Barrier Dysfunction In Patients Research Articles

Oncostatin M promotes epithelial barrier dysfunction in patients with eosinophilic chronic rhinosinusitis with nasal polyps

ABSTRACT Background Oncostatin M (OSM) may be involved in the promotion of mucosal epithelial barrier dysfunction in patients with eosinophilic chronic rhinosinusitis with nasal polyps (Eos CRSwNP) by inducing matrix metalloproteinase (MMP) −1 and −7. The aim was to evaluate the roles and mechanisms of action of OSM on MMP-1 and −7 synthesis from nasal epithelial cells (NECs). Methods OSM, OSM receptor (OSMR), MMP-1 and −7 expression was evaluated in nasal mucosa or primary NECs from scrapings by quantitative polymerase chain reaction (qPCR), immunofluorescence and immunohistochemistry. OSM and other cytokines were used to stimulate air-liquid interface (ALI) cultured NECs. qPCR, enzyme-linked immunosorbent assay (ELISA) and immunofluorescence were used to evaluate the expression of OSMR, MMP-1, −7 and occludin in NECs. Results Elevated levels of OSMRβ, MMP-1 and −7 were found in the tissues and scraped NECs of Eos CRSwNP in comparison to them obtained from the inferior turbinate (IT) and control subjects. The levels of OSM and OSMRβ mRNA in tissues were positively correlated with the levels of MMP-1 and −7. OSM stimulation of NECs increased the expression of MMP-1 and −7, and the responses were suppressed by a STAT3 inhibitor, and a PI3K inhibitor respectively. In parallel studies, we found that stimulation with OSM disrupted the localization of occludin, a tight junction protein in NECs. The response was suppressed by a pan-MMP inhibitor. Conclusion OSM induces the synthesis and release of MMP-1 and −7 in NECs. Furthermore, MMP-1 and −7 promote mucosal epithelial barrier dysfunction in patients with Eos CRSwNP.

Clinical Significance of Serum CTRP3 Level in the Prediction of Cardiac and Intestinal Mucosal Barrier Dysfunction in Patients with Severe Acute Pancreatitis.

C1q/tumor necrosis factor-related protein 3 (CTRP3) has been demonstrated to play a protective role in mice with severe acute pancreatitis (SAP). However, its clinical significance in SAP remains unknown. This study was conducted to explore the clinical values of serum C1q/tumor necrosis factor-related protein 3 (CTRP3) level in the diagnosis of cardiac dysfunction (CD) and intestinal mucosal barrier dysfunction (IMBD) in SAP. Through RT-qPCR, we observed decreased CTRP3 level in the serum of SAP patients. Serum CTRP3 level was correlated with C-reactive protein, procalcitonin, creatine, modified computed tomography severity index score, and Acute Physiology and Chronic Health Evaluation II score. The receiver-operating characteristic curve revealed that CTRP3 serum level < 1.005 was conducive to SAP diagnosis with 72.55% sensitivity and 60.00% specificity, CTRP3 < 0.8400 was conducive to CD diagnosis with 80.49% sensitivity and specificity 65.57%, CTRP3 < 0.8900 was conducive to IMBD diagnosis with 94.87% sensitivity and 63.49% specificity, and CTRP3 < 0.6250 was conducive to the diagnosis of CD and IMBD co-existence with 65.22% sensitivity and 89.87% specificity. Generally, CTRP3 was downregulated in the serum of SAP patients and served as a candidate biomarker for the diagnosis of SAP and SAP-induced CD and IMBD.

The Alleviating Effects and Mechanisms of Betaine on Dextran Sulfate Sodium-Induced Colitis in Mice.

