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Lactadherin promotes microvesicle clearance to prevent coagulopathy and improves survival of severe TBI mice.

ABSTRACT: Coagulopathy is common in patients with traumatic brain injury (TBI) and predicts poor clinical outcomes. We have shown that brain-derived extracellular microvesicles, including extracellular mitochondria, play a key role in the development of TBI-induced coagulopathy. Here, we further show in mouse models that the apoptotic cell-scavenging factor lactadherin, given at a single dose of 400 ?g/kg 30 minutes before (preconditioning) or 30 minutes after cerebral fluid percussion injury, prevented coagulopathy as defined by clotting time, fibrinolysis, intravascular fibrin deposition, and microvascular bleeding of the lungs. Lactadherin also reduced cerebral edema, improved neurological function, and increased survival. It achieved these protective effects by enhancing the clearance of circulating microvesicles through phosphatidylserine-mediated phagocytosis. Together, these results identify the scavenging system for apoptotic cells as a potential therapeutic target to prevent TBI-induced coagulopathy and improve the outcome of TBI.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC5794502 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Lactadherin promotes microvesicle clearance to prevent coagulopathy and improves survival of severe TBI mice.

Zhou Yuan Y Cai Wei W Zhao Zilong Z Hilton Tristan T Wang Min M Yeon Jason J Liu Wei W Zhang Fangyi F Shi Fu-Dong FD Wu Xiaoping X Thiagarajan Perumal P Li Min M Zhang Jianning J Dong Jing-Fei JF

Blood 20171121 5

Coagulopathy is common in patients with traumatic brain injury (TBI) and predicts poor clinical outcomes. We have shown that brain-derived extracellular microvesicles, including extracellular mitochondria, play a key role in the development of TBI-induced coagulopathy. Here, we further show in mouse models that the apoptotic cell-scavenging factor lactadherin, given at a single dose of 400 μg/kg 30 minutes before (preconditioning) or 30 minutes after cerebral fluid percussion injury, prevented c ...[more]

PMID: 29162596

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Project description:IntroductionTraumatic brain injury (TBI) induces acute hypocoagulability, subacute hypercoagulability, and persistently elevated risk for thromboembolic events. Splenectomy is associated with increased mortality in patients with moderate or severe TBI. We hypothesized that the adverse effects of splenectomy in TBI patients may be secondary to the exacerbation of pathologic coagulation and platelet activation changes.MethodsAn established murine weight-drop TBI model was utilized and a splenectomy was performed immediately following TBI. Sham as well as TBI and splenectomy alone mice were used as injury controls. Mice were sacrificed for blood draws at 1, 6, and 24 h, as well as 7 days post-TBI. Viscoelastic coagulation parameters were assessed by rotational thromboelastometry (ROTEM) and platelet activation was measured by expression of P-selectin via flow cytometry analysis of platelet rich plasma samples.ResultsAt 6 h following injury, TBI/splenectomy demonstrated hypocoagulability with prolonged clot formation time (CFT) compared to TBI alone. By 24 h following injury, TBI/splenectomy and splenectomy mice were hypercoagulable with a shorter CFT, a higher alpha angle, and increased MCF, despite a lower percentage of platelet contribution to clot compared to TBI alone. However, only the TBI/splenectomy continued to display this hypercoagulable state at 7 days. While TBI/splenectomy had greater P-selectin expression at 1-h post-injury, TBI alone had significantly greater P-selectin expression at 24 h post-injury compared to TBI/splenectomy. Interestingly, P-selectin expression remained elevated only in TBI/splenectomy at 7 days post-injury.ConclusionSplenectomy following TBI exacerbates changes in the post-injury coagulation state. The combination of TBI and splenectomy induces an acute hypocoagulable state that could contribute to an increase in intracranial bleeding. Subacutely, the addition of splenectomy to TBI exacerbates post-injury hypercoagulability and induces persistent platelet activation. These polytrauma effects on coagulation may contribute to the increased mortality observed in patients with combined brain and splenic injuries.

