Soluble programmed cell death receptor-1 (sPD-1): a potential biomarker with anti-inflammatory properties in human and experimental acute respiratory distress syndrome (ARDS).
Monaghan Sean F,Chung Chun-Shiang,Chen Yaping,Lomas-Neira Joanne,Fairbrother William G,Heffernan Daithi S,Cioffi William G,Ayala Alfred
Journal of translational medicine
BACKGROUND:Acute respiratory distress syndrome (ARDS) remains a common organ dysfunction in the critically ill patient. Mechanisms for its development have focused on immune mediated causes, aspects of our understanding are not complete, and we lack biomarkers. DESIGN, SETTING, AND SUBJECTS:Blood and bronchial alveolar lavage fluid (BAL) from humans (n = 10-13) with ARDS and controls (n = 5-10) as well as a murine model of ARDS (n = 5-6) with controls (n = 6-7) were studied. METHODS:ARDS was induced in mice by hemorrhagic shock (day 1) followed by poly-microbial sepsis (day 2). Samples were then collected on the third day after the animals were euthanized. Ex vivo experiments used splenocytes from animals with ARDS cultured with and without soluble programmed death receptor-1 (sPD-1). RESULTS:Levels of sPD-1 are increased in both the serum (11,429.3 pg/mL(SD 2133.3) vs. 8061.4(SD 4187.8), p = 0.036) and bronchial alveolar lavage (BAL) fluid (6,311.1 pg/mL(SD 3758.0) vs. 90.7 pg/mL(SD 202.8), p = 0.002) of humans with ARDS. Similar results are seen in the serum (9396.1 pg/mL(SD 1546.0) vs. 3464.5 pg/mL(SD 2511.8), p = 0.001) and BAL fluid (2891.7 pg/mL(SD 868.1) vs. 1385.9 pg/mL(SD 927.8), p = 0.012) of mice. sPD-1 levels in murine blood (AUC = 1(1-1), p = 0.006), murine BAL fluid (AUC = 0.905(0.717-1.093), p = 0.015), and human BAL (AUC = 1(1-1), p = 0.001) fluid predicted ARDS. To assess the importance of sPD-1 in ARDS, ex vivo experiments were undertaken. BAL fluid from mice with ARDS dampens the TNF-α production compared to cells cultured with BAL lacking sPD-1 (2.7 pg/mL(SD 3.8) vs. 52.38 pg/mL(SD 25.1), p = 0.002). CONCLUSIONS:This suggests sPD-1 is elevated in critical illness and may represent a potential biomarker for ARDS. In addition, sPD-1 has an anti-inflammatory mechanism in conditions of marked stress and aids in the resolution of severe inflammation. sPD-1 could be used to not only diagnose ARDS, but may be a potential therapy.
10.1186/s12967-016-1071-x
Soluble B and T Lymphocyte Attenuator Correlates to Disease Severity in Sepsis and High Levels Are Associated with an Increased Risk of Mortality.
Lange Anna,Sundén-Cullberg Jonas,Magnuson Anders,Hultgren Olof
PloS one
INTRODUCTION AND AIMS:B- and T-lymphocyte Attenuator (BTLA), Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and Programmed Death 1 (PD-1) are co-inhibitory receptors that regulate T cell activation. In the present study of ICU-treated patients we measured plasma concentrations of their soluble isoforms, with the aim to evaluate their potential as sepsis biomarkers and utility as prognostic indicators. METHODS:101 patients with sepsis, 28 patients with non-infectious critical illness (ICU controls) and 31 blood donors (healthy controls, HC) were included in the study. Plasma concentrations of soluble BTLA (sBTLA), CTLA-4 (sCTLA-4) and PD-1 (sPD-1) were measured with ELISA in serial blood samples. Comparisons were made with Mann-Whitney U test and correlations were assessed with Spearman's Rank correlation test. Cox proportional hazard models, with sBTLA and sPD-1 as fixed and sBTLA as time-varying covariates, were used to determine association with 28-day mortality. RESULTS:sBTLA levels were significantly higher in the sepsis cohort (median 14 ng/mL, IQR 8-29) compared to ICU controls (9 ng/mL, IQR 5-26, p = 0.048) and HC (2.9 ng/mL, IQR 0.9-9.1, p<0.01), and correlated to SOFA score. sBTLA levels were higher in 28 day sepsis non-survivors than in survivors (baseline median 28 ng/mL, IQR 13-41 vs 13 ng/mL, IQR 8-23, p = 0.04). After adjustment for age and comorbidities, the relative risk of 28 day mortality was nearly 5-fold higher in sepsis patients with a baseline sBTLA > 21 ng/mL, compared to those with a level below this threshold. sBTLA was even more associated with mortality in the time-varying analysis. sPD-1 levels were lower in the sepsis cohort compared to HC but not compared to ICU controls and were not associated with mortality. sCTLA-4 was detectable in only one subject. CONCLUSION:Plasma concentrations of soluble BTLA were increased early in sepsis/septic shock and correlated to severity of disease. A baseline concentration >21ng/mL was associated with a poor prognosis.
