Abstract
BackgroundThis study tested whether human induced-pluripotent stem-cell-derived mesenchymal-stem-cells (iPS-MSCs) would offer an additional benefit to the rodent with acute kidney injury (AKI) (ischemia for 1 h followed by reperfusion for 120 h) associated sepsis syndrome (SS) (by cecal-ligation-puncture immediately after AKI-induction) undergoing ciprofloxacin therapy.ResultsMale-adult SD rats (n = 80) were categorized into group 1 (sham-operated-control, n = 10), group 2 (AKI + SS, n = 24), group 3 (AKI + SS + ciprofloxacin/3 mg/kg, orally for 120 h, n = 12), group 4 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI, n = 12), group 5 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 18 h after AKI, n = 12), group 6 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI induction + ciprofloxacin, n = 10] and euthanized by 120 h. The result showed that the mortality was significantly higher in group 2 than in other groups (all p < 0.01). The creatinine level was highest in group 2, lowest in group 1, significantly lower in group 6 than in groups 3, 4 and 5, (all p < 0.0001), but it showed no difference among the latter 3 groups. Flow cytometric analysis showed that the circulatory inflammatory cells (Ly6G/CD11b/c), early (AN-V+/PI−)/late (AN-V+/PI+) apoptosis, and circulatory/splenic immune cells (CD3+/CD4+, CD3+/CD8a+) were highest in group 2, lowest in group 1, significantly lower in group 6 than in groups 3/4/5 and significantly lower in group 4 than in groups 3/5 (all p < 0.0001), but they showed no difference between groups 3/5. Protein expressions of oxidative-stress (NOX-1/NOX2/oxidized protein), apoptotic (cleaved-caspase3/cleaved-PARP/mitochondrial-Bax), fibrotic (TGF-ß/Smad3), inflammatory (MMP-9/IL-6/TNF-α) and autophagic (Atg5/Beclin) biomarkers in kidney exhibited an identical pattern of circulatory inflammatory cells (all p < 0.0001).ConclusionCombined iPS-MSCs-ciprofloxacin therapy was superior to either one alone for protecting AKI complicated by SS.
Highlights
Acute kidney injury (AKI) commonly takes place in critically ill patients, especially in those of adult intensive care unit (ICU) patients
Observational studies have even more shown that in a large 10-year cohort study that enrolled more than 90,000 patients from more than 20 ICUs, acute kidney injury (AKI) incidence increased by 2.8% per year [3], highlighting that this disease entity is in the increasing process worldwide
Results iPSC‐mesenchymal stem cell (MSC) possessed the capacities of anti‐inflammation and immunomodulation (Fig. 1) To test whether the iPS-MSCs had properties of downregulation of inflammation and immunogenicity, the cell culture in Transwell was categorized into Group A [raw 264.7 cell line], Group B [Raw 264.7 + lipopolysaccharide (LPS) (5 × 105/well co-cultured for 6 h)], Group C [raw 264.7 + iPS-MSC (5 × 105/well)] and Group D
Summary
Acute kidney injury (AKI) commonly takes place in critically ill patients, especially in those of adult intensive care unit (ICU) patients. The fundamental causes of AKI have been keenly surveyed from many perspectives [4,5,6,7,8,9,10,11,12,13,14,15], including toxic substances such as chemical compounds and medicines, sepsis syndrome (SS)-associated ischemic kidney injury and acute ischemia–reperfusion (IR) injury, contrast medium, obstruction of the urinary tract, chronic advanced heart failure, hepato-renal syndrome, hypoperfusion/shock, etc. SS is one of the most common contributors for worsening an acute IR injury in kidney, highlighting an extremely strong positive correlation between SS-kidney IR injury and AKI. This study tested whether human induced-pluripotent stem-cell-derived mesenchymal-stem-cells (iPS-MSCs) would offer an additional benefit to the rodent with acute kidney injury (AKI) (ischemia for 1 h followed by reperfusion for 120 h) associated sepsis syndrome (SS) (by cecal-ligation-puncture immediately after AKI-induction) undergoing ciprofloxacin therapy
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