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PURPOSE: Emerging data suggest that trastuzumab deruxtecan (T-DXd) is an active treatment for brain metastases from HER2 + breast cancer. We aimed to characterize the activity of T-DXd in the treatment of leptomeningeal metastases (LM) from a range of HER2-altered cancers. METHODS: We reviewed neuro-oncology clinic records between July 2020 and December 2023 to identify patients who received T-DXd to treat LM. RESULTS: Of 18 patients identified, 6 had HER2 + breast cancer, 8 had HER2-low/negative breast cancer, 2 had HER2 + gastroesophageal cancer, and 2 had HER2-mutant non-small cell lung cancer (NSCLC). 10/18 (56%) patients had cytologically confirmed LM by CSF cytology or circulating tumor cell (CTC) capture. A partial response (PR) on MRI using the EORTC/RANO-LM Revised-Scorecard occurred in 4/6 (67%) patients with HER2 + breast LM, 2/8 (25%) patients with HER2-low/negative breast cancer, and 0/4 (0%) patients with HER2 + gastroesophageal cancer or HER2-mutant NSCLC. Median overall survival after initiating T-DXd was 5.8 months. Survival after initiating T-DXd was numerically longer for HER2 + breast cancer patients compared with HER2-low/negative breast and HER2-altered non-breast cancer patients (13.9 months vs. 5.2 months and 4.6 months, respectively). Landmark analysis showed that patients with radiologic LM response to T-DXd by 2.5 months had longer survival than non-responders (14.2 months vs. 2.6 months, HR 0.18, 95% CI 0.05-0.63, p < 0.05), and landmark analyses at 3.5 and 4.5 months after starting T-DXd showed a similar but nonsignificant trend. CONCLUSION: T-DXd induces LM responses in a subset of patients, and such responses may be associated with prolongation of survival. Prospective trials are needed to clarify the role of T-DXd in treating LM and which patients are most likely to benefit.
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PURPOSE OF REVIEW: Leptomeningeal disease (LMD) is a devastating complication of advanced metastatic cancer associated with a poor prognosis and limited treatment options. This study reviews the current understanding of the clinical presentation, pathogenesis, diagnosis, and treatment of LMD. We highlight opportunities for advances in this disease. RECENT FINDINGS: In recent years, the use of soluble CSF biomarkers has expanded, suggesting improved sensitivity over traditional cytology, identification of targetable mutations, and potential utility for monitoring disease burden. Recent studies of targeted small molecules and intrathecal based therapies have demonstrated an increase in overall and progression-free survival. In addition, there are several ongoing trials evaluating immunotherapy in LMD. Though overall prognosis of LMD remains poor, studies suggest a potential role for soluble CSF biomarkers in diagnosis and management and demonstrate promising findings in patient outcomes with targeted therapies for specific solid tumors. Despite these advances, there continues to be a gap of knowledge in this disease, emphasizing the importance of inclusion of LMD patients in clinical trials.
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Neoplasias Meníngeas , Humanos , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/terapia , Neoplasias Meníngeas/patologia , Prognóstico , MutaçãoRESUMO
Inter-α inhibitor proteins (IAIPs) are a family of endogenous plasma and extracellular matrix molecules. IAIPs suppress proinflammatory cytokines, limit excess complement activation, and bind extracellular histones to form IAIP-histone complexes, leading to neutralization of histone-associated cytotoxicity in models of sepsis. Many of these detrimental processes also play critical roles in the pathophysiology of ischemic stroke. In this study, we first assessed the clinical relevance of IAIPs in stroke and then tested the therapeutic efficacy of exogenous IAIPs in several experimental stroke models. IAIP levels were reduced in both ischemic stroke patients and in mice subjected to experimental ischemic stroke when compared with controls. Post-stroke administration of IAIP significantly improved stroke outcomes across multiple stroke models, even when given 6 hours after stroke onset. Importantly, the beneficial effects of delayed IAIP treatment were observed in both young and aged mice. Using targeted gene expression analysis, we identified a receptor for complement activation, C5aR1, that was highly suppressed in both the blood and brain of IAIP-treated animals. Subsequent experiments using C5aR1-knockout mice demonstrated that the beneficial effects of IAIPs are mediated in part by C5aR1. These results indicate that IAIP is a potential therapeutic candidate for the treatment of ischemic stroke.