Ulcerative colitis (UC) is an intestinal disease that is becoming increasingly prevalent and is often overlooked in early stages, and its pathogenesis is often closely related to inflammatory processes. Betaine is a natural product with anti-inflammatory effects that exists in a wide range of plants and animals. In this study, the protective effects of betaine are investigated on intestinal barrier function in a mouse model, a dextran sulfate sodium-induced ulcerative colitis and its mechanism of action in the inflammatory context. FITC-dextran 4000Da (FD-4) flux, disease activity index, histopathological scores, and inflammatory factor levels in sera are determined across different groups. In addition, Caco-2 cell monolayer barrier function is evaluated by transepithelial resistance and FD-4 flux. The expression levels and distribution of tight junction proteins are determined using Western blot and immunofluorescence, respectively. Activation of the NF-κBp65/MLCK/p-MLC signaling pathway is detected by Western blot. Chromatin immunoprecipitation is performed to examine the binding of NF-κB to the MLCK gene promoter. The results indicated that betaine inhibits NF-κB-mediated activation of the MLCK/p-MLC signaling pathway to protect the intestinal barrier function of mice with UC. Betaine can be used as a potential candidate drug to improve intestinal barrier dysfunction in patients with UC.

Amelioration of intestinal barrier function and reduction of blood lead level in adult women with recurrent spontaneous abortion by a novel product of dietary fiber mixture, Holofood

BackgroundThe elevated circulating toxins secondary to the impairment of intestinal barrier integrity commonly elicit a chronic inflammatory response and finally contribute to multiple diseases. These toxins, including bacterial by-products and heavy metals, are the potent risk factors for the development of recurrent spontaneous abortion (RSA). Preclinical evidence suggests that several dietary fibers can restore intestinal barrier function and decrease the accumulation of heavy metals. However, it is uncertain whether treatment with a newly developed blend of dietary fibers product (Holofood) benefits patients with RSA.MethodsIn this trial, we enrolled 70 adult women with RSA, who were randomly assigned into the experiment group and the control group in a 2:1 ratio. Upon the basis of conventional therapy, subjects in the experiment group (n = 48) received 8 weeks oral administration with Holofood three times daily at a dose of 10 g each time. Subjects without Holofood consumption were set as the control (n = 22). Blood samples were collected for the determinations of metabolic parameters, heavy mental lead, and the indices related to intestinal barrier integrity (d-lactate, bacterial endotoxin, and diamine oxidase activity).ResultsThe reduction amplitude in blood lead from baseline to week 8 was 40.50 ± 54.28 (μg/L) in the experiment group as compared with 13.35 ± 36.81 (μg/L) in the control group (P = 0.037). The decreased level of serum d-lactate from baseline to week 8 was 5.58 ± 6.09 (mg/L) in the experiment group as compared with − 2.38 ± 8.90 (mg/L, P < 0.0001) in the control group. The change in serum DAO activity from baseline to week 8 was 3.26 ± 2.23 (U/L) in the experiment group as compared with − 1.24 ± 2.22 (U/L, P < 0.0001) in the control group. Participants who received Holofood had a greater decline in blood endotoxin from baseline to week 8 than those in the control group. Moreover, by comparing with the self-baseline, Holofood consumption significantly decreased the blood levels of lead, d-lactate, bacterial endotoxin, and DAO activity.ConclusionOur results suggest that Holofood affords a clinically relevant improvements in blood lead level and intestinal barrier dysfunction in patients with RSA.

MicroRNA-1-3p and T-synthase mRNA have high diagnostic efficacy on intestinal mucosal barrier dysfunction in patients with severe acute pancreatitis.

Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can be complicated by intestinal mucosal barrier dysfunction (SAP&IBD). The current study sought to examine the diagnostic efficacy of miR-1-3p and T-synthase mRNA in SAP&IBD patients. First, SAP patients were assigned to SAP&IBD and SAP groups. Serum miR-1-3p expression and T-synthase mRNA expression patterns in peripheral blood B lymphocytes were measured using RT-qPCR. Pearson tests, ROC curve analysis, and multivariate logistic regression were used to analyze the correlation between miR-1-3p/T-synthase mRNA and clinical data, their diagnostic efficiency, and independent risk factors for SAP&IBD patients, respectively. The results showed that serum miR-1-3p in the SAP&IBD group was elevated, and T-synthase mRNA expression in peripheral blood B lymphocytes was diminished. Additionally, serum miR-1-3p expression in SAP&IBD patients was negatively correlated with T-synthase mRNA expression, and positively correlated with their Ranson score, CRP, IL-6, DAO, and D-Lactate levels. Meanwhile, T-synthase mRNA level was negatively correlated with IL-6, DAO, and D-Lactate levels. Both, serum miR-1-3p, T-synthase mRNA, and their combination were found to exhibit diagnostic efficiency for SAP&IBD patients, and were independently associated with IBD in SAP patients. Collectively, our findings suggest that miR-1-3p and T-synthase serve as independent risk factors for SAP&IBD patients and can aid the diagnosis of IBD in SAP patients.

