Qiyi Chen

The effect of venovenous extra-corporeal membrane oxygenation (ECMO) therapy on immune inflammatory response of cerebral tissues in porcine model

BackgroundExtra-Corporeal Membrane Oxygenation (ECMO) therapy is associated with high risk of neurologic injury. But the mechanism of neurologic injury during and/or after ECMO therapy is still unclear. Recent animal experiments confirmed that ECMO treatment increases the immune inflammatory response. The aim of this study is to investigate the effect of VV- ECMO on immune inflammatory response of cerebral tissues and neurological impairment.Methods18 porcine were randomly divided into control, sham and ECMO group (n = 6/group). ECMO was run 24 h in the ECMO group, and serum collected at 0, 2, 6, 12 and 24 h during ECMO treatment for the analysis of cytokine (IL-1β, IL-6, IL-10, TNF-a) and cerebral injury specific biomarker S100B and NSE. After 24 h ECMO treatment, all animals were euthanized and cerebral tissues (hypothalamus, hippocampus and cortex) were collected for measure of mRNA and protein levels of cytokine (IL-1β, IL-6, IL-10, TNF-a).ResultsThe results during ECMO treatment showed that all the pro-inflammation cytokines were increased significantly after 2 h, and anti-inflammation IL-10 showed transient hoist in the first 2 h in serum. After 24 h ECMO therapy, the mRNA levels of pro-inflammation cytokines and anti-inflammation IL-10 were simultaneously up-regulated in cerebral tissues (hypothalamus, hippocampus and cortex). And protein concentrations also showed different increasing levels in cerebral tissues. However, during the ECMO treatment, S100B and NSE protein in serum did not change significantly.ConclusionThese findings suggest VV-ECMO treatment can not only lead to immune inflammatory response in blood, but can also produce immune and inflammatory response in cerebral tissues. However the extent of immune inflammation was not sufficient to cause significant neurological impairment in this study. But the correlation between cerebral inflammatory response and cerebral impairment need to further explore.

Treatment of Slow Transit Constipation With Fecal Microbiota Transplantation: A Pilot Study

Background: Fecal microbiota transplantation (FMT) has been proposed as a therapeutic approach for functional gastrointestinal disease. We launched a clinical study to examine the safety and efficacy of FMT for slow transit constipation (STC). Materials and Methods: Twenty-four patients with STC, aged from 20 to 74 were enrolled in this prospective open-label study. Patients received FMT on 3 consecutive days through nasojejunal tubes and followed up for 12 weeks after treatment. Rate of clinical improvement and remission, Wexner constipation scale, Bowel movement per week, and gastrointestinal quality-of-life index were evaluated. Results: The rate of clinical improvement and remission based on clinical activity at week 12 was 50% (12/24) and 37.5% (9/24), respectively. The patient’s stool frequency increased from a mean of 1.8 (SD 1.3) per week pre-FMT to 4.1 (SD 2.6) at week 12 post-FMT without laxative usage (P<0.01). The stool consistency showed a tendency to improve after FMT administration. Comparison of pre-FMT and post-FMT Wexner constipation scores demonstrated a significant reduction between baseline (14.1±3.3) and the first week (9.8±4.9), which was maintained up to the following 12 weeks (7.5±3.2; P<0.01). Compared with baseline, significant overall improvements were also seen in gastrointestinal quality-of-life index score at week 1, week 2, week 4, week 8, and week 12 of follow-up (P<0.01). The improvements were accompanied by the decline of colonic transit time. No severe adverse events during the whole FMT procedure follow-up except for venting (6/24), abdominal pain (3/24), bloating (2/24), and diarrhea (7/24). Conclusion: This is a pilot study demonstrating that FMT was safe and may have the potential to improve symptoms in patients with STC.