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alfa-Globulinas/uso terapêutico , AVC Isquêmico/tratamento farmacológico , alfa-Globulinas/administração & dosagem , alfa-Globulinas/metabolismo , Animais , Edema Encefálico/tratamento farmacológico , Edema Encefálico/patologia , Infarto Encefálico/tratamento farmacológico , Infarto Encefálico/patologia , Morte Celular/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Humanos , AVC Isquêmico/metabolismo , AVC Isquêmico/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor da Anafilatoxina C5a/deficiência , Receptor da Anafilatoxina C5a/genética , Receptor da Anafilatoxina C5a/metabolismo , Ativador de Plasminogênio Tecidual/administração & dosagemRESUMO
During spaceflight, the central nervous system (CNS) is exposed to a complex array of environmental stressors. However, the effects of long-duration spaceflight on the CNS and the resulting impact to crew health and operational performance remain largely unknown. In this review, we summarize the current knowledge regarding spaceflight-associated changes to the brain as measured by magnetic resonance imaging, particularly as they relate to mission duration. Numerous studies have reported macrostructural changes to the brain after spaceflight, including alterations in brain position, tissue volumes and cerebrospinal fluid distribution and dynamics. Changes in brain tissue microstructure and connectivity were also described, involving regions related to vestibular, cerebellar, visual, motor, somatosensory and cognitive function. Several alterations were also associated with exposure to analogs of spaceflight, providing evidence that brain changes likely result from cumulative exposure to multiple independent environmental stressors. Whereas several studies noted that changes to the brain become more pronounced with increasing mission duration, it remains unclear if these changes represent compensatory phenomena or maladaptive dysregulations. Future work is needed to understand how spaceflight-associated changes to the brain affect crew health and performance, with the goal of developing comprehensive monitoring and countermeasure strategies for future long-duration space exploration.
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BACKGROUND: Ischemic stroke is a devastating disease, often resulting in death or permanent neurological deficits. EMMPRIN/CD147 is a plasma membrane protein that induces the production of matrix metalloproteinases (MMPs), which contribute to secondary damage after stroke by disrupting the blood brain barrier (BBB) and facilitating peripheral leukocyte infiltration into the brain. RESULTS: CD147 surface expression increased significantly after stroke on infiltrating leukocytes, astrocytes and endothelial cells, but not on resident microglia. Inhibition of CD147 reduced MMP levels, decreased ischemic damage, and improved functional, cognitive and histological outcomes after experimental ischemic stroke in both young and aged mice. In stroke patients, high levels of serum CD147 24 hours after stroke predicted poor functional outcome at 12 months. Brain CD147 levels were correlated with MMP-9 and secondary hemorrhage in post-mortem samples from stroke patients. CONCLUSIONS: Acute inhibition of CD147 decreases levels of MMP-9, limits tissue loss, and improves long-term cognitive outcomes following experimental stroke in aged mice. High serum CD147 correlates with poor outcomes in stroke patients. This study identifies CD147 as a novel, clinically relevant target in ischemic stroke.
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Basigina/metabolismo , AVC Isquêmico/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Astrócitos/metabolismo , Barreira Hematoencefálica/metabolismo , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Feminino , Humanos , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Stroke is a disease that presents with well-known sex differences. While women account for more stroke deaths, recent data show that after adjusting for age and pre-stroke functional status, mortality is higher in men. Immune responses are key determinants of stroke outcome and may differ by sex. This study examined sex differences in central and peripheral T cell immune responses, systemic effects on gut permeability and microbiota diversity and behavioral outcomes after stroke in aged mice. We hypothesized that there are sex differences in the immune response to stroke in aged animals. METHODS: C57BL/6CR mice (20-22â¯months) were subjected to 60â¯min middle cerebral artery occlusion, or sham surgery. T cells were quantified in brain and blood at 3, 7 and 15â¯days (d) post-stroke by flow cytometry. Peripheral effects on gut permeability and microbiota diversity, as well as neurological function were assessed up to 14â¯d, and at 21â¯d (cognitive function) post-stroke. Brain glial fibrillary acidic protein (GFAP) expression was evaluated at 42â¯d post-stroke. RESULTS AND DISCUSSION: Mortality (50% vs 14%, pâ¯<â¯0.05) and hemorrhagic transformation (44% vs 0%) were significantly higher in males than in females. No difference in infarct size at 3d were observed. Peripherally, stroke induced greater gut permeability of FITC-dextran in males at d3 (pâ¯<â¯0.05), and non-reversible alterations in microbiota diversity in males. Following the sub-acute phase, both sexes demonstrated a time-dependent increase of CD4+ and CD8+ T cells in the brain, with significantly higher levels of CD8+ T cells and Regulatory T cells in males at d15 (pâ¯<â¯0.01). Aged males demonstrated greater neurological deficits up to d5 and impaired sensorimotor function up to d15 when assessed by the corner asymmetry test (pâ¯<â¯0.001 and pâ¯<â¯0.01, respectively). A trend in greater cognitive decline was observed at d21 in males. Increased GFAP expression in the ischemic hemisphere, indicating astroglial activation and gliosis, was demonstrated in both males and females 42d post-stroke. Our findings indicate that despite a similar initial ischemic brain injury, aged male mice experience greater peripheral effects on the gut and ongoing central neuroinflammation past the sub-acute phase after stroke.