10.1371/journal.pone.0169176
Predictive Value of Soluble Programmed Death-1 for Severe Sepsis and Septic Shock During the First Week in an Intensive Care Unit.
Zhao Yongzhen,Jia Yumei,Li Chunsheng,Shao Rui,Fang Yingying
Shock (Augusta, Ga.)
OBJECTIVE:Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) exists in both membrane-bound and soluble forms. In this study, we evaluated the predictive value of soluble PD-1 (sPD-1) for severity and 28-day mortality in patients with severe sepsis and septic shock during the first week in an intensive care unit (ICU). METHODS:In this prospective cohort study, patients were classified into the severe sepsis group or the septic shock group according to the severity of their condition on ICU admission. All patients were also separated into the survivor or nonsurvivor groups according to their 28-day outcomes. Peripheral blood sPD-1 and soluble PD-L1 (sPD-L1) levels, PD-1 expression on CD4 and CD8 T cells, and PD-L1 expression on monocytes were measured and compared between the groups on days 1 and 7 after ICU admission. RESULTS:In all, 45 healthy volunteers and 112 patients were recruited. Serum sPD-1 levels were positively correlated with the severity of sepsis, sPD-L1 levels, PD-1 expression on CD4 or CD8 T cells, and PD-L1 expression on monocytes. The sPD-1 was an independent predictive factor for 28-day mortality both on day 1 and day 7. The area under the curve (AUC) of the sPD-1 on day 7 (0.871) was higher than that on day 1 (0.785) (P < 0.05), and better than the AUC of the percentages of PD-L1 on monocytes (0.770) on day 7 (P < 0.05). CONCLUSION:Serum sPD-1 shows valuable predictive ability for the severity and 28-day mortality of severe sepsis and septic shock during the first week of ICU treatment.
10.1097/SHK.0000000000001171
The risk stratification and prognostic evaluation of soluble programmed death-1 on patients with sepsis in emergency department.
Zhao Yongzhen,Jia Yumei,Li Chunsheng,Fang Yingying,Shao Rui
The American journal of emergency medicine
OBJECTIVE:To evaluate the efficacy of soluble programmed death-1 (sPD-1) for risk stratification and prediction of 28-day mortality in patients with sepsis, we compared serum sPD-1 with procalcitonin (PCT), C-reactive protein (CRP), and the Mortality in Emergency Department Sepsis (MEDS) score. METHODS:A total of 60 healthy volunteers and 595 emergency department (ED) patients were recruited for this prospective cohort study. According to the severity of their condition on ED arrival, the patients were allocated to the systemic inflammatory response syndrome group (130 cases), sepsis group (276 cases), severe sepsis group (121 cases), and septic shock group (68 cases). In addition, all patients with sepsis were also divided into the survivor group (349 cases) and nonsurvivor group (116 cases) according to the 28-day outcomes. RESULTS:When the severity of sepsis increased, the levels of sPD-1 gradually increased. The levels of sPD-1, PCT, CRP and the MEDS score were also higher in the nonsurvivor group compared to the survivor group. Logistic regression suggested that sPD-1, PCT, and the MEDS score were independent risk factors for 28-day mortality of patients with sepsis. Area under the curve (AUC) of sPD-1, PCT and the MEDS score for 28-day mortality was 0.725, 0.693, and 0.767, respectively, and the AUC was improved when all 3 factors were combined (0.843). CONCLUSION:Serum sPD-1 is positively correlated with the severity of sepsis, and it is valuable for risk stratification of patients and prediction of 28-day mortality. Combining sPD-1 with PCT and the MEDS score improves the prognostic evaluation.
10.1016/j.ajem.2017.07.002
Serum sPD-L1, Upregulated in Sepsis, May Reflect Disease Severity and Clinical Outcomes in Septic Patients.