Fecal microbiota transplantation in patients with slow-transit constipation: A randomized, clinical trial

Fecal microbiota transplantation has been proposed as a therapeutic approach for chronic constipation. This randomized, controlled trial aimed to compare the effects of conventional treatment alone (control) with additional treatment with FMT (intervention) in patients with slow-transit constipation (STC). Adults with STC were randomized to receive intervention or control treatment. The control group received education, behavioral strategies, and oral laxatives. The intervention group was additionally provided 6 days of FMT. The primary endpoint was the clinical cure rate (proportion of patients achieving a mean of ≥ three complete spontaneous bowel movements [CSBMs] per week]. Secondary outcomes and safety parameters were assessed throughout the study. Sixty patients were randomized to either conventional treatment alone (n = 30) or FMT (n = 30) through a nasointestinal tube. There were significant differences between the intervention group and control group in the clinical improvement rate (intention-to-treat [ITT]: 53.3% vs. 20.0%, P = 0.009), clinical cure rate (ITT: 36.7% vs. 13.3%, P = 0.04), mean number of CSBMs per week (ITT: 3.2 ± 1.4 vs. 2.1 ± 1.2, P = 0.001), and the Wexner constipation score (ITT: 8.6 ± 1.5 vs. 12.7 ± 2.5, P < 0.00001). Compared with the control group, the intervention group showed better results in the stool consistency score (ITT: 3.9 vs. 2.4, P < 0.00001) and colonic transit time (ITT: 58.5 vs. 73.6 h, P < 0.00001). The intervention group had more treatment-related adverse events than did the control group (50 vs. 4 cases). FMT was significantly more effective (30% higher cure rate) for treatment of STC than conventional treatment. No serious adverse events were observed.

Peritoneal Air Exposure Elicits an Intestinal Inflammation Resulting in Postoperative Ileus

Background. The pathogenesis of postoperative ileus (POI) is complex. The present study was designed to investigate the effects of peritoneal air exposure on the POI intestinal inflammation and the underlying mechanism. Methods. Sprague-Dawley rats were randomized into five groups (6/group): the control group, the sham group, and three exposure groups with peritoneal air exposure for 1, 2, or 3 h. At 24 h after surgery, we analyzed the gastrointestinal transit, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-10, the myeloperoxidase activity, and the levels of TNF-α, IL-1β, IL-6, and IL-10 in the ileum and colon. The oxidant and antioxidant levels in the ileum and colon were analyzed by measuring malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC). Results. Peritoneal air exposure caused an air-exposure-time-dependent decrease in the gastrointestinal transit. The length of peritoneal air exposure is correlated with the severity of both systemic and intestinal inflammations and the increases in the levels of MDA, SOD, GSH-Px, and T-AOC. Conclusions. The length of peritoneal air exposure is proportional to the degree of intestinal paralysis and the severity of intestinal inflammation, which is linked to the oxidative stress response.

Berberine ameliorates intestinal mucosal barrier damage induced by peritoneal air exposure.

Berberine, an isoquinoline alkaloid derived from many medicinal plants, has been extensively used to treat various gastrointestinal diseases. In the present study, we investigated whether berberine could ameliorate intestinal mucosal barrier damage induced by peritoneal air exposure for 3 h. Peritoneal air-exposure rats received 100, 150, and 200 mg/kg berberine orally via gavage four times before and after surgery. Blood and terminal ileum samples were collected 24 h after surgery. The serum D-lactate levels were determined using an enzyme-linked immunosorbent assay (ELISA) kit. Intestinal permeability was determined by measuring the intestinal clearance of fluorescein isothiocyanate (FITC)-dextran (FD4). Intestinal inflammation was assessed by measuring myeloperoxidase activity. Intestinal histopathology was also assessed. The results revealed that berberine decreased the serum D-lactate level, intestinal FD4 clearance, and myeloperoxidase activity. Edema and inflammation were reduced by berberine in the intestinal mucosa and submucosa, and the Chius scores, indices of intestinal mucosal injury, also decreased in the berberine-treated group. In addition, berberine exerted these protective effects in a dose-dependent manner, with a significant difference from the control group at doses of 150 and 200 mg/kg. The results suggest that berberine could ameliorate intestinal mucosal barrier damage induced by peritoneal air exposure, which is linked to its anti-inflammatory activity. Berberine may be a promising treatment for intestinal mucosal barrier damage in open abdominal surgery.

