Abstract
ObjectivesWe tried to investigate the mechanism of continuous venovenous hemodiafiltration (CVVHDF) treatment in monocytes function, endoplasmic reticulum (ER) stress signaling pathways, metabolomics and histopathological changes of MODS dogs, and aimed to enhance the understanding of pathogenesis and provide novel avenues to potential therapies.Methods12 male Beagle dogs were used to develop the stable models of MODS by using hemorrhagic shock plus resuscitation and endotoxemia, and assigned randomly to CVVHDF group (n=6) and MODS group (n=6). The dogs in CVVHDF group were given the typical CVVHDF treatment for 24h after the completion of endotoxin intravenous infusion, while those in MODS group were offered the i.v heparin instead only. Serum sample were collected at five time points, i.e. before anesthesia, 0h, 6h, 12h and 24h after the endotoxin injection (T1˜T5, respectively), and meanwhile, the changes of mRNA, protein and human umbilical vein endothelial cells (HUVECs) apoptosis rates in JNK, CHOP and Caspase-12 were observed before and after interfered by RNA interference technology.ResultsThe levels of DLA-DR, IL-1β and IL-4 were higher than those in MODS group after the CVVHDF treatment, and the early and late apoptosis rates showed downward trend compared with MODS group. In vitro and prior to RNA interference (RNAi), the levels of mRNA and protein expression and HUVECs apoptosis rates of JNK, CHOP and Caspase-12 in CVVHDF group were significantly lower compared to T1 and MODS group respectively. However, the levels of mRNA and protein expression and HUVECs apoptosis rates were significantly lower than those before interfered by RNAi in both two groups. The serum levels of LPCs, ornithine, proline, methionine, etc. were down-regulated while carnitines, FFAs, PC, etc. were increased significantly in MODS (T4), and the serum levels of methionine, proline, arginine and lysine were increased while carnitine, LPCs, PCs, SMs and orthophosporic acid were decreased after 12 hours CVVHDF treatment (T4).ConclusionCVVHDF treatment could reduce the apoptosis of the cells by enhancing the antigen presentation, improving the anti-inflammatory and proinflammatory imbalance and even correcting the metabolic disorder of amino acids and phospholipids.
Highlights
Multiple organ dysfunction syndrome (MODS) is defined as dysfunction affecting two or more body organs or systems which occurs simultaneously or sequentially after shock, injury, infection, burn, etc [1]
In vitro and prior to RNA interference (RNAi), the levels of mRNA and protein expression and human umbilical vein endothelial cells (HUVECs) apoptosis rates of JNK, CHOP and Caspase-12 in continuous venovenous hemodiafiltration (CVVHDF) group were significantly lower compared to T1 and MODS group respectively
The serum levels of LPCs, ornithine, proline, methionine, etc. were down-regulated while carnitines, FFAs, PC, etc. were increased significantly in MODS (T4), and the serum levels of methionine, proline, arginine and lysine were increased while carnitine, LPCs, PCs, SMs and orthophosporic acid were decreased after 12 hours CVVHDF treatment (T4)
Summary
Multiple organ dysfunction syndrome (MODS) is defined as dysfunction affecting two or more body organs or systems which occurs simultaneously or sequentially after shock, injury, infection, burn, etc [1]. CVVHDF is a kind of purification method can effectively remove toxins and inflammatory substances of the blood, and it has been widely used in the treatment of MODS because it has the characteristics of high efficiency and safety, and the theory of endoplasmic reticulum stress has been gained acceptance on injury and sepsis. Study has considered the imbalance in antiinflammatory/pro-inflammatory cytokines, decline of monocyte antigen presentation function, ER stress and the disorder of amino acids and lipids which can stimulate or increase apoptosis of endothelial cells, further aggravating inflammation and dysfunction of various organs and creating a vicious cycle which can lead to MODS [5, 10,11,12]. The ER stress response can promote either cell survival or cell death depending on the degree of injury and other factors [13, 16, 17]
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