Diffusion prepared pseudo-continuous arterial spin labeling reveals blood-brain barrier dysfunction in patients with CADASIL.

Diffusion prepared pseudo-continuous arterial spin labeling (DP-pCASL) is a newly proposed MRI method to noninvasively measure the function of the blood-brain barrier (BBB). We aim to investigate whether the water exchange rate across the BBB, estimated with DP-pCASL, is changed in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and to analyze the association between the BBB water exchange rate and MRI/clinical features of these patients. Forty-one patients with CADASIL and thirty-six age- and sex-matched controls were scanned with DP-pCASL MRI to estimate the BBB water exchange rate (kw). The MRI lesion burden, the modified Rankin scale (mRS), and the neuropsychological scales were also examined. The association between kw and MRI/clinical features was analyzed. Compared with that in the controls, kw in patients with CADASIL was decreased at normal-appearing white matter (NAWM) (t = - 4.742, p < 0.001), cortical gray matter (t = - 5.137, p < 0.001), and deep gray matter (t = - 3.552, p = 0.001). After adjustment for age, gender, and arterial transit time, kw at NAWM was negatively associated with the volume of white matter hyperintensities (β = - 0.754, p = 0.001), whereas decreased kw at NAWM was independently associated with an increased risk of abnormal mRS scale (OR = 1.058, 95% CI: 1.013-1.106, p = 0.011) in these patients. This study found that the BBB water exchange rate was decreased in patients with CADASIL. The decreased BBB water exchange rate was associated with an increased MRI lesion burden and functional dependence of the patients, suggesting the involvement of BBB dysfunction in the pathogenesis of CADASIL. DP-pCASL reveals BBB dysfunction in patients with CADASIL. The decreased BBB water exchange rate is associated with MRI lesion burden and functional dependence, indicating the potential of DP-pCASL as an evaluation method for disease severity. • DP-pCASL reveals blood-brain barrier dysfunction in patients with CADASIL. • Decreased BBB water exchange rate, an indicator of BBB dysfunction detected by DP-pCASL, was associated with MRI/clinical features of patients with CADASIL. • DP-pCASL can be used as an evaluation method to assess the severity of disease in patients with CADASIL.

Cutaneous dysbiosis may amplify barrier dysfunction in patients with atopic dermatitis.

Atopic dermatitis (AD) is associated with cutaneous dysbiosis, barrier defects, and immune dysregulation, but the interplay between these factors needs further study. Early-onset barrier dysfunction may facilitate an innate immune response to commensal organisms and, consequently, the development of allergic sensitization. We aimed to compare the cutaneous microbiome in patients with active dermatitis with and without a history of childhood flexural dermatitis (atopic dermatitis). Next-gen Ion-Torrent deep-sequencing identified AD-associated changes in the skin bacterial microbiome ("bacteriome") and fungal microbiome ("mycobiome") of affected skin in swabs from areas of skin affected by dermatitis. Data were analyzed for diversity, abundance, and inter-kingdom correlations. Microbial interactions were assessed in biofilms using metabolic activity (XTT) assay and scanning electron microscopy (SEM), while host-pathogen interactions were determined in cultured primary keratinocytes exposed to biofilms. Increased richness and abundance of Staphylococcus, Lactococcus, and Alternaria were found in atopics. Staphylococcus and Alternaria formed robust mixed-species biofilms (based on XTT and SEM) that were resistant to antifungals/antimicrobials. Furthermore, their biofilm supernatant was capable of influencing keratinocytes biology (pro-inflammatory cytokines and structural proteins), suggesting an additive effect on AD-associated host response. In conclusion, microbial inter-kingdom and host-microbiome interactions may play a critical role in the modulation of atopic dermatitis to a greater extent than in non-atopic adults with allergic contact dermatitis.

