Guanwei Li

Exclusive enteral nutritional therapy can relieve inflammatory bowel stricture in Crohn's disease.

Goals: To examine the efficiency of exclusive enteral nutrition (EEN) in relieving inflammatory bowel stricture in patients with Crohn’s disease (CD). Background: Patients with CD usually develop bowel strictures due to transmural edema of intestinal wall, which can potentially be managed with conservative medical treatment. Previous studies showed that EEN therapy could induce clinical remission through its anti-inflammation effect. Methods: We achieved a prospective observational study. CD patients with inflammatory bowel stricture were preliminarily differentiated from a fibrous one, and further treated with EEN therapy for 12 weeks. Demographics and clinical variables were recorded. Nutritional (body mass index, albumin, pre-albumin, transferrin, etc.), inflammatory (C-reactive protein, erythrocyte sedimentation rate, white blood cell, etc.), and radiologic parameters (bowel wall thickness, luminal diameter, and luminal cross-sectional area) were evaluated at baseline, week 4, and week 12, respectively. Results: Between May 2012 and January 2013, 65 patients with CD were preliminarily diagnosed with inflammatory bowel stricture and 6 patients were further excluded. Among the remaining 59 cases, 50 patients (84.7%) finished the whole EEN treatment, whereas the other 9 patients (15.3%) gained progressive bowel obstruction resulting in surgery. Intention-to-treat analyses showed that 48 patients (81.4%) achieved symptomatic remission, 35 patients (53.8%) achieved radiologic remission, and 42 patients (64.6%) achieved clinical remission. Among those patients who complete the whole EEN therapy, inflammatory, nutritional, and radiologic parameters improved significantly compared with baseline. Of note, the average luminal cross-sectional area at the site of stricture increased approximately 331% at week 12 (195.7±18.79 vs. 59.09±10.64 mm2, P<0.001). Conclusions: EEN therapy can effectively relieve inflammatory bowel stricture in CD, which replenishes roles of enteral nutrition in the treatment of CD. Further studies are expected to investigate the underlying mechanisms of this effect in the future.

Diagnostic delay in Crohn's disease is associated with increased rate of abdominal surgery: A retrospective study in Chinese patients

BACKGROUND Diagnostic delay of Crohns disease presents a challenge, and may increase the abdominal surgery rate. There have been no reports regarding diagnostic delay in Chinese patients. AIMS We aimed to evaluate the impact of diagnostic delay on outcomes of Chinese Crohns disease patients, and identify potential risk factors for the delay. METHODS Altogether, 343 Crohns disease patients from our hospital were retrospectively included. We assessed the effects of diagnostic delay on the outcomes, and identified the underlying risk factors. RESULTS Diagnostic interval was defined as the interval between the first symptoms and the diagnosis of Crohns disease. Diagnostic delay was defined according to the time interval in which the 76th to 100th percentiles of patients were diagnosed. The rates of subsequent surgery for diagnostic-delay and non-diagnostic-delay patients were 84.7% and 62.4%, respectively (odds ratio=1.108, P<0.0001). We found statistical differences between the two groups regarding age >40 years at diagnosis (35.3% versus 18.2%, P=0.004), basic educational level (48.2% versus 30.6%, P=0.005), and no family history of Crohns disease (0 versus 1.6%, P=0.045). CONCLUSIONS Diagnostic delay of Crohns disease was significantly associated with increased rates of intestinal surgery. Risk factors for diagnostic delay were age >40 years at diagnosis, basic educational level, and no family history of Crohns disease.

Injectable in situ cross-linking chitosan-hyaluronic acid based hydrogels for abdominal tissue regeneration

Abdominal wall defect caused by open abdomen (OA) or abdominal trauma is a serious issue since it induces several clinical problems. Although a variety of prosthetic materials are commonly employed, complications occur including host soft tissue response, fistula formation and chronic patient discomfort. Recently, abundant natural polymers have been used for injectable hydrogel synthesis in tissue regeneration. In this study, we produced the chitosan - hyaluronic acid (CS/HA) hydrogel and investigated its effects on abdominal tissue regeneration. The physical and biological properties of the hydrogel were demonstrated to be suitable for application in abdominal wounds. In a rat model simulating open abdomen and large abdominal wall defect, rapid cellular response, sufficient ECM deposition and marked neovascularization were found after the application of the hydrogel, compared to the control group and fibrin gel group. Further, the possible mechanism of these findings was studied. Cytokines involved in angiogenesis and cellular response were increased and the skew toward M2 macrophages credited with the functions of anti-inflammation and tissue repair was showed in CS/HA hydrogel group. These findings suggested that CS/HA hydrogel could prevent the complications and was promising for abdominal tissue regeneration.