Liu M,Zhang X,Chen H,Wang G,Zhang J,Dong P,Liu Y,An S,Wang L
Scandinavian journal of immunology
We aimed to find the correlation between serum sPD-L1 (soluble programmed cell death L-1 ligand) and sepsis. Totally 91 consecutive patients with sepsis were performed in a 15-bed medical intensive care unit (ICU) of the second affiliated hospital, Xi'an Jiaotong University in Xi'an, China, between February 2015 and May 2016. Healthy controls (HC) consisted of 29 healthy volunteer. Baseline demographic data were recorded. Blood samples were collected through an indwelling central venous or by peripheral venipuncture. Serum sPD-L1 and sPD-1 levels were determined with enzyme-linked immunosorbent assay kits (Elabscience Biotechnology Co. Ltd, Wuhan, China). SPSS19.0 software (SPSS Inc., Chicago, Illinois, USA) was used for statistical analysis. Kaplan-Meier survival analysis and Cox regression analysis were also performed. Serum sPD-L1 levels and sPD-1 levels were significantly increased in septic patients compared with HC (P = 0.000). Serum sPD-L1 levels were significantly increased in non-survivors compared with survivors (P < 0.05), but there was no statistically difference on serum sPD-1 levels between non-survivors and survivors (P > 0.05). Serum sPD-L1 levels were correlated with absolute lymphocyte (ALC), platelets and SOFA scores. Serum sPD-L1/sPD-1 levels were negatively correlated with ALC and platelets, and SOFA scores. The prognostic accuracy of the sPD-L1 level to predict 28-day mortality was similar to that of the APACHE-II scores and SOFA scores. Cox regression analysis showed that sPD-L1 was an independent prognostic factor. Serum sPD-L1 is upregulated in sepsis and may reflect disease severity and clinical outcomes in patients. Serum sPD-L1 may be an independent prognostic factor for sepsis.
10.1111/sji.12509
Electroacupuncture at Zusanli (ST36), Guanyuan (CV4), and Qihai (CV6) Acupoints Regulates Immune Function in Patients with Sepsis via the PD-1 Pathway.
BioMed research international
Objective:The present study is aimed at investigating the biochemical and clinical effects of electroacupuncture in patients with sepsis. Methods:Patients with sepsis treated at Guangdong Provincial Hospital of Chinese Medicine from July 2019 to December 2020 were included. Patients were randomly assigned to treatment with routine Western medicine (WM group) or treatment with Western medicine plus electroacupuncture based on Western medicine (EA group). Indices associated with immune function and clinical efficacy were determined before and at 3 and 5 days after treatment. Indicators of immune function included the percentage of T lymphocyte subsets, natural killer (NK) cells, and soluble programmed death protein 1 (sPD-1) levels. Indicators of clinical efficacy included infection-related indicators in whole blood; levels of tumor necrosis factor- (TNF-), C-reactive protein (CRP), and interferon- (INF-); and assessments using acute physiology and chronic health evaluation-II (APACHE-II) and sequential organ failure assessment (SOFA) scores. Results:Baseline data were not different between WM ( = 30) and EA groups ( = 30). At day 5 following treatment, the level of sPD-1 in the EA group was lower than that in the WM group. Proportions of CD3 + T lymphocytes, CD4 + T lymphocytes, and NK cells, the percentage of lymphocytes, and INF- levels in the EA group were significantly higher than those in the WM group. Compared with the WM group, the white blood cell count (WBC), percentage and count of neutrophils, ratio of neutrophils to lymphocytes, and levels of CRP and TNF- were significantly decreased in the EA group 5 days after treatment. The APACHE-II score of the EA group was significantly lower than that of the WM group 5 days after treatment. Conclusion:Electroacupuncture may regulate the immune function of patients with sepsis through the PD-1 pathway to achieve an anti-inflammatory state and improve clinical symptoms.
10.1155/2022/7037497
Correlation of sPD1 with Procalcitonin and C-Reactive Protein Levels in Patients with Sepsis.
Bakhshiani Zahra,Fouladi Saloomeh,Mohammadzadeh Samaneh,Eskandari Nahid
Cell journal
Objective:Sepsis results from dysregulated host responses to infection, and it is a major cause of mortality in the world. Co-inhibitory molecules, such as PD-1, play a critical role in this process. Considering the lack of information on the relation between sPD1 and sepsis, the present study aimed to examine the sPD1 level in septic patients and evaluate its correlation with procalcitonin (PCT) and C-reactive protein (CRP) levels. Materials and Methods:This descriptive cross-sectional study consisted of three groups, including septic patients (n=15), suspected of sepsis (n=15), and healthy subjects (n=15). White blood cells (WBCs) and platelet (PLT) counts are evaluated. The serum levels of CRP, PCT, and sPD1 were measured by immunoturbidimetric assay, electrochemiluminescence technology, and the enzyme-linked immunosorbent assay (ELISA), respectively. Results:Our study indicated that there was a significant difference in WBC and PLT counts between the septic group compared to suspected and control groups (P<0.001, P<0.01, respectively). The CRP level was significantly higher in septic compared to suspected and control groups (P<0.001). There was also a significant difference between the PCT level in septic and suspected groups in comparison with the controls (P<0.001, P<0.01). The sPD1 level was significantly higher in septic patients compared to suspected and control groups (P< 0.001). In septic patients, sPD1 levels were correlated positively with the CRP and PCT levels. Conclusion:Overall, sPD1 correlation with inflammatory markers, might propose it as a potential biomarker to sepsis diagnosis. However, the clinical application of serum sPD-1 testing in patients with sepsis requires further investigation.