Insulin alleviates degradation of skeletal muscle protein by inhibiting the ubiquitin-proteasome system in septic rats

Hypercatabolism is common under septic conditions. Skeletal muscle is the main target organ for hypercatabolism, and this phenomenon is a vital factor in the deterioration of recovery in septic patients. In skeletal muscle, activation of the ubiquitin-proteasome system plays an important role in hypercatabolism under septic status. Insulin is a vital anticatabolic hormone and previous evidence suggests that insulin administration inhibits various steps in the ubiquitin-proteasome system. However, whether insulin can alleviate the degradation of skeletal muscle protein by inhibiting the ubiquitin-proteasome system under septic condition is unclear. This paper confirmed that mRNA and protein levels of the ubiquitin-proteasome system were upregulated and molecular markers of skeletal muscle proteolysis (tyrosine and 3-methylhistidine) simultaneously increased in the skeletal muscle of septic rats. Septic rats were infused with insulin at a constant rate of 2.4 mU.kg-1.min-1 for 8 hours. Concentrations of mRNA and proteins of the ubiquitin-proteasome system and molecular markers of skeletal muscle proteolysis were mildly affected. When the insulin infusion dose increased to 4.8 mU.kg-1.min-1, mRNA for ubiquitin, E2-14 KDa, and the C2 subunit were all sharply downregulated. At the same time, the levels of ubiquitinated proteins, E2-14KDa, and the C2 subunit protein were significantly reduced. Tyrosine and 3-methylhistidine decreased significantly. We concluded that the ubiquitin-proteasome system is important skeletal muscle hypercatabolism in septic rats. Infusion of insulin can reverse the detrimental metabolism of skeletal muscle by inhibiting the ubiquitin-proteasome system, and the effect is proportional to the insulin infusion dose.

The effect of extracorporeal membrane oxygenation therapy on systemic oxidative stress injury in a porcine model.

Extracorporeal membrane oxygenation (ECMO) therapy can result in systemic immune inflammation and trigger a hemolytic response, both of which can lead to oxidative stress injury. However, currently, there are few studies about whether ECMO can lead to oxidative stress injury. The objective of this study was to determine the effect of ECMO therapy on systemic oxidative stress. Twelve pigs were randomly divided into control and ECMO treatment groups. Blood samples were collected at -1, 0, 2, 6, 12, and 24 h during ECMO therapy in order to measure the levels of various oxidative stress markers in plasma. All animals included in the study were euthanized after 24 h of ECMO treatment. Malondialdehyde (MDA) was used as a marker of oxidation, and superoxide dismutase (SOD), glutathione (GSH), and total antioxidant capacity (T-AOC) were used as indices for antioxidant activity. The plasma levels of each molecule were similar when measured at -1 and 0 h (P > 0.05). In the control group, MDA, SOD, GSH, and T-AOC remained relatively constant throughout the study period. However, when ECMO was administered for 2 h, plasma levels of MDA increased significantly; conversely, levels of SOD, GSH, and T-AOC decreased. Maximum MDA levels and minimal SOD, GSH, and T-AOC levels were observed after 6 h of ECMO treatment. MDA and SOD levels had returned to baseline at 24 h. At this time-point, levels of MDA and T-AOC in samples from the right frontal cortex and jejunum differed significantly between the control and ECMO treatment groups. These results show that early ECMO treatment can induce significant oxidative stress injury in plasma. However, in the latter stage of the treatment, the oxidative stress injury can be repaired gradually. ECMO treatment can also result in mild oxidative stress injury in the jejunum and brain tissue.