Urinary Mitochondrial DNA Levels Identify Acute Kidney Injury in Surgical Critical Illness Patients.

Background: Recent studies showed that mitochondrial injury and mitochondrial DNA (mtDNA) damage are associated with the initiation and progression of acute kidney injury (AKI). However, practical limitations of existing assays of mitochondrial function have limited our ability to study the link between mitochondrial dysfunction and renal injury. Therefore, we evaluated urinary mtDNA (UmtDNA) as a biomarker of AKI in critical illness patients. Methods: DNA was isolated from urine samples in surgical intensive care unit (SICU) patients and quantified by quantitative polymerase chain reaction (PCR). Correlation analyses showed the relationships between the UmtDNA and several biomarkers of renal dysfunction. Moreover, we evaluated the predictive and diagnostic values of UmtDNA in newly developed AKI, renal replacement therapy (RRT), and hospital mortality using receiver operating characteristics curves. Results: MtDNA were expressed as PCR threshold cycle (Tc) number. Lower Tc indicated increased urinary mtDNA concentration. The baseline UmtDNA levels were elevated in SICU patients especially in AKI patients, compared with that in healthy controls. UmtDNA Tc number inversely correlated with serum creatine and urinary neutrophil gelatinase-associated lipocalin and directly with estimated glomerular filtration rate. Furthermore, baseline UmtDNA levels had high effectiveness in predicting development of AKI, initiation of RRT, and hospital mortality. Conclusions: Elevated UmtDNA levels could identify newly developed AKI and predict RRT or hospital mortality in SICU patients. UmtDNA Tc number correlated with markers of renal injury and dysfunction, suggesting the involvement of mitochondrial injury in kidney damage among surgical critical illness patients.

Oral pirfenidone protects against fibrosis by inhibiting fibroblast proliferation and TGF-β signaling in a murine colitis model.

Inflammatory bowel disease (IBD), particularly Crohns disease, frequently causes intestinal fibrosis that ultimately leads to formation of strictures requiring bowel resection. Currently there is no effective antifibrotic therapy available for this disease. Pirfenidone is a small compound that has a broad spectrum of antifibrogenic effect and has been used for the treatment of fibrotic diseases in various organs. The present study aimed to investigate the antifibrogenic effect of pirfenidone in a dextran sulfate sodium (DSS)-induced murine colitis model. C57BL/6 mice were used and animals were randomly divided into groups receiving pirfenidone or vehicle by oral or transanal routes. Inflammation- and fibrosis-related indexes including body weight, colon length, disease activity, histological change, mRNA expression of pro-inflammatory and pro-fibrogenic cytokines were assessed. Furthermore, we performed in vitro analysis using CCD18-Co fibroblasts to evaluate cell proliferation, transdifferentiation, and viability after the cells were cultured with pirfenidone. It was found that oral administration of pirfenidone reduced deposition of collagen in colitis-associated fibrosis, and significantly suppressed the mRNA expression of col1a2, col3a1, and TGF-β. Moreover, pirfenidone inhibited the activation of TGF-β-related smad and MAPK pathways both in vitro and in vivo. Clinical and histological evaluation demonstrated that pirfenidone had no anti-inflammatory effect. The antifibrogenic effect was reduced when pirfenidone was administered in a delayed manner and was unobserved if given locally. Pirfenidone suppressed fibroblast proliferation and transdifferentiation without observed toxicity. Altogether, our results suggested that oral pirfenidone protects against fibrosis of DSS-induced colitis through inhibiting the proliferation of colonic fibroblasts and TGF-β signaling pathways.

T2 enhances in situ level of Foxp3+ regulatory cells and modulates inflammatory cytokines in Crohn's disease.

