Despite improvements, lung transplantation remains hampered by both a scarcity of donor organs and by mortality following primary graft dysfunction (PGD). Since acute respiratory distress syndrome (ARDS) limits donor lungs utilization, we investigated cytokine adsorption as a means of treating ARDS donor lungs. We induced mild to moderate ARDS using lipopolysaccharide in 16 donor pigs. Lungs were then treated with or without cytokine adsorption during ex vivo lung perfusion (EVLP) and/or post-transplantation using extracorporeal hemoperfusion. The treatment significantly decreased cytokine levels during EVLP and decreased levels of immune cells post-transplantation. Histology demonstrated fewer signs of lung injury across both treatment periods and the incidence of PGD was significantly reduced among treated animals. Overall, cytokine adsorption was able to restore lung function and reduce PGD in lung transplantation. We suggest this treatment will increase the availability of donor lungs and increase the tolerability of donor lungs in the recipient.
Mesenchymal stem cells (MSCs) have been studied for their potential benefits in treating acute respiratory distress syndrome (ARDS) and have reported mild effects when trialed within human clinical trials. MSCs have been investigated in preclinical models with efficacy when administered at the time of lung injury. Human integrin α10β1-selected adipose tissue-derived MSCs (integrin α10β1-MSCs) have shown immunomodulatory and regenerative effects in various disease models. We hypothesized that integrin α10β1 selected-MSCs can be used to treat a sepsis-induced ARDS in a porcine model when administering cells after established injury rather than simultaneously. This was hypothesized to reflect a clinical picture of treatment with MSCs in human ARDS. 12 pigs were randomized to the treated or placebo-controlled group prior to the induction of mild to moderate ARDS via lipopolysaccharide administration. The treated group received 5 × 106 cells/kg integrin α10β1-selected MSCs and both groups were followed for 12 h. ARDS was confirmed with blood gases and retrospectively with histological changes. After intervention, the treated group showed decreased need for inotropic support, fewer signs of histopathological lung injury including less alveolar wall thickening and reduction of the hypercoagulative disease state. The MSC treatment was not associated with adverse events over the monitoring period. This provides new opportunities to investigate integrin α10β1-selected MSCs as a treatment for a disease which does not yet have any definitive therapeutic options.
Introduction: As an immunosuppressive cell, myeloid-derived suppressor cells (MDSC) has been reported to play a positive role in kidney transplantation. ATF/cyclic AMP-responsive element-binding (CREB), as a transcription factor, has been reported in macrophages with PGE2 addition. Hypermethylated MDSC induced by PGE2 are also myeloid-origin cells.There have been no reports on whether CREB also plays a regulatory role in this differentiation process. Method: Bone marrow (BM) cells of C57BL/6 were used to induced MDSC with GM-CSF (20ng/mL) and PGE2(1μg/mL) or with GM-CSF (20ng/mL) and EP1/2/4 antagonists. The expression of CREB, DUSP2 and MYD88 were assessed. The methylation level of their promoter region was measured using BSPCR. CREB inhibitor was used to study its effects. Results: In hypermethylated MDSC induced by GM-CSF and PGE2 and bone marrow cells induced by GM-CSF and EP1/2/4 antagonists, CREB was found in both of them. Meanwhile, two other proteins, DUSP2 and MYD88, which had been reported to be elevated in LPS-stimulated macrophages and did not decrease after the addition of PGE2, were also increased in MDSC compared with cultured BM cells. After adding CREB inhibitor (KG-501) to the hypermethylated MDSC culture system, we tested the expression of these two proteins again. The expression levels of both proteins were reduced. The methylation level of the promoter region of the two was higher than that of the group without CREB inhibitor. The DNA methyltransferase 3 Alpha (Dnmt3a) was not found any difference with or without inhibitor. Conclusion:In MDSC induced by GM-CSF and PGE2, CREB is involved in the regulation of DUSP2 and MYD88, possibly by competing with Dnmt3a on DNA binding in the regulation of promoter methylation. This is the first study focusing on the relation between CREB and DNA methylation by Dnmt3a.
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