Plasma Microbiome in COVID-19 Subjects: An Indicator of Gut Barrier Defects and Dysbiosis.

The gut is a well-established route of infection and target for viral damage by SARS-CoV-2. This is supported by the clinical observation that about half of COVID-19 patients exhibit gastrointestinal (GI) complications. We aimed to investigate whether the analysis of plasma could provide insight into gut barrier dysfunction in patients with COVID-19 infection. Plasma samples of COVID-19 patients (n = 146) and healthy individuals (n = 47) were collected during hospitalization and routine visits. Plasma microbiome was analyzed using 16S rRNA sequencing and gut permeability markers including fatty acid binding protein 2 (FABP2), peptidoglycan (PGN), and lipopolysaccharide (LPS) in both patient cohorts. Plasma samples of both cohorts contained predominately Proteobacteria, Firmicutes, Bacteroides, and Actinobacteria. COVID-19 subjects exhibit significant dysbiosis (p = 0.001) of the plasma microbiome with increased abundance of Actinobacteria spp. (p = 0.0332), decreased abundance of Bacteroides spp. (p = 0.0003), and an increased Firmicutes:Bacteroidetes ratio (p = 0.0003) compared to healthy subjects. The concentration of the plasma gut permeability marker FABP2 (p = 0.0013) and the gut microbial antigens PGN (p < 0.0001) and LPS (p = 0.0049) were significantly elevated in COVID-19 patients compared to healthy subjects. These findings support the notion that the intestine may represent a source for bacteremia and contribute to worsening COVID-19 outcomes. Therapies targeting the gut and prevention of gut barrier defects may represent a strategy to improve outcomes in COVID-19 patients.

STRUCTURAL AND FUNCTIONAL INTESTINAL BARRIER ABNORMALITIES AND CHRONIC KIDNEY DISEASE. LITERATURE REVIEW. PART II

The last few decades have been marked by significant progress in the investigation of the intestinal microbial-tissue complex and its role in the pathogenesis of a wide range of diseases. The presence of intestinal barrier dysfunction has also been confirmed in various nephropathies. Patients with chronic kidney disease (CKD) are characterized by specific alterations of the qualitative and quantitative composition of the gut microbiota. These changes contribute to an increase in the fermentation of food proteins into uremic toxins, such as p-cresyl sulfate, indoxyl sulfate and trimethylaminoxide, disorders of immune tolerance mechanisms of the mucous membrane, disorganization of intestinal epithelium tight junctions, which inevitably leads to an increase of transepithelial permeability. Translocation of bacteria and microbial metabolism products from the intestinal lumen into the systemic circulation is responsible for systemic inflammation, which is currently considered as one of the leading causes of the CKD progression and related complications. However, the exact mechanisms of gut-kidney interaction remain poorly understood. The second part of the review gives a detailed description of the structural and functional disorders of the intestinal muco-epithelial barrier identified in various nephropathies. The mechanisms of uremia-induced intestinal epithelial disruption are discussed, as well as the current therapeutic strategies that may attenuate consequences of intestinal barrier dysfunction in patients with CKD.

1139: PRIMARY AND FOOD-INDUCED SECONDARY BARRIER DYSFUNCTION IN PATIENTS WITH CROHNS DISEASE

1139: PRIMARY AND FOOD-INDUCED SECONDARY BARRIER DYSFUNCTION IN PATIENTS WITH CROHNS DISEASE

Ictal hypoperfusion and iron deposition in the symptomatogenic zone of epilepsia partialis continua – A case report

Ictal hypoperfusion and iron deposition in the symptomatogenic zone of epilepsia partialis continua – A case report

Glucagon-like peptide-1 is associated with poor clinical outcome, lipopolysaccharide translocation and inflammation in patients undergoing cardiac surgery with cardiopulmonary bypass

