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Clinical Aspects

Prognostic Value of Plasma Tight-Junction Proteins for Sepsis in Emergency Department

an Observational Study

Zhao, Guang-Ju; Li, Dong; Zhao, Qian; Lian, Jie; Hu, Tian-Tian; Hong, Guang-liang; Yao, Yong-Ming; Lu, Zhong-Qiu

Author Information
doi: 10.1097/SHK.0000000000000524

Abstract

INTRODUCTION

Sepsis, as a severe systemic inflammatory response to bacterial infection, has remained a challenge in intensive care despite improvements in modern treatment, with an estimated mortality rate of 25%, and up to 60% when shock is present (1, 2). Vascular, which is highly responsive to their extracellular environment, is the primary targets of sepsis-induced damage and capillary leak accounts for leukocyte extravasation, protein-rich tissue edema, hypotension and organ dysfunction of severe sepsis and septic shock (3–5). Capillary leakage is mediated by transcellular and paracellular pathways. The transcellular pathway includes vesicular transport systems, fenestrae, and biochemical transporters (6). On the other hand, paracellular leakage is controlled by the dynamic opening and closing of endothelial junctions (6).

Intercellular junction of endothelial cells (ECs) is mediated by adhesion structures, which can be divided into tight junction (TJ), adherent junction (AJ), and gap junction (GJ) (6, 7). The types of endothelial junctions show considerable variability among different segments of the vascular tree (8). Venular ECs primarily form AJs, whereas TJs are less complex in venular than in capillaries and arterioles (7, 8). TJs are formed by multiprotein complexes containing cytosolic and transmembrane proteins (6–8). Claudin (CLDN) is a family of transmembrane proteins with four transmembrane domains (9). Previously studies indicated that endothelial TJs specifically and highly express CLDN-5, with a few exceptions (7, 10). CLDNs and occludin (OCLN), another plasma membrane component, bind to the cytosolic protein zonula occludens (ZO)-1, which links to the cytoskeletion and thereby provides junctional stability (6, 7, 11).

It has been demonstrated that disruption of TJ-associated proteins contributed to the breakdown of TJs and an increase in vascular permeability in response to stimulation of inflammatory cytokines (10, 12, 13). Additionally, the breakdown of TJs and release of TJ-associated proteins into the circulation were identified to occur during celiac disease, type 1 diabetes, as well as hemorrhagic transformation after ischemic stroke (14–16). Accordingly, the present study was designed to investigate whether plasma levels of OCLN, CLDN-5, and ZO-1 could serve as predictors of severity and clinical outcome of sepsis.

MATERIALS AND METHODS

Patients

Patients with sepsis (n = 51) were selected from the emergency department (ED) of the First Affiliated Hospital of Wenzhou Medical University, an urban university tertiary hospital with approximately 130,000 ED admissions per year. Patients included were enrolled between September 2013 and June 2014. All patients were met the American College of Chest Physicians/Society of Critical Care Medicine (ACCP/SCCM) criteria of sepsis (17). Sepsis is defined as at least two of the signs of systemic inflammatory response syndrome (SIRS) in response to infection. Patients with sepsis plus acute organ dysfunction or tissue hypoperfusion (lactate>4 mmol/L or oliguria <0.5 mL/kg/h) were enrolled into the severe sepsis group. Septic shock is sepsis-induced hypotension that persists despite adequate fluid resuscitation. Exclusion criteria were cardiaogenic or hemorrhagic shock, use of statins, glucocorticoid, and activated protein C as these drugs might influence the expression of TJ-associated proteins (11, 18, 19). All patients were treated according to the strategy described in the Surviving Sepsis Campaign Guidelines (20). The study was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China. Prior to the study, an informed consent was signed by the patient or next of kin.

Data collection

Data collection included demographics, diagnoses, comorbidities, source of sepsis, and in-hospital outcomes. Laboratory results on ED arrival were documented. Serum procalcitonin (PCT) levels were measured by electrochemiluminescent analysis (Roche Diagnostics GmbH, Mannheim, Germany). Serum lactate levels were analyzed by a dry chemistry method using Vitros 5.1 FS Chemistry System (Ortho Clinical Diagnostics, Johnson & Johnson, Rochester, New York, USA). Clinical and laboratory data necessary for the acute physiology and chronic health evaluation (APACHE) II score were collected within the first 24 h after ED admission. The sequential organ failure assessment (SOFA) scale was used to identify the number of organ failures. Additionally, the date and time of inclusion into the study and in-hospital mortality were recorded.

