Impact of apoptotic adipose-derived mesenchymal stem cells on attenuating organ damage and reducing mortality in Rat sepsis syndrome induced by cecal puncture and ligation

Abstract

BackgroundWe tested whether apoptotic adipose-derived mesenchymal stem cells (A-ADMSCs) were superior to healthy (H)-ADMSCs at attenuating organ damage and mortality in sepsis syndrome following cecal ligation and puncture (CLP).MethodsAdult male rats were categorized into group 1 (sham control), group 2 (CLP), group 3 [CLP + H-ADMSC administered 0.5, 6, and 18 h after CLP], group 4 [CLP + A-ADMSC administered as per group 3].ResultsCirculating peak TNF-α level, at 6 h, was highest in groups 2 and 3, and higher in group 4 than group 1 (p < 0.0001). Immune reactivity (indicated by circulating and splenic helper-, cytoxic-, and regulatory-T cells) at 24 and 72 h exhibited the same pattern as TNF-α amongst the groups (all p < 0.0001). The mononuclear-cell early and late apoptosis level and organ damage parameters of liver (AST, ALT), kidney (creatinine) and lung (arterial oxygen saturation) also displayed a similar pattern to TNF-α levels (all p < 0.001). Protein levels of inflammatory (TNF-α, MMP-9, NF-κB, ICAM-1), oxidative (oxidized protein) and apoptotic (Bax, caspase-3, PARP) biomarkers were higher in groups 2 and 3 than group 1, whereas anti-apoptotic (Bcl-2) biomarker was lower in groups 2 and 3 than in group 1 but anti-oxidant (GR, GPx, HO-1, NQO-1) showed an opposite way of Bcl-2; these patterns were reversed for group 4 (all p < 0.001). Mortality was highest in group 3 and higher in group 2 than group 4 than group 1 (all p < 0.001).ConclusionsA-ADMSC therapy protected major organs from damage and improved prognosis in rats with sepsis syndrome.

Mesenchymal stem cells as a therapeutic tool to treat sepsis

“…Thus, Sepúlveda et al [67] found that while intraperitoneal administration of normal human BM-MSCs 30 min after LPS injection reduced mortality in an LPS sepsis model in mice, senescent human BM-MSCs failed to protect them, despite the fact they conserved the capacity to modulate the function of lymphocytes and macrophages in vitro. However, in contrast to these positive results, Chang et al [69] reported that three intraperitoneal administrations of 1.2 × 10 6 living rat ASCs (at 0.5, 6 and 18 h) did not reduce, but moderately increased, mortality in a rat model of CLP, whereas the administration of apoptotic rat ASCs protected rats from death. Further studies will be needed to better understand these results.…”

“…No specific side effects of MSC treatment have been reported in sepsis models (only Chang et al [69] reported increased mortality when using living rat ASCs compared to the untreated group in a rat model of CLP). The fate of MSCs in sepsis models have been also investigated in some studies.…”

“…The effects of MSC treatment on survival are a consequence of the reduction of inflammation-associated organ injury and the improvement in organ function. MSC treatment has been reported to reduce damage in kidney (i.e., reduced levels of apoptotic cells, serum creatinine and tubular injury score), liver (i.e., reduced levels of apoptotic cells, serum liver enzymes and blood urea nitrogen), pancreatic (i.e., reduced levels of serum amylase), spleen (i.e., reduced levels of apoptotic cells), lung (i.e., reduced levels of apoptotic cells and vascular leakage) and heart function (i.e., improved cardiac depression) in a variety of sepsis models and experimental settings [61,62,[64][65][66][68][69][70][71][72][73][74][75] . Improvement in organ damage correlates with reduction on neutrophil infiltration and myeloperoxidase (MPO) activity in target organs [52,61] .…”

“…Zhao et al [68] CLP, rat rASCs (auto) living/ apoptotic I.P/after 0.5 h and I.P/after 6 h and I.P/after 18 h [69] administrations of 5 × 10 5 , 2.5 × 10 5 and 2.5 × 10 5 mouse BM-MSCs at 2, 24 and 48 h after CLP, respectively, also reduced mortality rates on mice, although they did not compare with the effects of one single dose [64] . Unfortunately, so far, different timing of administration have only been compared in the same study by Németh et al [61] who reported that a prophylactic intravenous treatment with mouse BM-MSCs 24 h prior to CLP had similar therapeutic effects than a therapeutic treatment after 1 h of CLP.…”

Glycyrrhizic Acid Prevents Sepsis-Induced Acute Lung Injury and Mortality in Rats

“…Some recent studies have found that wound, infection, inflammatory mediators, and ROS cam induce apoptosis in pulmonary vascular endothelial cells and alveolar epithelial cells (Wang et al 2013). Cell apoptosis in pulmonary tissues is involved in the development and progression of lung injury during sepsis (Chang et al 2012). Research shows that the activation of caspase-3 plays an important role in the apoptosis of lung tissue cells.…”