Coculture with bone marrow‑derived mesenchymal stem cells attenuates inflammation and apoptosis in lipopolysaccharide‑stimulated alveolar epithelial cells via enhanced secretion of keratinocyte growth factor and angiopoietin‑1 modulating the Toll‑like receptor‑4 signal pathway

Abstract

Acute lung injury (ALI) is a common, costly and potentially lethal disease with characteristics of alveolar-capillary membrane disruption, pulmonary edema and impaired gas exchange due to increased apoptosis and pulmonary inflammation. There is no effective and specific therapy for ALI; however, mesenchymal stem cells (MSCs) have been demonstrated to be a potential option. Lipopolysaccharide (LPS) is a highly proinflammatory molecule that is used to mimic an in vivo inflammatory and damaged state in vitro. The present study investigated the effect of bone marrow-derived MSCs on an LPS-induced alveolar epithelial cell (A549 cell line) injury and its underlying mechanisms by a Transwell system. It was identified that a high LPS concentration caused a decrease in cell viability, increases in apoptosis, inflammatory cytokine release and NF-κB activity, disruption of the caspase-3/Bcl-2 ratio, upregulation of Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and toll-interleukin-1 receptor domain-containing adaptor inducing interferon (TRIF) expression, and facilitation of TLR4/MyD88 and TLR4/TRIF complex formation in A549 cells. Coculture with MSCs attenuated all of these activities induced by LPS in A549 cells. In addition, an increased level of keratinocyte growth factor (KGF) and angiopoietin-1 (ANGPT1) secretion from MSCs was observed under inflammatory stimulation. KGF and/or ANGPT1 neutralizing antibodies diminished the beneficial effect of MSC conditioned medium. These data suggest that MSCs alleviate inflammatory damage and cellular apoptosis induced by LPS in A549 cells by modulating TLR4 signals. These changes may be partly associated with an increased secretion of KGF and ANGPT1 from MSCs under inflammatory conditions. These data provide the basis for development of MSC-based therapies for ALI.

Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics

“…In vivo administration of MSCs into ARDS models can reduce the apoptotic cell counts in the lung tissues and distal organs in ARDS (Silva et al, 2018). MSCs have also been reported to reduce apoptosis of the alveolar epithelial cells and endothelial cell by secretion of keratinocyte growth factor (KGF), angiopoietin -1, and HGF (Bernard et al, 2018;Chen et al, 2019a;Meng et al, 2019). Alveolar macrophage apoptosis induced by lipopolysaccharide (LPS) was also attenuated after MSC treatment, which may be partially mediated by inhibition of the Wnt/β-catenin pathway (Li et al, 2015).…”

Stem cell therapy for COVID‐19, ARDS and pulmonary fibrosis

“…42 It has been reported that MSCs can reduce apoptosis of the alveolar epithelial cells and endothelial cell by secretion these three growth factors. [77][78][79] The VEGF and FGF secreted by MSCs can also promote lung tissue repair. 80,81 In addition, MSCs can reduce the levels of pro-fibrotic factors to The MSC-like IMRCs could also reverse pulmonary fibrosis by overexpressing the matrix metalloproteinase MMP1 and reducing collagen I levels during fibrogenesis induced by TGF-β1.…”

Macrophage polarization and its role in the pathogenesis of acute lung injury/acute respiratory distress syndrome

“…Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders characterized by increased non-hydrostatic extravascular lung water, reduced pulmonary compliance, and acute hypoxemic respiratory failure [1]. Despite substantial progress in mechanical ventilatory strategies, significant advances in the quality of care of critically ill patients, and an enhanced understanding of molecular mechanisms, the mortality rate among patients with ALI/ARDS remains unacceptably high [2,3].…”