Tight-junction proteins measurement

Venous blood samples were obtained immediately after the patients arrived at ED. Blood samples were centrifuged at 1,000 g at 4°C for 10 min. Plasma was collected, frozen, and stored at −80°C. Principal TJ components OCLN, CLDN5 and ZO-1 levels were measured by enzyme-linked immunosorbent assay (ELISA) using commercially available kits, in accordance with the manufacturer's instructions (Shanghai Westang Bio-Tech Co. Ltd., Shanghai, China). The concentrations of OCLN, CLDN5, and ZO-1 in the samples were determined by comparing the O.D. of the samples to the standard curve, respectively.

Statistical analysis

Continuous variables were described as either a mean ± standard deviation (SD), or as a median with interquartile range and frequencies for categorical date. Univariate analyses were conducted using one-way analysis of variance (ANOVA) or Mann–Whitney U test (Kruskal–Wallis H test for multigroup comparisons) for continuous variables, Chi-square test, or Fisher exact test for categorical date. Scatter plot and Spearman correlation analysis were used to access correlation between TJ-associated protein levels and APACHE II score or SOFA score. To determine the discriminative power of the variables for in-hospital mortality and MODS, we constructed ROC curves and calculated areas under the curve (AUC) with 95% CI. The best predictive cutoff values maximizing the sum of sensitivity and specificity were defined. In addition, Z test was used to determine the difference between AUCs. In all test, two-tailed P < 0.05 was considered significant. The calculations were performed with SPSS 18.0, Medcalc 11.4.2.0, and Prism 6.01 statistical software.

RESULTS

Demographics

The baseline characteristics of the patients admitted with sepsis including age, sex, lactate levels, PCT levels, the first 24 h maximum APACHE II score and SOFA score, history of cardiovascular diseases, infection date are shown in Table 1. A total of 51 patients had been included into the study: 35.3% of the patients (n = 18) suffered from severe sepsis and 43.1% of the patients (n = 22) suffered from septic shock. There were 21.6% of the patients (n = 11) classified to sepsis. 43.1% of the patients suffered from MODS and the overall mortality was 19.6%. The major sites of infection of the subjects were the respiratory tract (n = 21), followed by genitourinary tract (n = 13), gastro-intestinal tract (n = 5), and other sites of infection (n = 12). There were no significant differences in age, sex, and history of cardiovascular diseases between MODS and non-MODS groups, as well as survivor and non-survivor groups. Compared with the non-MODS group, PCT, lactate, the APACHE II score and SOFA score were higher in the MODS group (P < 0.05 or P < 0.01) (Table 1 and Figure S1, Supplemental Digital Content 1, at https://links.lww.com/SHK/A347). In addition, lactate levels, the APACHE II score, and SOFA score were markedly higher in survivors than in non-survivors (P < 0.01) (Table 1 and Figure S1, Supplemental Digital Content 1, at https://links.lww.com/SHK/A347).

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Table 1:
Clinical baseline characteristics of patients

Comparison of median plasma concentrations of OCLN, CLDN5, and ZO-1

The median OCLN, CLDN5, and ZO-1 concentrations in each group are presented in Table 1 and Figure 1. Plasma concentrations of OCLN and ZO-1 were significantly different among the groups. OCLN and ZO-1 levels were higher in patients with severe sepsis and septic shock than in sepsis, and were obviously higher in septic shock than in severe sepsis (P < 0.05 or P < 0.01). Plasma ZO-1 and OCLN levels were elevated in non-survivors compared with survivors (P < 0.01). In addition, compared with the non-MODS groups, the plasma concentrations of ZO-1, but not OCLN, were significantly higher in patients with MODS. In contrast, there were no significant differences in CLND-5 levels between survivors and non-survivors, or between MODS and non-MODS groups.

F1-13
Fig. 1:
Plasma CLND-5, ZO-1, OCLN levels (pg/mL) in patients with sepsis (n = 11), severe sepsis (n = 18), and septic shock (n = 22), and in septic patients with MODS (n = 22) and non-MODS (n = 29), and in survivors (n = 41) and non-survivors (n = 10).CLND-5 indicates Claudin-5; Lac, lactate; OCLN, occludin; PCT, procalcitonin; ZO-1, zonula occludens-1. Each circle represents an individual.

The correlation between tight-junction proteins levels and the severity of sepsis

In the correlation analysis, we found that the OCLN levels were positively correlated with disease severity of septic patients, which was reflected by SOFA score (rc = 0.337, P = 0.016). However, OCLN levels were not correlated with the APACHE II score (rc = 0.224, P = 0.085). Plasma levels of ZO-1 were positively correlated with SOFA score (rc = 0.502, P < 0.001) and APACHE II score (rc = 0.380, P = 0.006), respectively. Nevertheless, there was no correlation between CLND-5 levels and SOFA score (rc = −0.157, P = 0.270) or APACHE II score (rc = −0.087, P = 0.542) (Fig. 2). Interestingly, the positive correlation between ZO-1 levels and lactate concentrations was also observed (Figure not shown, rc = 0.604, P < 0.01).

