Exosomes Released by Bone Marrow Mesenchymal Stem Cells Attenuate Lung Injury Induced by Intestinal Ischemia Reperfusion via the TLR4/NF-κB Pathway

Abstract

Purpose: Acute lung injury (ALI) is a primary component of multiple organ dysfunction syndromes triggered by intestinal ischemia-reperfusion (IIR) which results in high mortality. Existing treatment options remain unsatisfactory. Mesenchymal stem cells (MSCs) have shown considerable promise as a biological therapy for ALI in preclinical studies. However, there are many limitations to stem cell treatment. This study aimed to investigate whether MSC-derived exosomes, a non-cellular alternative, are able to act in a protective capacity similar to that of MSCs for ALI triggered by IIR in a rat model and to explore the underlying mechanisms.Methods: The IIR model involved occlusion of the superior mesenteric artery of a rat for 75 min then reperfusion for 20 h. Rats then received an intravenous injection of either bone marrow-derived MSCs or MSC-derived exosomes. Pathologic alteration of lung tissue, levels of pro-inflammatory cytokines, apoptotic proteins and TLR4/NF-κB signaling were measured to evaluate the therapeutic effect of treatment with either MSCs or exosomes.Results: Manifestations of acute lung injury after IIR were observed as edema and hemorrhage of alveoli and mesenchyme, and inflammatory cell infiltration. MSCs and MSC-derived exosomes both attenuated IIR-induced lung damage by decreased apoptosis and inflammation accompanied by down-regulation of TLR4 and NF-κB expression.Conclusions: MSC-derived exosomes provide protection similar to that of MSCs against IIR-induced ALI via inhibition of TLR4/NF-κB signaling, suggesting that a potential strategy against IIR-mediated acute lung injury could be therapy with exosomes as a non-cellular alternative to MSC transplantation.

Exosomes derived from mesenchymal stem cells inhibit neointimal hyperplasia by activating the Erk1/2 signalling pathway in rats

“…Similarly, a study into the role of exosomes in the progression of atherosclerosis employed exosomes derived from oxidized low-density lipoprotein (oxLDL)-stimulated macrophages and revealed that intravenous administration of oxLDL-treated macrophage cell-derived exosomes into male ApoE-deficient atherosclerosis mice significantly deteriorated atherosclerosis in vivo [38]. In another study, MSC-Exo were shown to exert antiapoptotic and anti-inflammatory effects on intestinal ischaemia-reperfusion-induced lung damage; their effects were accompanied by the downregulation of TLR4 and NF-κB expression, which further protected the lungs against ischeamia-reperfusion-induced acute lung injury [39].…”

“…Accumulating evidence suggested that MSC-Exo could exert effects via activating/inactivating signalling pathways including the TGF-β1 [42], NF-κB [39,43] and Wnt [44] signalling pathways. However, to date, the Erk signalling pathway has rarely been studied with MSC-Exo.…”

MicroRNA-377-3p released by mesenchymal stem cell exosomes ameliorates lipopolysaccharide-induced acute lung injury by targeting RPTOR to induce autophagy

“…Recently, more and more studies illustrate that exosomes from MSCs display beneficial roles in ALI. MSC-derived exosomes protect against intestinal ischemia-induced ALI via inhibition of TLR4/NF-κB signaling 38 and MSCs-exosomes confer protective effects against ALI by inducing the expression of miR-30b-3p 39 . In addition, hucMSCs-exosomes successfully decrease inflammatory factors in rats after burn, and this reduction is reversed by miR-451 expression in hucMSCs-exosomes via the TLR4/NF-κB pathway 40 .…”

Mesenchymal stem cells reverse EMT process through blocking the activation of NF-κB and Hedgehog pathways in LPS-induced acute lung injury

“…Based on the recent references, we learned that MSC reduces epithelial permeability following phosgene-induced ALI through regulating the classical signaling pathways, such as Wnt/β-catenin signaling pathway 31 and NF-κB signaling pathway 32 . Here, we also investigated the effect of MSC on several classical signaling pathways in ALI cell model.…”