Project description:BACKGROUND:Septic shock-induced disseminated intravascular coagulation is responsible for increased occurrence of multiple organ dysfunction and mortality. Immunothrombosis-induced coagulopathy may contribute to hypercoagulability. We aimed at determining whether recombinant human thrombomodulin (rhTM) could control exaggerated immunothrombosis by studying procoagulant responses, fibrinolysis activity borne by microvesicles (MVs) and NETosis in septic shock. METHODS:In a septic shock model after a cecal ligation and puncture-induced peritonitis (H0), rats were treated with rhTM or a placebo at H18, resuscitated and monitored during 4 h. At H22, blood was sampled to perform coagulation tests, to characterize MVs and to detect neutrophils extracellular traps (NETs). Lungs were stained with hematoxylin-eosin for inflammatory injury assessment. RESULTS:Coagulopathy was attenuated in rhTM-treated septic rats compared to placebo-treated rats, as attested by a significant decrease in procoagulant annexin A5+-MVs and plasma procoagulant activity of phospholipids and by a significant increase in antithrombin levels (84 ± 8 vs. 64 ± 6%, p < 0.05), platelet count (582 ± 157 vs. 319 ± 91 × 109/L, p < 0.05) and fibrinolysis activity borne by MVs (2.9 ± 0.26 vs. 0.48 ± 0.29 U/mL urokinase, p < 0.05). Lung histological injury score showed significantly less leukocyte infiltration. Decreased procoagulant activity and lung injury were concomitant with decreased leukocyte activation as attested by plasma leukocyte-derived MVs and NETosis reduction after rhTM treatment (neutrophil elastase/DNA: 93 ± 33 vs. 227 ± 48 and citrullinated histones H3/DNA: 96 ± 16 vs. 242 ± 180, mOD for 109 neutrophils/L, p < 0.05). CONCLUSION:Thrombomodulin limits procoagulant responses and NETosis and at least partly restores hemostasis control during immunothrombosis. Neutrophils might thus stand as a promising therapeutic target in septic shock-induced coagulopathy.

Project description:BACKGROUND:Airway neutrophils are abundant in some children with severe asthma, but their functions are poorly understood. OBJECTIVE:To characterize that the inflammatory airway environment of children with neutrophil-predominant severe asthma promotes neutrophil survival and disrupts neutrophil-associated innate immune defenses. METHODS:Sixty-seven children with severe asthma refractory to high-dose inhaled corticosteroid treatment undergoing bronchoscopy with bronchoalveolar lavage (BAL) for clinical indications were stratified into neutrophil "high" versus "low" groups on the basis of BAL differential counts. Neutrophil activation markers, functional assays, and phenotyping studies were performed, as well as airway macrophage functional assays. Results were compared with those from children with moderate asthma treated with inhaled corticosteroids. RESULTS:Children with neutrophil-predominant severe asthma had increased markers of neutrophil activation/degranulation and a greater magnitude of airway proinflammatory cytokine and chemokine release. Primary neutrophils exposed to BAL of these children exhibited greater phagocytic capability and greater neutrophil extracellular trap formation, but a more impaired respiratory burst. Despite greater abundance of airway TGF-?1, the neutrophils were not more apoptotic. Instead, neutrophils had a highly proinflammatory phenotype associated with a number of surface markers that regulate neutrophil activation, recruitment/migration, and granule release. Airway macrophages from children with neutrophil-predominant severe asthma were also more proinflammatory with impaired phagocytosis and increased apoptosis. CONCLUSIONS:Children with neutrophil-predominant severe asthma have proinflammatory neutrophils with enhanced survival. Airway macrophages are also proinflammatory and dysfunctional and may contribute to global innate immune impairment. Therapies that target neutrophils and related inflammation may be warranted in this subset of children.

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Lactadherin promotes microvesicle clearance to prevent coagulopathy and improves survival of severe TBI mice.

Publications

Lactadherin promotes microvesicle clearance to prevent coagulopathy and improves survival of severe TBI mice.

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