The GM/WM ratio correlates with the outcome of hypoxic ischaemic encephalopathy and may be useful as an objective early predictor of vegetative state or death in comatose patients after cardiac arrest.
Excessive systemic inflammation following sepsis, trauma or burn could lead to multi-organ damage and death. Bone marrow stromal cells (BMSCs), commonly referred to as mesenchymal stem cells (MSCs), has been studied in several immune-associated diseases in human and animal by modulating the inflammatory response. Adipose tissue derived mesenchymal stem cells (ATSCs), which can be obtained more easily, compared with BMSCs, has emerged as an attractive alternative MSCs source for cell therapy. We investigated the therapeutic effects of human ATSCs (hATSCs) in endotoxemic rat model and their capacity to modulate the inflammatory response. Endotoxemia was induced with Lipopolysaccaride intravenously injection (LPS, 10mg/kg). Animals were divided into the following three groups: (1) saline + saline (n=5), (2) LPS + saline (n=5) and (3) LPS + hATSCs (2x106) (n=5). The administration of LPS caused a consistent systemic inflammatory responses, increased concentrations of the pro-inflammatory cytokines that have an important role in sepsis. Treatment of endotoxemia with hATSCs decreased the level of inflammatory cytokines both in serum and in the lung, reduced inflammatory changes in the lung, prevented apoptosis in the kidney and improved multi-organ injury. In conclusion, our data demonstrates that hATSCs regulate the immue/inflammatory responses and improve multi-organ injury and they could be attractive candidates for cell therapy to treat endotoxemia.
Immunomodulatory or immunosuppressive properties of bone marrow-derived mesenchymal stem cells (BM-MSCs) facilitate the treatment of acute respiratory distress syndrome and acute lung injury (ALI). Dysregulated miRNA (miRNA or miR) expression associated with the effects of BM-MSCs was assessed in a rat model of lipopolysaccharide (LPS)-induced ALI. The present study performed biochemical tests to assess five analytes, including alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate, blood urea nitrogen (BUN), and creatinine (CREA). Total cell count was assessed and the percentage of bronchoalveolar lavage neutrophil content was also examined. The results Histopathological examination of rat upper lobe lung tissue was then used to estimate lung injury score (LIS). The levels of AST, lactate, BUN and creatinine (excluding ALT), released into the circulation upon injury, were significantly lower in ALI rats treated with BM-MSCs than in ALI rats alone (P<0.05). BM-MSC rats exhibited a significantly decreased bronchoalveolar lavage neutrophil percentage and LIS compared with that of LPS treated rats alone (P<0.05). In addition, the miRNA expression profile was determined following treatment with BM-MSCs via microarray analysis. A total of 95/690 miRNAs were differentially expressed following the treatment of BM-MSCs in rats with ALI. Among the 95 miRNAs, 66 were upregulated and 29 were downregulated; 9 miRNAs were significantly upregulated (miR-1843-3p, miR-323-3p, miR-183-5p, miR-182 and miR-196b-3p) or downregulated (miR-547-3p, miR-301b-5p, miR-503-3p and miR-142-3p). A total of 3 miRNAs were inversely expressed in ALI treated with BM-MSCs compared with untreated ALI. Of these 3 miRNAs, the expression of miR-142-3p and miR-503-3p was upregulated in the LPS groups and downregulated in the BM-MSC groups. miR-196b-3p was downregulated in the LPS group and upregulated in the BM-MSC groups. miRNAs have a role in cell proliferation, immune response, inflammation and apoptosis, which may be associated with the therapeutic effects of BM-MSCs in ALI. In summary, BM-MSCs improved multi-organ damage and attenuated lung injury. Different miRNA profiles were expressed following BM-MSC treatment of ALI. These dysregulated miRNAs participated in BM-MSC-mediated immunomodulation of ALI.
SUMMARYThe effects of 3-deazaadenosine (DZA), 3-deaza(Ϯ)-aristeromycin (DZAri) and 3-deazaneplanocin (DZNep) on tumour necrosis factor-␣ (TNF-␣) production were examined in the mouse macrophage cell line, RAW264.7, stimulated with lipopolysaccharide (LPS). The 3-deazaadenosine analogues inhibited the TNF-␣ production and the inhibition was dependent upon the concentration of the analogue. DZA reduced the level of TNF-␣ mRNA suggesting that DZA acts at a transcriptional step. In contrast, DZAri and DZNep had little effect on mRNA levels for TNF-␣, implying that these compounds inhibit a post-transcriptional or translational biosynthetic step of TNF-␣ synthesis. The observation that homocysteine (Hcy) potentiated the DZA inhibition of TNF-␣ production and of TNF-␣ mRNA levels suggests that the inhibition of TNF-␣ production may be caused by elevated levels of 3-deazaadenosylhomocysteine (DZAHcy). The results show that the 3-deazaadenosine analogues are potent inhibitors of TNF-␣ production in the RAW264.7 cell line stimulated with LPS and suggest that these analogues may be effective agents for the treatment of diseases in which TNF-␣ plays an important pathogenic role.
Intravenous (IV) infusion of oleic acid (OA) distributes OA microemboli in the pulmonary capillaries, which results in severe vascular congestion, hemorrhage vascular congestion, interstitial edema, intravascular coagulation and bleeding. The immune response to acute lung injury (ALI) is known to be associated with rapid and widespread changes in microRNA (miRNA) expression in the lung. The present study of a model of rat lung injury aimed to investigate how the lung miRNA profile changes to mediate ALI. For the induction of ALI, OA (200 µl/kg) suspended in 20% ethyl alcohol was injected through the tail vein for 20 min. Lung tissue samples were acquired at 3, 6 and 24 h, and miRNA microarray and quantitative polymerase chain reaction were performed using these samples. The activation of phosphatase and tensin homolog (PTEN), protein kinase B (Akt), extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK) were analyzed by western blot analysis. There were 75 miRNAs that demonstrated >1.5‑fold changes in expression levels. miR-101a was highly upregulated at 3 h. miR-21 was upregulated in the OA group throughout the 24 h following OA challenge. miR-1 was the most downregulated miRNA at 24 h. In order to examine the expression levels of PTEN and Akt as targets of miR-21, western blot analysis was performed. At 3 h, the levels of PTEN were attenuated in the OA group as compared with those in the control group; however, p-Akt/Akt levels were increased at 3 h for the OA group. PTEN and p-Akt/Akt were significantly higher in the OA group at 3 h and were rapidly decreased at 6 h. The immunohistochemical stain of α-smooth muscle actin in the bronchial and alveolar wall increased 24 h after OA‑induced ALI. These results indicated that the profile of miRNAs dynamically changed throughout the OA-induced ALI process, and mitogen-activated protein kinase activation, PTEN/Akt pathway alteration and smooth muscle actin activation were observed in this ALI model.
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