Continuous Renal Replacement Therapy (CRRT) Attenuates Myocardial Inflammation and Mitochondrial Injury Induced by Venovenous Extracorporeal Membrane Oxygenation (VV ECMO) in a Healthy Piglet Model

In this study, we investigated the myocardial inflammation and mitochondrial function during venovenous extracorporeal membrane oxygenation (VV ECMO) and further evaluated the effects of continuous renal replacement therapy (CRRT) on them. Eighteen piglets were assigned to the control group, ECMO group, and ECMO+CRRT group. Myocardial inflammation was assessed by the activity of myeloperoxidase (MPO), myocardial concentrations, and mRNA expression of TNF-α, IL-1β, and IL-6; mitochondrial function was assessed by activities of mitochondrial complexes I–V. VV ECMO elicited a general activation of serum and myocardial inflammation and significantly decreased the activities of mitochondrial complexes I and IV. After being combined with CRRT, serum and myocardial concentrations of IL-1β and IL-6, myocardial mRNA expression of IL-6, and the activity of MPO were decreased significantly; the activities of mitochondrial complexes were increased. We conclude that myocardial inflammation was activated during ECMO therapy, inducing mitochondrial injury; moreover, CRRT reduced myocardial inflammation and partially ameliorated mitochondrial function.

The Effect of Peritoneal Air Exposure on Intestinal Mucosal Barrier

Background. Damage of the intestinal mucosa barrier may result in intestinal bacterial and endotoxin translocation, leading to local and systemic inflammation. The present study was designed to investigate whether peritoneal air exposure induces damage of intestinal mucosal barrier. Methods. Sprague-Dawley rats (weighing 210 to 230 g) were randomized into five groups (6/group): a control group, a sham group, and three exposure groups with peritoneal air exposure for 1, 2, and 3 h, respectively. At 24 h after surgery, blood and terminal ileum were sampled. The serum D-lactate levels were determined using an ELISA kit. The intestinal permeability was determined by measuring the intestinal clearance of FITC-dextran (FD4). The histopathological changes in terminal ileum were also assessed. Results. Compared with the controls, peritoneal air exposure caused an increase in both serum D-lactate level and intestinal FD4 clearance, which were proportional to the length of peritoneal air exposure and correlated to Chius scores, indices for intestinal mucosal injury. Edema and inflammatory cells were also observed in mucosa and submucosa of ileum in three exposure groups. Conclusions. Peritoneal air exposure could induce damage to the intestinal mucosal barrier, which is proportional to the time length of peritoneal air exposure.

Hypothalamic activation is essential for endotoxemia-induced acute muscle wasting

Growing evidence suggests acute skeletal muscle wasting is a key factor affecting nutritional support and prognosis in critical patients. Previously, plenty of studies of muscle wasting focused on the peripheral pathway, little was known about the central role. We tested the hypothesis whether central inflammatory pathway and neuropeptides were involved in the process. In lipopolysaccharide (LPS) treated rats, hypothalamic NF-κB pathway and inflammation were highly activated, which was accompanied with severe muscle wasting. Central inhibition of nuclear factor kappa-B (NF-κB) pathway activation by infusion of an inhibitor (PS1145) can efficiently reduce muscle wasting as well as attenuate hypothalamic neuropeptides alteration. Furthermore, knockdown the expression of anorexigenic neuropeptide proopiomelanocortin (POMC) expression with a lentiviral vector containing shRNA can significantly alleviate LPS-induced muscle wasting, whereas hypothalamic inflammation or NF-κB pathway was barely affected. Taken together, these results suggest activation of hypothalamic POMC is pivotal for acute muscle wasting caused by endotoxemia. Neuropeptide POMC expression may have mediated the contribution of hypothalamic inflammation to peripheral muscle wasting. Pharmaceuticals with the ability of inhibiting hypothalamic NF-κB pathway or POMC activation may have a therapeutic potential for acute muscle wasting and nutritional therapy in septic patients.