30][31][32]. Recent studies have reported efficient and direct derivation of lung alveolar epithelium from murine embryonic stem cells (ESCs) [10,11,14,16] for in vitro and in vivo applications.…”

“…This effect was considered to occur in a paracrine manner, and to be mediated by reductions in nuclear factor kB activity and neutrophil accumulation [41]. Transfer of MSCs also reduced BLM-induced lung injury and fibrosis partly through downregulation of inflammatory cytokines, such as TNF-a and IL-6 [23]. However, our data showed that To our knowledge, this is the first report of the threedimensional alveolar lung structure regenerative potential and lung injury therapeutic potential of differentiated mouse iPSCs.…”

“…The wet/dry weight ratio of the lung was measured to quantitatively evaluate the degree of pulmonary inflammation induced by BLM treatment, according to a method described previously [22,23]. The wet weight of lungs was measured immediately after sacrifice.…”

Intravenous administration of adipose-derived stromal cells does not ameliorate bleomycin-induced lung injury in rats

“…Under certain circumstances, MSCs can differentiate into chondrocytes, myoblasts, endothelial cells, epithelial cells, and neurocytes [9]. Furthermore, MSCs have been observed to display immunomodulatory properties [10][11][12][13].…”

Stem cell therapy for idiopathic pulmonary fibrosis: How far are we from the bench to the bedside?

“…Accumulating data obtained from animal studies has identified the curing role of stem cells in experimental lung fibrosis. Intravenous injection of bone marrow-derived mesenchymal stem cells (BM-MSCs) significantly reduced bleomycin-induced increase in wet/ dry ratio, degree of neutrophilic infiltration, collagen deposition, and levels of the cytokines and nitric oxide [50]. Another study indicates that intravenous mesenchymal stem cell transfer reduces bleomycin injectioninduced expressions of TGF-beta1, PDGF-A, PDGF-B, and IGF-1 mRNA, and that some MSC engrafts presenting in injured lung tissue are positive for pan-cytokeratin staining, which indicates the differentiation of MSCs into alveolar epithelial cells in vivo [51].…”