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tPA Mobilizes Immune Cells That Exacerbate Hemorrhagic Transformation in Stroke.
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- Author(s): Shi K;Shi K;Shi K; Zou M; Zou M; Jia DM; Jia DM; Shi S; Shi S; Yang X; Yang X; Liu Q; Liu Q; Dong JF; Dong JF; Sheth KN; Sheth KN; Wang X; Wang X; Shi FD; Shi FD; Shi FD
- Source:
Circulation research [Circ Res] 2021 Jan 08; Vol. 128 (1), pp. 62-75. Date of Electronic Publication: 2020 Oct 19.- Publication Type:
Journal Article; Research Support, Non-U.S. Gov't- Language:
English - Source:
- Additional Information
- Source: Publisher: Lippincott Williams & Wilkins Country of Publication: United States NLM ID: 0047103 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1524-4571 (Electronic) Linking ISSN: 00097330 NLM ISO Abbreviation: Circ Res Subsets: MEDLINE
- Publication Information: Publication: Baltimore, MD : Lippincott Williams & Wilkins
Original Publication: Baltimore, Md. Grune & Stratton. - Subject Terms: Thrombolytic Therapy*; Embolic Stroke/*drug therapy ; Fibrinolytic Agents/*toxicity ; Infarction, Middle Cerebral Artery/*drug therapy ; Intracranial Hemorrhages/*chemically induced ; Ischemic Stroke/*drug therapy ; Neutrophils/*drug effects ; T-Lymphocytes/*drug effects ; Tissue Plasminogen Activator/*toxicity; Animals ; Annexin A2/metabolism ; Cell Line ; Chemokine CCL2/metabolism ; Chemotaxis, Leukocyte/drug effects ; Disease Models, Animal ; Embolic Stroke/blood ; Embolic Stroke/immunology ; Female ; Fibrinolytic Agents/administration & dosage ; Humans ; Infarction, Middle Cerebral Artery/blood ; Infarction, Middle Cerebral Artery/immunology ; Infusions, Intravenous ; Intracranial Hemorrhages/blood ; Intracranial Hemorrhages/immunology ; Ischemic Stroke/blood ; Ischemic Stroke/immunology ; Male ; Neutrophil Infiltration/drug effects ; Neutrophils/immunology ; Neutrophils/metabolism ; Rats, Wistar ; Sphingosine-1-Phosphate Receptors/metabolism ; T-Lymphocytes/immunology ; T-Lymphocytes/metabolism ; Tissue Plasminogen Activator/administration & dosage ; Rats
- Abstract: Rationale: Hemorrhagic complications represent a major limitation of intravenous thrombolysis using tPA (tissue-type plasminogen activator) in patients with ischemic stroke. The expression of tPA receptors on immune cells raises the question of what effects tPA exerts on these cells and whether these effects contribute to thrombolysis-related hemorrhagic transformation.
Objective: We aim to determine the impact of tPA on immune cells and investigate the association between observed immune alteration with hemorrhagic transformation in ischemic stroke patients and in a rat model of embolic stroke.
Methods and Results: Paired blood samples were collected before and 1 hour after tPA infusion from 71 patients with ischemic stroke. Control blood samples were collected from 27 ischemic stroke patients without tPA treatment. A rat embolic middle cerebral artery occlusion model was adopted to investigate the underlying mechanisms of hemorrhagic transformation. We report that tPA induces a swift surge of circulating neutrophils and T cells with profoundly altered molecular features in ischemic stroke patients and a rat model of focal embolic stroke. tPA exacerbates endothelial injury, increases adhesion and migration of neutrophils and T cells, which are associated with brain hemorrhage in rats subjected to embolic stroke. Genetic ablation of annexin A2 in neutrophils and T cells diminishes the effect of tPA on these cells. Decoupling the interaction between mobilized neutrophils/T cells and the neurovascular unit, achieved via a S1PR (sphingosine-1-phosphate receptor) 1 modulator RP101075 and a CCL2 (C-C motif chemokine ligand 2) synthesis inhibitor bindarit, which block lymphocyte egress and myeloid cell recruitment, respectively, attenuates hemorrhagic transformation and improves neurological function after tPA thrombolysis.
Conclusions: Our findings suggest that immune invasion of the neurovascular unit represents a previously unrecognized mechanism underlying tPA-mediated brain hemorrhage, which can be overcome by precise immune modulation during thrombolytic therapy. - Contributed Indexing: Keywords: brain ischemia; immune system; inflammation; stroke; tissue-type plasminogen activator
- Accession Number: 0 (Annexin A2)
0 (Anxa2 protein, rat)
0 (Ccl2 protein, rat)
0 (Chemokine CCL2)
0 (Fibrinolytic Agents)
0 (S1PR1 protein, rat)
0 (Sphingosine-1-Phosphate Receptors)
EC 3.4.21.68 (Tissue Plasminogen Activator) - Publication Date: Date Created: 20201019 Date Completed: 20210726 Latest Revision: 20240226
- Publication Date: 20240226
- Accession Number: 10.1161/CIRCRESAHA.120.317596
- Accession Number: 33070717
- Source:
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