BACKGROUND Acting via IL-10 and transforming growth factor-β (TGF-β), t regulatory cells (Tregs) that express the Forkhead Box P3 (Foxp3) play a vital role in maintaining intestinal immune homeostasis. Many studies have found correlation between Foxp3(+) Treg cells and Crohns disease (CD). T2, extracted from the medicinal plant Tripterygium wilfordii Hook F, has already been proved to be therapeutically effective in inducing the remission of CD. However, the mechanisms in human studies remain largely unknown. AIM We aimed to explore the effect of T2 on the in situ levels of inflammatory cytokines and the number of Foxp3(+) Tregs in inflamed mucosa of CD. METHODS Mucosal biopsies from 20 patients treated with T2 were taken by colonoscopy. The changes of Foxp3(+) Tregs as well as TNF-α and IL-10 in diseased tissue were visualized by immunochemistry. Western blot and ELISA were used to quantify levels of Foxp3 protein expression and inflammatory cytokines. RESULTS T2 treatment ameliorated the pathological inflammation of CD. We observed that the significantly elevated Foxp3(+) Tregs and IL-10 levels in the mucosa of CD patients after T2 treatment concurred with the down-regulation of proinflammatory TNF-α. CONCLUSION We confirmed the efficacy of T2 treatment in CD and showed that microscopic inflammation was attenuated by the modulation of in situ levels of inflammatory cytokines. The therapeutic mechanisms might involve the up-regulation of Foxp3(+) Tregs.

The mitochondrially targeted antioxidant MitoQ protects the intestinal barrier by ameliorating mitochondrial DNA damage via the Nrf2/ARE signaling pathway

Disruption of the mucosal barrier following intestinal ischemia reperfusion (I/R) is life threatening in clinical practice. Mitochondrial dysfunction and oxidative stress significantly contribute to the early phase of I/R injury and amplify the inflammatory response. MitoQ is a mitochondrially targeted antioxidant that exerts protective effects following I/R injury. In the present study, we aimed to determine whether and how MitoQ protects intestinal epithelial cells (IECs) from I/R injury. In both in vivo and in vitro studies, we found that MitoQ pretreatment downregulated I/R-induced oxidative stress and stabilized the intestinal barrier, as evidenced by MitoQ-treated I/R mice exhibiting attenuated intestinal hyperpermeability, inflammatory response, epithelial apoptosis, and tight junction damage compared to controls. Mechanistically, I/R elevated mitochondrial 8-hydroxyguanine content, reduced mitochondrial DNA (mtDNA) copy number and mRNA transcription levels, and induced mitochondrial disruption in IECs. However, MitoQ pretreatment dramatically inhibited these deleterious effects. mtDNA depletion alone was sufficient to induce apoptosis and mitochondrial dysfunction of IECs. Mitochondrial transcription factor A (TFAM), a key activator of mitochondrial transcription, was significantly reduced during I/R injury, a phenomenon that was prevented by MitoQ treatment. Furthermore, we observed that thee protective properties of MitoQ were affected by upregulation of cellular antioxidant genes, including HO-1, NQO-1, and γ-GCLC. Transfection with Nrf2 siRNA in IECs exposed to hypoxia/reperfusion conditions partially blocked the effects of MitoQ on mtDNA damage and mitochondrial oxidative stress. In conclusion, our data suggest that MitoQ exerts protective effect on I/R-induced intestinal barrier dysfunction.

Systemic blockade of P2X7 receptor protects against sepsis-induced intestinal barrier disruption

Sepsis, during which the intestinal epithelial barrier is frequently disrupted, remains a challenging and life-threatening problem in clinical practice. The P2X7 receptor (P2X7R) is a non-selective adenosine triphosphate-gated cation channel present in macrophages that is involved in inflammatory responses. However, little is known about the role of P2X7R in macrophages during sepsis-induced intestinal barrier disruption. In this study, mice were treated with the P2X7R antagonist A740003 or the agonist BzATP by intra-peritoneal injection after the induction of gut-origin sepsis. The survival rates, inflammatory responses, intestinal barrier integrity, macrophage marker expression, and ERK and NF-κB activities were evaluated. Intestinal macrophages were also isolated and studied after exposure to Brilliant Blue G or BzATP. We found that a systemic P2X7R blockade downregulated sepsis-induced inflammatory responses and attenuated intestinal barrier dysfunction based on the evidence that mice in the A740003-treated group exhibited alleviated pro-inflammatory cytokine synthesis, intestinal hyperpermeability, epithelial apoptosis rates and tight junction damage compared with the septic mice. These changes were partly mediated by the inhibition of M1 macrophages activation via ERK/NF-κB pathways. Our data presented herein show that a P2X7R blockade could be a potential therapeutic target for the treatment of sepsis-induced intestinal barrier dysfunction.