IntroductionCardiac surgery with cardiopulmonary bypass (CPB) is associated with gut barrier dysfunction. Gut barrier dysfunction might be estimated non-invasively by lipopolysaccharide (LPS) plasma concentration. Glucagon-like peptide-1 (GLP-1) is a gut secreted hormone that is a potential marker of mucosal integrity. Our objective was to evaluate GLP-1 as a peri-operative marker of gut barrier dysfunction in patients undergoing cardiac surgery with CPB. MethodsGLP-1, intestinal fatty acid binding protein (I-FABP) and lipopolysaccharide were assayed: at induction, after CPB and 24 h after admission in the intensive care unit. The primary end-point was peri-operative lipopolysaccharide concentration (LPS concentration at those 3 time points). ResultsSeventy-two patients were included in the present analysis. The highest measured post-operative GLP-1 concentration was in the sample taken 24 h after admission to intensive care, which was associated with peri-operative lipopolysaccharide plasma concentration. Patients who had the highest GLP-1 concentrations at 24 h experienced more severe inflammation and worse clinical outcomes. ConclusionOur study supports that GLP-1 is not only a hormone of glucose metabolism but is also secreted when gut barrier is impaired in cardiac surgery with CPB. The GLP-1 levels measured 24 h after admission to the intensive care unit were associated with LPS concentration, inflammation and clinical outcomes.

Angiopoietin-2 Is an Early Predictor for Acute Gastrointestinal Injury and Intestinal Barrier Dysfunction in Patients with Acute Pancreatitis.

Angiopoietin-2 (Ang-2) is a new predictor for acute pancreatitis (AP). To assess the predictive value of Ang-2 in determining the progress of AP and the subsequent acute gastrointestinal injury (AGI). This was a prospective study that enrolled 170 patients with AP and 100 healthy controls. Blood samples were collected within 24h of the onset of AP. The majority (108) of the patients were categorized as having MAP with the rest (62) classified as suffering from SAP. Considering AGI grading, there were 118 grade 1 and 12 grade 4 patients; in grades 2 and 3, there were 20 patients each. AP was accompanied by MODS and pancreatic necrosis in 46 and 24 cases, respectively. Eighty patients were admitted to the ICU, while mortality was reported among 7.1% patients. The plasma Ang-2 levels were higher among patients with AP than in controls. A similar trend prevailed, in patients with SAP compared to those with MAP. Ang-2 was significantly increased from AGI grade 1 through to grade 4, showing a desirable positive predictive accuracy. Moreover, Ang-2 also showed strong correlations with intestinal permeability as evaluated by d-lactate (DLA), diamine oxidase (DAO), and intestinal fatty acid binding proteins (I-FABPs). Tools (Ranson and APACHE II scores, CRP), which are used more conventionally, could not effectively distinguish the various grades of AGI. Furthermore, Ang-2 predicted poor prognosis and adverse outcomes, including mortality, among patients with AP. This study showed Ang-2 to be an accurate early predictor for SAP, AGI, and intestinal barrier dysfunction, outperforming conventional biomarkers. Ang-2 levels also predicted the adverse outcomes and mortality due to AP.

Screening and combining serum biomarkers to improve their diagnostic performance in the detection of intestinal barrier dysfunction in patients after major abdominal surgery.

The aim of this prospective study was to screen and combine effective biomarkers to improve their diagnostic performance in detecting intestinal barrier dysfunction in patients after major abdominal surgery. Patients undergoing major abdominal surgery were enrolled after signing informed consent in this study. The serum concentrations of α-GST, DAO, D-lactate, citrulline and I-FABP were detected 24 hours before and after surgery. The diagnostic performance of five biomarkers on intestinal barrier dysfunction was assessed using logistic regression models and receiver operating characteristic (ROC) curve analyses. Thirty-nine patients with major abdominal surgery were enrolled in and successfully completed this study. ROC analysis revealed that the sensitivities of D-lactate, citrulline and I-FABP were very high (0.91, 0.91 and 1.00, respectively), but the specificities of these biomarkers were less than 0.70. The sensitivity of DAO was very low [0.25; 95% confidence interval (CI), 0.05-0.57], but its specificity was high (0.92; 95% CI, 0.75-0.99). The accuracies of D-lactate and I-FABP were very high, and the areas under the curves (AUCs) of the biomarkers were 0.84 (95% CI, 0.68-0.93) and 0.81 (95% CI, 0.65-0.92), respectively. Different combinations of five biomarkers were also analysed. The sensitivity, specificity and AUC values of the combination of I-FABP, citrulline and D-lactate were 1.00, 0.74 and 0.89, respectively. These results were similar to those derived from the combination of α-GST, DAO, D-lactate, citrulline and I-FABP (P=1.000). The combination of serum D-lactic acid, citrulline and I-FABP greatly improved the diagnostic performance for identifying intestinal barrier dysfunction in patients after major abdominal surgery.