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Fig. 2:
The association between TJ-associated proteins levels and the severity of sepsis.Data represent individual plasma TJ-associated protein levels (pg/mL) at the study entry and maximum APACHE II score and SOFA score within 24 h of admission. Linear regression line is drawn. APACHE II indicates acute physiology and chronic health evaluation; SOFA, sequential organ failure assessment.

Values of tight-junction proteins levels for diagnosis of MODS in septic patient

The diagnostic value of tight-junction proteins levels to diagnose MODS in septic patient was determined by ROC curve analysis. The diagnostic value of ZO-1 (AUC = 0.748) to diagnose MODS was similar to that of lactate (AUC = 0.822) (AUC difference, P>0.05), whereas PCT, OCLN, CLND-5 did not exceed an AUC > 0.7 (Table 2 and Fig. 3).

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Table 2:
Area under the curve of various parameters for diagnosis of MODS and predicting hospital mortality in septic patients
F3-13
Fig. 3:
ROC curve for PCT, lactate, and TJ-associated proteins levels for diagnosis of MODS in septic patients.CLND-5 indicates Claudin-5; Lac, lactate; OCLN, occludin; PCT, procalcitonin; ZO-1, zonula occludens-1.

The cutoff value for ZO-1 to diagnose MODS in septic patients was 272.36 pg/mL. Using this cutoff value, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were 63.64%, 79.31%, 70.0%, and 84.2%, respectively. Using a lactate cutoff value of 2.3 mmol/L, a sensitivity of 95%, specificity of 58.06%, PPV of 59.4%, and an NPV of 94.7% in proven MODS in septic patients were noted. The detailed results are shown in Table 3.

T3-13
Table 3:
Performance of multivariable models for diagnosis of MODS and predicting in-hospital mortality in septic patients

Prognostic values of plasma levels of tight-junction proteins levels for in-hospital mortality in septic patients

The ZO-1, OCLN, and lactate have significant discrimination power for predicting mortality, with AUC 0.856 (95% CI: 0.720–0.992), 0.773 (95% CI: 0.594–0.952), and 0.862 (95% CI: 0.733–0.991), respectively. The AUCs of APACHE II score and SOFA score were 0.854 and 0.890, and did not differ significantly from those of ZO-1, OCLN, and lactate (P > 0.05). However, the AUCs of PCT and CLND-5 did not exceed 0.7 (Table 2 and Fig. 4).

F4-13
Fig. 4:
ROC curves for APACHE II score, SOFA score, PCT, lactate, and TJ-associated proteins for predicting motility in septic patients.APACHE II indicates acute physiology and chronic health evaluation; CLND-5, Claudin-5; Lac, lactate; OCLN, occludin; PCT, procalcitonin; SOFA, sequential organ failure assessment; ZO-1, zonula occludens-1.

Using a ZO-1 cutoff value of 354.3 pg/mL for predicting hospital-mortality among patients with sepsis, the sensitivity, specificity, PPV, and NPV were 90%, 87.80%, 64.3%, and 97.3%, respectively. For predicting hospital mortality, plasma OCLN at a cutoff value of 509.06 pg/mL had a sensitivity of 70.00%, specificity of 80.49%, PPV of 46.7%, and a NPV of 91.7%. In addition, lactate at a cutoff value of 4.9 mmol/L had a sensitivity of 80%, specificity of 90.2%, PPV of 66.7%, and NPV of 94.7% for predicting hospital mortality in septic patients. The detailed results are shown in Table 3.

DISCUSSION

The main findings of the presented study were that plasma tight junction protein levels were positively associated with the disease severity and clinical outcome in patients with sepsis. These data suggest that plasma ZO-1 and OCLN measurements may offer a clinically useful biomarker for identification of septic patients with MODS and worst outcome.

Sepsis is the leading cause of mortality in critically ill patients. The progression of sepsis usually leads to septic shock and life-threatening multiple organ dysfunction that correlate with poor outcome (1, 2). The pathogenesis of MODS is a result of a complex network of events involving immune cell activation, inflammation, coagulation abnormalities, as well as endothelial dysfunction (21, 22). Recently, experimental and clinical studies illustrated that inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-8, and IL-6, destabilized endothelial cell–cell interactions and crippled vascular barrier function in sepsis (10, 12, 23). Widespread damage of vascular endothelium contributes not only to vascular leak and edema, but also to the shock, microvascular thrombosis, and organ failure of the disease (24). Moreover, it has been identified that strengthen endothelial cell–cell interactions could reduce capillary leak, multiorgan edema, and death in multiple animal models of infections (25, 26). Consequently, the disruption of vascular endothelial junctions has been considered the central pathogenesis of MODS and sepsis.