An elevated percentage of reticulated platelet is associated with increased mortality in septic shock patients.

AbstractMicrocirculatory changes and coagulation disturbances are thought to play a key role in sepsis. Some evidence suggests that the percentage of reticulated platelets (RP%) may be a valuable and cost-effective sepsis screening parameter. This was a prospective study in surgical patients to investigate the potential value of RP% as a predictor of mortality in septic shock patients.This was a prospective study conducted in a surgical critical care center of a Chinese tertiary care hospital. Consecutive septic shock patients were enrolled at admission. Age- and sex-matched non-septic patients were recruited as control patients. RP% was determined by flow cytometry in 68 septic shock patients and 68 controls.Compared with survivors, septic patients who died presented with a significantly higher RP% (P < 0.001). The area under the receiver-operating characteristic curve for the RP% association with mortality was 0.867 (95 % CI 0.780–0.953, P < 0.001). Kaplan–Meier survival curves showed that mortality risk was significantly different when patients were stratified based on RP% (P < 0.001). This association was preserved in a multi-logistic regression analysis that included clinical confounders (P < 0.014).This prospective study demonstrates that increased RP% identifies septic shock patients who have a high risk of death. RP% has the potential to act as a marker for patient stratification in future clinical trials.

Prevalence and risk factors of acute lower gastrointestinal bleeding in Crohn disease.

AbstractAcute lower gastrointestinal bleeding (ALGIB) is a rare but potentially life-threatening complication of Crohn disease (CD). Thus far, few studies of ALGIB in the context of CD have been published, most of which were case reports with limited value. We aimed to explore the prevalence of ALGIB in CD patients, evaluate risk factors for hemorrhagic CD and its recurrence, and analyze clinical data of the death cases.A total of 1374 CD patients registered from January 2007 to June 2013 were examined. Medical records of 73 patients with ALGIB and 146 matched as controls were reviewed and analyzed retrospectively. Logistic regression and Cox proportional hazards analyses were performed to identify risk factors for ALGIB and the cumulative probability of rebleeding. Kaplan–Meier curves with log-rank tests were used to demonstrate the cumulative survival rates of rebleeding.The prevalence of ALGIB was 5.31% (73/1374) in this study. In the univariate analysis, possible risk factors for ALGIB were duration of CD (odds ratio [OR] 0.60, 95% confidence interval [CI] 0.33–1.09, P = 0.095), perianal disease (OR 1.96, 95% CI 0.92–4.20, P = 0.082), left colon involvement (OR 2.16, 95% CI 1.10–4.24, P = 0.025), azathioprine use ≥1 year (OR 0.46, 95% CI 0.23–0.90, P = 0.023), and previous hemorrhage history (OR 11.86, 95% CI 5.38–26.12, P < 0.0001). In the multivariate analysis, left colon involvement (OR 2.26, 95% CI 1.04–4.91, P = 0.039), azathioprine use ≥1 year (OR 0.44, 95% CI 0.20–0.99, P = 0.044), and previous hemorrhage history (OR 13.04, 95% CI 5.66–30.04, P < 0.0001) remained independent influencing factors. Older age (HR 0.23, 95% CI 0.07–0.77, P = 0.018), surgical treatment (HR 0.17, 95% CI 0.06–0.50, P < 0.001), and having bleeding episodes >3 months ago (HR 0.24, 95% CI 0.07–0.82, P = 0.022) resulted to be predictors associated with rebleeding after discharge. Patients who died often suffered severe concomitant diseases, and the overall mortality rate was 8.22% (6/73).We speculated that a special hemorrhagic phenotype of CD that was predisposed to rebleeding may exist. Further studies are warranted to investigate the pathogenesis and discover the optimum treatments of choice.