Evidence for peri-ictal blood-brain barrier dysfunction in patients with epilepsy.

Epilepsy has been associated with a dysfunction of the blood-brain barrier. While there is ample evidence that a dysfunction of the blood-brain barrier contributes to epileptogenesis, blood-brain barrier dysfunction as a consequence of single epileptic seizures has not been systematically investigated. We hypothesized that blood-brain barrier dysfunction is temporally and anatomically associated with epileptic seizures in patients and used a newly-established quantitative MRI protocol to test our hypothesis. Twenty-three patients with epilepsy undergoing inpatient monitoring as part of their presurgical evaluation were included in this study (10 females, mean age ± standard deviation: 28.78 ± 8.45). For each patient, we acquired quantitative T1 relaxation time maps (qT1) after both ictal and interictal injection of gadolinium-based contrast agent. The postictal enhancement of contrast agent was quantified by subtracting postictal qT1 from interictal qT1 and the resulting ΔqT1 was used as a surrogate imaging marker of peri-ictal blood-brain barrier dysfunction. Additionally, the serum concentrations of MMP9 and S100, both considered biomarkers of blood-brain barrier dysfunction, were assessed in serum samples obtained prior to and after the index seizure. Fifteen patients exhibited secondarily generalized tonic-clonic seizures and eight patients exhibited focal seizures at ictal injection of contrast agent. By comparing ΔqT1 of the generalized tonic-clonic seizures and focal seizures groups, the anatomical association between ictal epileptic activity and postictal enhancement of contrast agent could be probed. The generalized tonic-clonic seizures group showed significantly higher ΔqT1 in the whole brain as compared to the focal seizures group. Specific analysis of scans acquired later than 3 h after the onset of the seizure revealed higher ΔqT1 in the generalized tonic-clonic seizures group as compared to the focal seizures group, which was strictly lateralized to the hemisphere of seizure onset. Both MMP9 and S100 showed a significantly increased postictal concentration. The current study provides evidence for the occurrence of a blood-brain barrier dysfunction, which is temporally and anatomically associated with epileptic seizures. qT1 after ictal contrast agent injection is rendered as valuable imaging marker of seizure-associated blood-brain barrier dysfunction and may be measured hours after the seizure. The observation of the strong anatomical association of peri-ictal blood-brain barrier dysfunction may spark the development of new functional imaging modalities for the post hoc visualization of brain areas affected by the seizure.

Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in patients with high blood pressure.

Recent evidence indicates a link between gut pathology and microbiome with hypertension (HTN) in animal models. However, whether this association exists in humans is unknown. Thus, our objectives in the present study were to test the hypotheses that high blood pressure (BP) patients have distinct gut microbiomes and that gut-epithelial barrier function markers and microbiome composition could predict systolic BP (SBP). Fecal samples, analyzed by shotgun metagenomics, displayed taxonomic and functional changes, including altered butyrate production between patients with high BP and reference subjects. Significant increases in plasma of intestinal fatty acid binding protein (I-FABP), lipopolysaccharide (LPS), and augmented gut-targetting proinflammatory T helper 17 (Th17) cells in high BP patients demonstrated increased intestinal inflammation and permeability. Zonulin, a gut epithelial tight junction protein regulator, was markedly elevated, further supporting gut barrier dysfunction in high BP. Zonulin strongly correlated with SBP (R2 = 0.5301, P<0.0001). Two models predicting SBP were built using stepwise linear regression analysis of microbiome data and circulating markers of gut health, and validated in a separate cohort by prediction of SBP from zonulin in plasma (R2 = 0.4608, P<0.0001). The mouse model of HTN, chronic angiotensin II (Ang II) infusion, was used to confirm the effects of butyrate and gut barrier function on the cardiovascular system and BP. These results support our conclusion that intestinal barrier dysfunction and microbiome function are linked to HTN in humans. They suggest that manipulation of gut microbiome and its barrier functions could be the new therapeutic and diagnostic avenues for HTN.