Endothelial junction is mediated by adhesion structures, which can be divided into tight junction (TJ), adherent junction (AJ), and gap junction (GJ) (7, 8). AJs initiate cell-to-cell contacts and promote their maturation and maintenance, and TJs regulate the passage of ions and solutes through the paracellular route (7, 8). However, gap junctions play an important role in transmitting biochemical information among adjacent endothelial cells, and are not involved in control of endothelial permeability (8). Studies have illustrated that plasma levels of VE-cadherin, a major component of AJs, were related to the severity and prognosis of severe sepsis (27). Although the defect of TJs has been proved to contribute to the endothelial barrier dysfunction in sepsis (10, 12, 22), the prognostic value of circulation TJ proteins in the disease was not explored.

Studies have identified various molecular components of tight junctions, including the transmembrane proteins and cytoskeletal proteins. Endothelial cells express cell-type-specific transmembrane proteins such as claudin-5 (28, 29). Nitta et al. (30) found that in brains of claudin-5-dificient mice, the blood brain barrier against small molecules (<800D) was selectively affected, although the development and morphology of blood vessels were not altered. Another critical transmembrane component of TJs is OCLN. OCLN is not necessary for TJ strand formation, but it plays an important role in regulation of endothelial barrier function (8, 9). Through their cytoplasmic tails, transmembrane components of TJs bind to cytoskeletal proteins, such as ZO-1, that promote anchoring of junctions to actin microfilaments (8, 9). In response to inflammatory and other mediators, the rearrangements of TJ-associated proteins were occurred and may be responsible for the changes in circulating levels of them (13, 16, 31). Here, we found that plasma OCLN and ZO-1 levels increased with sepsis severity. Additionally, the OCLN levels were higher in non-survivors, while ZO-1 levels were significantly higher in both MODS and non-survival groups.

To the timely management of septic patients, initial evaluation and risk stratification are important. Accordingly, many researchers are focusing on the early evaluation of the severity and death risk of septic patients. PCT is one of the most widely used biomarkers for clinical diagnosis of sepsis (32, 33). Some studies observed that PCT concentrations were closely correlated with the severity of MODS in septic patients (33, 34). Additionally, initial serum lactate levels have also been demonstrated to be associated with the development of MODS in patients with severe sepsis and septic shock (35–37). In our study, we found that the difference in PCT and lactate levels between MODS and non-MODS was significant. From the ROC analysis of septic patients, we found that initial PCT has a lower discriminative capacity for suspected MODS in septic patients (AUC = 0.666), which was consistent with the studies of other researchers (37). However, our study demonstrated that initial lactate and ZO-1 levels had good diagnostic capacity for diagnosis MODS in septic patients (i.e., ZO-1, ACU = 0.856; lactate, AUC = 0.822).

Our study suggested that initial lactate levels, but not PCT levels, have a prognostic value for predicting in-hospital mortality of sepsis (i.e., lactate, AUC = 0.862; PCT, AUC = 0.593). In accordance with the presented results, Guzman et al. previously demonstrated that lactate had an AUC of 0.72 and PCT 0.64 for mortality prediction based on values on admission (38). Similar result was also observed by Mihajlovic et al (39). Due to the crucial role of endothelial cells in the pathogenesis of MODS and sepsis (22–24), the value of TJ-associated proteins for predicting in-hospital mortality in sepsis was also analyzed. We found that OCLN and ZO-1 have greater prognostic value than PCT. In addition, the AUCs of ZO-1 were comparable to those of lactate, APACHE II score, and SOFA score in the early prediction of in-hospital mortality. According to the results mentioned above, initial OCLN and ZO-1 levels may be useful to identify septic patients at risk of hospital death.

Some limitations should be considered when interpreting the present findings. First, it was a single-center study with a relatively small number of patients, and it would be necessary to repeat the study on a larger sample of patients in multiple centers. Second, sepsis was defined as the presence of both infection and a systemic inflammatory response because of the difficulty in obtaining pathogen samples. Third, the levels of TJ-associated proteins and other markers (PCT and lactate) were measured only initially, and the dynamics of concentration of them had not been evaluated. In this case, the continuous development of the disease may cause the overlap in TJ-proteins levels between groups.

In summary, the present study provides clinical evidence that the defects of tight junctions participate in the process of pathogenesis of MODS and sepsis. TJs may be a potential therapeutic target to reduce capillary leakage, organ dysfunction, and mortality of sepsis.

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Keywords:

Lactate; multiple organ dysfunction syndromes; procalcitonin; sepsis; tight-junction proteins; zonula occludens

Supplemental Digital Content

© 2016 by the Shock Society