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Novel Insight into Inflammatory Pathways in Acute Pulmonary Embolism in Humans

Archivum Immunologiae et Therapiae Experimentalis
Volume 72 (2024): Issue 1 (January 2024)
By:
Open Access
|Oct 2024

Figures & Tables

Fig 1.

General view on APE pathogenesis. The figure presents the concept of the role of immune system and inflammation as a substrate in APE development and progression. APE, acute pulmonary embolism; CRP, C-reactive protein; IL-6, interleukin-6; NLR, neutrophil-to-lymphocyte ratio. This figure has been created with BioRender.com.
General view on APE pathogenesis. The figure presents the concept of the role of immune system and inflammation as a substrate in APE development and progression. APE, acute pulmonary embolism; CRP, C-reactive protein; IL-6, interleukin-6; NLR, neutrophil-to-lymphocyte ratio. This figure has been created with BioRender.com.

Fig 2.

Schematic of immune reactive oxygen species (ROS) response in vessel during VTE. Early in thrombogenesis, adhesion molecules initiate leukocyte accumulation, and adhesion to endothelium for subsequent platelet accumulation. Endothelium injury releases DAMP. Proinflammatory cytokines and ROS, promote inflammasome activation in innate immune cells, primarily macrophages, and neutrophils. IL-1β promotes leukocytes adhesion as well as neutrophils and PLT recruitment. IL-6 is released by infiltrating leukocytes and monocytes and induced endothelial IL-1 production and expression of adhesion molecules and prothrombotic factors, facilitating further platelet recruitment. Systemic inflammatory state can be measured by higher concentration of circulating GDF-15, IL-6, TNF-α. As a response to proinflammatory state and higher IL6 level, CRP is synthesized by the liver. IL-6 also promotes lymphocytes T activation. DAMP and PAMPs are presented to lymphocytes T, resulting in higher sCD40 in bloodstream. Activation of platelet and macrophage NLRP-3 inflammasome induces exaggerated production of IL-1 and NETosis formation. The interaction between NETs DNA and vWF, leads to further thrombus growing. Inflammasome activation results in release of TF, which leads to thrombin generation and fibrin clot formation. Neutrophil express TF resulting in extrinsic pathway activation, however, NETs lead to factor XII activation and intrinsic pathway activation, finally contributing to thrombus development and growth. CRP, C-reactive protein; DAMP, danger-associated molecular pattern; EGF, epidermal growth factor; GDF-15, growth differentiation factor-15; ICAM, intercellular adhesion molecule; IL, interleukin; miRNAs, micro-RNAs; MHC, Major histocompatibility complex; NETs, neutrophil extracellular traps; NLR, neutrophil-to-lymphocyte ratio; NLRP-3, NOD-like receptor protein 3; NT-proBNP, N-terminal pro-brain natriuretic peptide; PAMPs, pathogen-associated molecular patterns; PLT, platelets; PMN, Polymorphonuclear cells; sCD40L, soluble CD40 ligand; TCR, T-cell receptor; TF, tissue factor; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VTE, Venous thromboembolism; vWF, von Willebrand factor. This figure has been created with BioRender.com.
Schematic of immune reactive oxygen species (ROS) response in vessel during VTE. Early in thrombogenesis, adhesion molecules initiate leukocyte accumulation, and adhesion to endothelium for subsequent platelet accumulation. Endothelium injury releases DAMP. Proinflammatory cytokines and ROS, promote inflammasome activation in innate immune cells, primarily macrophages, and neutrophils. IL-1β promotes leukocytes adhesion as well as neutrophils and PLT recruitment. IL-6 is released by infiltrating leukocytes and monocytes and induced endothelial IL-1 production and expression of adhesion molecules and prothrombotic factors, facilitating further platelet recruitment. Systemic inflammatory state can be measured by higher concentration of circulating GDF-15, IL-6, TNF-α. As a response to proinflammatory state and higher IL6 level, CRP is synthesized by the liver. IL-6 also promotes lymphocytes T activation. DAMP and PAMPs are presented to lymphocytes T, resulting in higher sCD40 in bloodstream. Activation of platelet and macrophage NLRP-3 inflammasome induces exaggerated production of IL-1 and NETosis formation. The interaction between NETs DNA and vWF, leads to further thrombus growing. Inflammasome activation results in release of TF, which leads to thrombin generation and fibrin clot formation. Neutrophil express TF resulting in extrinsic pathway activation, however, NETs lead to factor XII activation and intrinsic pathway activation, finally contributing to thrombus development and growth. CRP, C-reactive protein; DAMP, danger-associated molecular pattern; EGF, epidermal growth factor; GDF-15, growth differentiation factor-15; ICAM, intercellular adhesion molecule; IL, interleukin; miRNAs, micro-RNAs; MHC, Major histocompatibility complex; NETs, neutrophil extracellular traps; NLR, neutrophil-to-lymphocyte ratio; NLRP-3, NOD-like receptor protein 3; NT-proBNP, N-terminal pro-brain natriuretic peptide; PAMPs, pathogen-associated molecular patterns; PLT, platelets; PMN, Polymorphonuclear cells; sCD40L, soluble CD40 ligand; TCR, T-cell receptor; TF, tissue factor; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; VTE, Venous thromboembolism; vWF, von Willebrand factor. This figure has been created with BioRender.com.