MicroRNA expression profiling of intestinal mucosa tissue predicts multiple crucial regulatory molecules and signaling pathways for gut barrier dysfunction of AIDS patients.

Human immunodeficiency virus-1 (HIV-1) infection severely damages the gut-associated lymphoid tissue (GALT), the immune system and the gut barrier, which leads to accelerating the disease progression for patients with acquired immune deficiency syndrome (AIDS). Dysregulation of microRNAs (miRNAs) may contribute to this process. However, few studies have investigated the importance of miRNAs in AIDS pathogenesis and progression. The whole miRNA profile of patients with HIV infection from southwest P.R. China and the mode of interaction between HIV-1 and miRNAs remains to be elucidated. Colon mucosal samples were collected from HIV+ patients and HIV− healthy individuals, miRNAs were isolated and subjected to array hybridization in the present study. A total of 476 human and virus-derived microRNAs were significantly altered in the HIV+ group when compared with the control group (P<0.05), which may be involved in the progression to AIDS. Target genes of the significantly altered miRNAs were predicted using the TargetScan, miRbase and miRanda databases and the 10 shared target genes of upregulated miRNAs and the 391 target genes of downregulated miRNAs were selected. As only 10 target genes were predicted for upregulated miRNAs, subsequent GO and KEGG pathway analyses were focused on the 391 target genes of the downregulated miRNAs. The findings of the present study identified a series of crucial pathways, including cell-extracellular matrix interaction and chemokine regulation, which indicated close affinity with CD4+ T cell activation. These pathways, involving genes such as integrin α5, led to a gut barrier dysfunction of patients with HIV. Important miRNAs include hsa-miRNA-32-5p, hsa-miRNA-195-5p, hsa-miRNA-20b-5p, hsa-miRNA-590-5p. The expression levels of the miRNAs and their target genes were confirmed using RT-qPCR. Taking into previous observations, the findings of the present study identified the importance of miRNAs for regulating gut barrier dysfunction via multiple regulatory molecules and signaling pathways, which elucidated the underlying molecular mechanism of gut barrier dysfunction in patients with HIV.

Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases

Epithelial barriers of the skin, gastrointestinal tract, and airway serve common critical functions, such as maintaining a physical barrier against environmental insults and allergens and providing a tissue interface balancing the communication between the internal and external environments. We now understand that in patients with allergic disease, regardless of tissue location, the homeostatic balance of the epithelial barrier is skewed toward loss of differentiation, reduced junctional integrity, and impaired innate defense. Importantly, epithelial dysfunction characterized by these traits appears to pre-date atopy and development of allergic disease. Despite our growing appreciation of the centrality of barrier dysfunction in initiation of allergic disease, many important questions remain to be answered regarding mechanisms disrupting normal barrier function. Although our external environment (proteases, allergens, and injury) is classically thought of as a principal contributor to barrier disruption associated with allergic sensitization, there is a need to better understand contributions of the internal environment (hormones, diet, and circadian clock). Systemic drivers of disease, such as alterations of the endocrine system, metabolism, and aberrant control of developmental signaling, are emerging as new players in driving epithelial dysfunction and allergic predisposition at various barrier sites. Identifying such central mediators of epithelial dysfunction using both systems biology tools and causality-driven laboratory experimentation will be essential in building new strategic interventions to prevent or reverse the process of barrier loss in allergic patients.