10.22074/cellj.2021.6941
Serum soluble PD-1 plays a role in predicting infection complications in patients with acute pancreatitis.
Immunity, inflammation and disease
BACKGROUND:Most of acute pancreatitis (AP) are mild and self-limiting, however, 15%-20% of patients develop severe acute pancreatitis (SAP) or moderately acute pancreatitis (MSAP) with local or systemic complications. Infection complications (ICs) result in 40%-70% morbidity and high mortality rates among SAP and MSAP patients. It is more important to early recognize of ICs of MSAP or SAP. Several studies have indicated that serum soluble programmed cell death protein (sPD-1) or programmed cell death 1 ligand (sPD-L1) levels were higher in patients with severe sepsis than in healthy volunteers and have a predictive capacity for mortality. However, the role of serum sPD-1/sPD-L1 in AP remains unclear. This study aimed to investigate whether the ICs of AP patients is associated with their sPD-1 and sPD-L1 levels, which were determined via enzyme-linked immunosorbent assay of peripheral blood samples from 63 MSAP and SAP patients and 30 healthy volunteers. RESULTS:The serum sPD-1 levels in AP patients on Days 1, 3, and 10 after onset were significantly increased in a time-dependent manner compared with that in healthy volunteers. Moreover, the AP patients with ICs had significantly higher serum sPD-1 levels than the AP without ICs. While serum sPD-L1 levels in AP were similar to that in healthy volunteers. Besides, serum levels of sPD-1/sPD-L1 were negatively correlated with circulating lymphocytes. Univariate and multivariate regression analyses showed that the upregulated serum sPD-1 level was an independent risk factor for ICs in AP. The area under the receiver operating characteristics curve indicated that combination with Acute Physiology and Chronic Health Evaluation II score and serum sPD-1 level had a high accuracy in predicting ICs in AP. CONCLUSION:Serum sPD-1/sPD-L1 may be involved in the immunosuppressive process in AP. Moreover, the serum sPD-1 level may be an independent risk factor for predicting ICs in AP patients.
10.1002/iid3.394
Soluble PD-L1 in blood correlates positively with neutrophil and negatively with lymphocyte mRNA markers and implies adverse sepsis outcome.
Immunologic research
Sepsis causes a myriad of immunological reactions that result in life-threatening alterations in the human body. Immunosuppression in sepsis is partly attributed to the programmed death receptor (PD-1) and its associated ligand (PD-L1) via the regulation of lymphocytes and neutrophils. Although the soluble forms of these proteins (i.e., sPD-1 and sPD-L1, respectively) are recognized as possible sepsis biomarkers, their functional implications are yet to be elucidated. Our research assessed the correlation between sPD-1 and sPD-L1 and blood mRNA markers and sepsis outcome. Blood samples of septic patients of urogenital origin versus control patients (both groups: n = 18) were analyzed. Blood serum sPD-1 and sPD-L1 levels were determined using the enzyme-linked immunosorbent assay (ELISA). The whole blood mRNA concentrations of PD-1, PD-L1, neutrophil markers (CEACAM8 and MPO), and T-lymphocyte markers (TCRβ, CD4 and CD8) were determined via reverse transcriptase quantitative PCR (RT-qPCR). sPD-L1 levels were significantly increased in septic patients when compared to the controls, whereas sPD-1 levels were unaltered. Patients with high sPD-L1 levels, as dichotomized to the median, had a significantly shorter survival rate than those with low sPD-L1 levels. The sensitivity/specificity characteristics of sPD-L1 proved significant for sepsis detection. Furthermore, sPD-L1 correlated with the mRNA concentrations of PD-L1, CEACAM, and MPO, as well as major inflammatory markers (C-reactive protein and procalcitonin). However, sPD-L1 negatively correlated with TCRβ, CD4, and CD8 mRNAs. sPD-L1 was found to be significantly increased in septic patients. Notably, sPD-L1 correlated with PD-L1 mRNA and neutrophil markers and was indicative of adverse outcomes.
10.1007/s12026-022-09302-y