Summary of the main studies in humans

MarkerAuthorCountryYearStudy designTotal patientsMain conclusion

  • IL-1α

  • IL-4

  • IL-6

  • IL-13

Beckers et al.Netherlands2010Prospective433The study demonstrated that four SNPs in inflammatory-related genes of IL-1α, IL-4, IL-6, IL-13 are related to VTE episodes.
IL-1Abuduhalike et al.China2020Prospective284In patients with gene variant of IL-1 rs1800587 GG + GA are at higher risk of VTE than subjects with AA genotype (or 4.444, 95% CI = 1.466–13.470).

  • IL-1β

  • IL-10

Zee et al.USA2009Prospective22,413Gene polymorphism rs1143634 in the IL-1β gene was associated with a reduced risk of idiopathic VTE (hazard ratio = 0.59, 95% CI = 0.440.80, P = 0.0007, FDR = 0.02). Gene polymorphism rs1800872 in the IL-10 gene was associated with increased risk (hazard ratio = 1.42, 95% CI = 1.12–1.80, P = 0.004, FDR = 0.07).
NETsZabczyk et al.Poland2020Prospective126Hypofibrinolysis is associated with enhanced NET formation and worst APE course.
IL-6Vormittag et al.Austria2006aProspective355No relationship was found between IL-6 and its promoter polymorphism (–174) G > C and the risk of spontaneous VTE.
IL-4, IL-6, IL-8, IL-10, IL-1β, MCP-1, EGFBontekoe et al.USA2021Prospective study157Cytokines IL-4, IL-6, IL-8, IL-10, IL-1β, MCP-1, and EGF demonstrated varying levels of significant increase (P < 0.05) in massive-risk PA patients compared to submassive- and low-risk PA patients.
CRPVormittag et al.Austria2006bProspective355CRP + 1444TT genotype was significantly associated with increased CRP plasma levels in healthy individuals. CRP + 1444TT was more frequent (14%) among controls than DVT patients (9%, P = 0.26) or PE PA patients (6%, P = 0.05).
Stewart et al.USA2017Prospective, double-blinded, randomized controlled trial, with 3-month follow-up60A significant reduction of IL-6, CRP, and MPO concentration was observed in the population of patients with APE after 3-month follow-up as compared to baseline (in group treated with Tenecteplase as well as placebo).

  • IL-6

  • CRP

Matos et al.Brazil2011Prospective245VTE was related to higher IL-6 level and it remained significant independently of hs-CRP concentration and BMI.
EGFDirican et al.Turkey2016Prospective57Higher SCUBE1 plasma concentration was observed in the APE than in the non-APE and controls.
EGFAlqudah et al.Jordan2017Prospective75Patients with VTE presented significantly lower EGF concentration in comparison with healthy subjects.
TNF-αMazetto et al.BrazilHumanProspective2012Circulatory levels of TNF-α were significantly increased in patients with VTE compared to healthy controls.
TGF-βMemon et al.Sweden2014Prospective with 39 months follow-up126Reduced plasma concentration of TGF-β1 and TGF-β2 in patients with recurrent VTE.
Wang et al.Sweden2019Prospective7812 mRNAs: (miR-15b-5p, miR106a-5p, miR-197-3p, miR-652-3p, miR-361-5p, miR-222-3p, miR-26b-5p, miR-532-5p, miR-27b-3p, miR-21-5p, miR-103a-3p, and miR-30c-5p) were related to higher VTE reoccurrence. Eight miRNAs significantly correlated with circulating TGFβ1/2.
sCD40LKaya et al.Turkey2012Prospective84sCD40L concentration was significantly higher among APE patients in compare with healthy controls.
GDFLankeit et al.Germany2008Prospective101GDF-15 is an independent predictor of a complicated 30-day outcome after APE.
Skowronska et al.Poland2020Prospective Plasma GDF‐15 concentration is a valuable biomarker in prediction of bleeding and hemodynamic destabilization in APE patients.
DOI: https://doi.org/10.2478/aite-2024-0021 | Journal eISSN: 1661-4917
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Language: English
Submitted on: Jun 28, 2024
Accepted on: Sep 4, 2024
Published on: Oct 28, 2024
Published by: Hirszfeld Institute of Immunology and Experimental Therapy
In partnership with: Paradigm Publishing Services
Publication frequency: 1 times per year
Keywords:
cytokines,
immunity,
inflammation,
pulmonary embolism
Related subjects:
Medicine,
Basic medical science,
Biochemistry,
Immunology,
Clinical medicine,
Clinical medicine, other,
Clinical chemistry

© 2024 Anna M. Imiela, Tomasz P. Mikołajczyk, Piotr Pruszczyk, published by Hirszfeld Institute of Immunology and Experimental Therapy
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License.

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