Abstract
BackgroundAcute lung injury (ALI) is a common lung disorder that affects millions of people every year. The infiltration of inflammatory cells into the lungs and death of the alveolar epithelial cells are key factors to trigger a pathological cascade. Trophoblast stem cells (TSCs) are immune privileged, and demonstrate the capability of self-renewal and multipotency with differentiation into three germ layers. We hypothesized that intratracheal transplantation of TSCs may alleviate ALI.MethodsALI was induced by intratracheal delivery of bleomycin (BLM) in mice. After exposure to BLM, pre-labeled TSCs or fibroblasts (FBs) were intratracheally administered into the lungs. Analyses of the lungs were performed for inflammatory infiltrates, cell apoptosis, and engraftment of TSCs. Pro-inflammatory cytokines/chemokines of lung tissue and in bronchoalveolar lavage fluid (BALF) were also assessed.ResultsThe lungs displayed a reduction in cellularity, with decreased CD45+ cells, and less thickening of the alveolar walls in ALI mice that received TSCs compared with ALI mice receiving PBS or FBs. TSCs decreased infiltration of neutrophils and macrophages, and the expression of interleukin (IL) 6, monocyte chemoattractant protein-1 (MCP-1) and keratinocyte-derived chemokine (KC) in the injured lungs. The levels of inflammatory cytokines in BALF, particularly IL-6, were decreased in ALI mice receiving TSCs, compared to ALI mice that received PBS or FBs. TSCs also significantly reduced BLM-induced apoptosis of alveolar epithelial cells in vitro and in vivo. Transplanted TSCs integrated into the alveolar walls and expressed aquaporin 5 and prosurfactant protein C, markers for alveolar epithelial type I and II cells, respectively.ConclusionIntratracheal transplantation of TSCs into the lungs of mice after acute exposure to BLM reduced pulmonary inflammation and cell death. Furthermore, TSCs engrafted into the alveolar walls to form alveolar epithelial type I and II cells. These data support the use of TSCs for the treatment of ALI.
Highlights
Acute lung injury (ALI) is a common lung disorder that affects millions of people every year
The lungs of ALI mice that received Trophoblast stem cells (TSCs) revealed much less cellularity compared with mice receiving PBS or FBs, and the alveolar appearance was similar to sham mice (Fig. 1a–d)
Immunostaining for CD45, a marker of inflammatory cells, confirmed that intratracheal exposure to BLM resulted in an increase in CD45 positive cells infiltrating into the lungs, compared with sham, while there were significantly less CD45 positive cells in the lungs of ALI mice that received TSCs compared with ALI mice receiving PBS or FBs (Fig. 1e–i)
Summary
Acute lung injury (ALI) is a common lung disorder that affects millions of people every year. The causes of ALI are diverse, including lung infections of various pathogens, sepsis, harmful chemicals, and antineoplastic therapies. One such therapeutic agent is bleomycin (BLM), which is used to treat various malignancies. The histopathological features of ALI in patients and animal models indicate that inflammatory cells infiltrate into the lungs, causing damage to the alveolar-capillary barrier due to the death of the alveolar epithelial type I/II and endothelial cells, which eventually causes impaired gas exchange, hypoxemia, and the development of acute respiratory distress syndrome (ARDS) [1, 2]. BLM-induced experimental lung injury, including the more acute injury response, has relevance for investigation
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