Restoring airway epithelial barrier dysfunction: a new therapeutic challenge in allergic airway disease

An intact functional mucosal barrier is considered to be crucial for the maintenance of airway homeostasis as it protects the host immune system from exposure to allergens and noxious environmental triggers. Recent data provided evidence for the contribution of barrier dysfunction to the development of inflammatory diseases in the airways, skin and gut. A defective barrier has been documented in chronic rhinosinusitis, allergic rhinitis, asthma, atopic dermatitis and inflammatory bowel diseases. However, it remains to be elucidated to what extent primary (genetic) versus secondary (inflammatory) mechanisms drive barrier dysfunction. The precise pathogenesis of barrier dysfunction in patients with chronic mucosal inflammation and its implications on tissue inflammation and systemic absorption of exogenous particles are only partly understood. Since epithelial barrier defects are linked with chronicity and severity of airway inflammation, restoring the barrier integrity may become a useful approach in the treatment of allergic diseases. We here provide a state-of-the-art review on epithelial barrier dysfunction in upper and lower airways as well as in the intestine and the skin and on how barrier dysfunction can be restored from a therapeutic perspective.

Intestinal barrier dysfunction and its related factors in patients with sepsis

Objective: To investigate the relationship between related factors of intestinal barrier dysfunction in patients with sepsis or septic shock and severity of the condition. Methods: A prospective observational study was conducted in 31 sepsis patients, 28 septic shock patients, and 21 postoperative patients without sepsis (control group) who were admitted to intensive care unit (ICU) of General Hospital of Ningxia Medical University between November 2015 and June 2016. Blood samples were collected from the patients within 24 hours following admission to ICU. D-lactic acid and endotoxin levels were measured by enzymatic method, serum high-sensitivity C-reactive protein (hsCRP) level by immune scatter turbidimetry. An arterial blood gas (ABG) measurement was carried out every 8 hours within the first 24 hours after admission to ICU, and average arterial blood lactate levels were calculated. Acute Physiology and Chronic Health Evaluation Ⅱ (APACHE Ⅱ) score, Sequential Organ Failure Assessment (SOFA) score of the patients within 24 hours following ICU admission were recorded. The patients with sepsis or septic shock were followed up for 28 days after admission to ICU, and divided into survival group (n=44) and death group (n=15). The patients with sepsis or septic shock were divided into two groups according to the site of infection, i. e. intra-abdominal infection group (n=37) and extra-abdominal infection group (n=22). Results: (1) In the control, sepsis, and septic shock groups, D-lactic acid [mg/L, M(P25, P75) ] were 11.68(7.49, 14.92), 19.78 (12.25, 34.85), and 32.45 (16.03, 46.95), respectively; endotoxin levels [U/L, M(P25, P75)] were 10.60(7.59, 13.39), 16.12(10.09, 20.23), and 17.31(14.09, 23.77), respectively. The levels of serum D-lactic acid and endotoxin in the patients with sepsis or septic shock were significantly higher than those in the control group (all P<0.01); while no statistically significant differences existed in these two indices between the sepsis and septic shock groups (both P>0.05). There were no statistically significant differences in serum D-lactic acid and endotoxin levels between the intra-abdominal infection group and the extra-abdominal infection group [20.07(14.70, 38.97)vs 21.65 (14.53, 56.56)mg/L; 17.23(13.38, 20.85)vs 17.17(9.93, 20.81)U/L; both P>0.05]. There were no statistically significant differences in levels of serum D-lactic acid and endotoxin between the survival group and the death group [21.65(15.11, 39.00) vs 19.78(14.41, 80.93)mg/L; 17.09(12.62, 20.42) vs 19.26(13.22, 26.27)U/L, both P>0.05]. (2) In the sepsis and septic shock patients, serum D-lactate level was significantly related to mean arterial blood lactate concentration, APACHE Ⅱ score, and SOFA score in the first 24 hours after admission to ICU (r=0.499, 0.447, 0.469, all P<0.01); serum endotoxin level was correlated with hsCRP, APACHE Ⅱ score, and SOFA score (r=0.224, 0.388, 0.393, all P<0.05). (3) Multivariate linear regression analysis showed that D-lactic acid level was independently associated with average arterial blood lactate concentration as well as with SOFA score(R2=0.34, F=19.91, P<0.01), and endotoxin was independently associated with only SOFA score(R2=0.14, F=12.68, P<0.01). Conclusions: Regardless of the site of infection, patients with sepsis or septic shock often have intestinal barrier injury, which is correlated with the severity of disease, but does not independently affect patient outcome. Tissue hypoperfusion in the early stage of sepsis may be one of the causes of intestinal barrier injury.