PAI-1 genetic polymorphisms influence septic patients' outcomes by regulating neutrophil activity

Abstract Background: Plasminogen activator inhibitor-1 (PAI-1) plays an important role in the pathophysiology of sepsis, but the exact mechanism remains debatable. In this study, we investigated the associations among the serum levels of PAI-1, the incidence of 4G/5G promoter PAI-1 gene polymorphisms, immunological indicators, and clinical outcomes in septic patients. Methods: A total of 181 patients aged 18–80 years with sepsis between November 2016 and August 2018 in the intensive care unit in the Xinhua Hospital were recruited in this retrospective study, with 28-day mortality as the primary outcome. The initial serum level of PAI-1 and the presence of rs1799768 single nucleotide polymorphisms (SNPs) were examined. Univariate logistic regression and multivariate analyses were performed to determine the factors associated with different genotypes of PAI-1, serum level of PAI-1, and 28-day mortality. Results: The logistic analysis suggested that a high serum level of PAI-1 was associated with the rs1799768 SNP of PAI-1 (4G/4G and 4G/5G) (Odds ratio [OR]: 2.49; 95% confidence interval [CI]: 1.09, 5.68). Furthermore, a high serum level of PAI-1 strongly influenced 28-day mortality (OR 3.36; 95% CI 1.51, 7.49). The expression and activation of neutrophils (OR 0.96; 95% CI 0.93, 0.99), as well as the changes in the expression patterns of cytokines and chemokine-associated neutrophils (OR: 1.00; 95% CI: 1.00, 1.00), were both regulated by the genotype of PAI-1. Conclusions: Genetic polymorphisms of PAI-1 can influence the serum levels of PAI-1, which might contribute to mortality by affecting neutrophil activity. Thus, patients with severe sepsis might clinically benefit from enhanced neutrophil clearance and the resolution of inflammation via the regulation of PAI-1 expression and activity.

[1]  Gao Zhou,et al.  Serum microtubule-associated protein light chain 3 type II levels correlate with aggravation and multi-organ dysfunction in septic patients , 2021, Chinese medical journal.

[2]  M. Brizzi,et al.  Type 2 diabetes mellitus and sepsis: state of the art, certainties and missing evidence , 2021, Acta Diabetologica.

[3]  G. Shan,et al.  Analysis of factors influencing 3-and 6-h compliance with the surviving sepsis campaign guidelines based on medical-quality intensive care unit data from China , 2021, Chinese medical journal.

[4]  M. Khan,et al.  Cytokine Response in SARS-CoV-2 Infection in the Elderly , 2020, Journal of inflammation research.

[5]  Wei Zhang,et al.  Gut-lymph-lung pathway mediates sepsis-induced acute lung injury , 2020, Chinese medical journal.

[6]  H. I. Satari,et al.  The association between plasminogen activator inhibitor type-1 and clinical outcome in paediatric sepsis. , 2020, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[7]  A. Shajari,et al.  Association of PAI-1 4G/5G and ACE I/D Polymorphisms with Susceptibility to Pediatric Sepsis: Evidence from a Meta-Analysis , 2020, Fetal and pediatric pathology.

[8]  Jingqian Su,et al.  The Pathogenesis of Sepsis and Potential Therapeutic Targets , 2019, International journal of molecular sciences.

[9]  Xinxing Lu,et al.  Identification of key pathogenic genes of sepsis based on the Gene Expression Omnibus database , 2017, Molecular medicine reports.

[10]  H. Ishikura,et al.  Usefulness of plasminogen activator inhibitor-1 as a predictive marker of mortality in sepsis , 2017, Journal of Intensive Care.

[11]  F. Castellino,et al.  Plasminogen activator inhibitor-1 stimulates macrophage activation through Toll-like Receptor-4. , 2016, Biochemical and biophysical research communications.

[12]  A. Zwinderman,et al.  Thrombocytopenia is associated with a dysregulated host response in critically ill sepsis patients. , 2016, Blood.

[13]  Xuan Liu,et al.  Prognostic Significance of Neutrophil-to-Lymphocyte Ratio in Patients with Sepsis: A Prospective Observational Study , 2016, Mediators of inflammation.

[14]  R. Bellomo,et al.  The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[15]  Liang Hong,et al.  SERPINE1 rs1799768 polymorphism contributes to sepsis risk and mortality , 2015, Journal of the renin-angiotensin-aldosterone system : JRAAS.

[16]  J. Solé-Violán,et al.  The 4G/4G Genotype of PAI-1 Polymorphism Is Associated with Higher Plasma PAI-1 Concentrations and Mortality in Patients with Severe Sepsis , 2015, PloS one.

[17]  T. Ohmori,et al.  Combination of thrombin-antithrombin complex, plasminogen activator inhibitor-1, and protein C activity for early identification of severe coagulopathy in initial phase of sepsis: a prospective observational study , 2014, Critical Care.

[18]  W. Nie,et al.  Association between Plasminogen Activator Inhibitor-1 -675 4G/5G Polymorphism and Sepsis: A Meta-Analysis , 2013, PloS one.

[19]  K. Berger,et al.  Promotor polymorphisms of plasminogen activator inhibitor-1 and other thrombophilic genotypes in cerebral venous thrombosis: a case-control study in adults , 2012, Journal of Neurology.

[20]  C. Feldman,et al.  CURB-65, PSI, and APACHE II to Assess Mortality Risk in Patients With Severe Sepsis and Community Acquired Pneumonia in PROWESS , 2011, Journal of intensive care medicine.

[21]  P. Carmeliet,et al.  Plasminogen activator inhibitor type 1 is protective during severe Gram-negative pneumonia. , 2007, Blood.

[22]  E. Abraham,et al.  Plasminogen activator inhibitor-1 potentiates LPS-induced neutrophil activation through a JNK–mediated pathway , 2006, Thrombosis and Haemostasis.

[23]  Yasuhiro Ohtomo,et al.  A multicenter, prospective validation of disseminated intravascular coagulation diagnostic criteria for critically ill patients: Comparing current criteria* , 2006, Critical care medicine.

[24]  Arthur S Slutsky,et al.  Pulmonary coagulopathy as a new target in therapeutic studies of acute lung injury or pneumonia—A review , 2006, Critical care medicine.

[25]  S. McColl,et al.  Immunomodulatory impact of the A2A adenosine receptor on the profile of chemokines produced by neutrophils , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  F B Taylor,et al.  Towards Definition, Clinical and Laboratory Criteria, and a Scoring System for Disseminated Intravascular Coagulation , 2001, Thrombosis and Haemostasis.

[27]  A. Hamsten,et al.  Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[28]  S. Zahler,et al.  Plasminogen Activator Inhibitor-1 Promotes Neutrophil Infiltration and Tissue Injury on Ischemia–Reperfusion , 2018, Arteriosclerosis, thrombosis, and vascular biology.

[29]  T. van der Poll,et al.  Coagulation and sepsis. , 2017, Thrombosis research.

[30]  Identi fi cation of differentially expressed genes and signaling pathways in neutrophils during sepsis-induced immunosuppression via bioinformatics analysis , 2022 .