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Isquemia Encefálica , Microbioma Gastrointestinal , AVC Isquêmico , Acidente Vascular Cerebral , Animais , Linfócitos T CD8-Positivos , Feminino , Imunidade , Infarto da Artéria Cerebral Média , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Permeabilidade , Caracteres SexuaisRESUMO
Ischemic stroke is major cause of disability and mortality worldwide, and aging is strong risk factor for poor post-stroke outcome. Neutrophils traffic rapidly to the brain following ischemic stroke, and recent evidence has suggested that aging may alter neutrophil function after tissue injury. In this study, we hypothesize that aging enhances the pro-inflammatory function of neutrophils, directly contributing to the poorer outcomes seen in aging patients. We utilized demographic data and biological specimens from ischemic stroke patients and an experimental mouse model to determine the correlation between age, neutrophil function and stroke outcomes. In ischemic stroke patients, age was associated with increased mortality and morbidity and higher levels of neutrophil-activating cytokines. In mice, aged animals had higher stroke mortality and morbidity, higher levels of neutrophil-activating cytokines and enhanced generation of neutrophil reactive oxygen species compared to young mice. Finally, depletion of neutrophils via a specific monoclonal antibody after ischemic stroke led to long-term benefits in functional outcome in aged male and female animals, with no benefit observed in young. These results demonstrate that aging is associated with augmented neutrophil pathogenicity in ischemic stroke, and that neutrophil-targeted therapies may confer greater benefit in aged subjects.
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Envelhecimento , Suscetibilidade a Doenças , Neutrófilos/imunologia , Neutrófilos/metabolismo , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/etiologia , Citocinas/sangue , Modelos Animais de Doenças , Humanos , Contagem de Leucócitos , Camundongos , Morbidade , Mortalidade , Ativação de Neutrófilo/imunologia , Infiltração de Neutrófilos , Estudos Retrospectivos , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia , VirulênciaRESUMO
T-lymphocytes have a multifaceted role in ischemic stroke, but the majority of studies have been conducted in young mice, which may limit the translational value of these findings. Previous studies have shown that aging results in T cell dysfunction, leading to enhanced production of pro-inflammatory cytokines and chemokines, including interferon gamma (IFN-γ) and interferon-gamma-inducible protein (IP-10). This study assessed the role of T cells and pro-inflammatory factors on histologic and functional outcomes in an aged mouse model. Levels of IP-10 were measured in the brain and serum of young and aged male mice following middle cerebral artery occlusion (MCAo) or sham surgery. Additionally, IP-10 levels were evaluated in stroke patients. To directly determine the role of brain-infiltrating T cells after stroke, a separate cohort of aged male and female animals received either an anti-CD4 depletion antibody or IgG isotype control at 72 and 96 h following experimental stroke. Behavioral assessments were performed on day 7 post-MCAo. CD4 T cell depletion resulted in improved behavioral outcomes, despite the lack of differences in infarct size between the isotype control and anti-CD4 antibody treated stroke groups. Circulating IP-10 levels were increased in both humans and mice with age and stroke, and depletion of CD4 T cells led to a reduction in IFN-γ and IP-10 levels in mice. Since anti-CD4 treatment was administered three days after stroke onset, targeting this inflammatory pathway may be beneficial to aged stroke patients who present outside of the current time window for thrombolysis and thrombectomy.
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Isquemia Encefálica/terapia , Linfócitos T CD4-Positivos , Acidente Vascular Cerebral/terapia , Envelhecimento , Animais , Comportamento Animal , Química Encefálica , Isquemia Encefálica/psicologia , Quimiocinas/biossíntese , Citocinas/biossíntese , Feminino , Infarto da Artéria Cerebral Média/metabolismo , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Acidente Vascular Cerebral/psicologia , Resultado do TratamentoRESUMO
Aging and stroke alter the composition of the basement membrane and reduce the perivascular distribution of cerebrospinal fluid and solutes, which may contribute to poor functional recovery in elderly patients. Following stroke, TGF-ß induces astrocyte activation and subsequent glial scar development. This is dysregulated with aging and could lead to chronic, detrimental changes within the basement membrane. We hypothesized that TGF-ß induces basement membrane fibrosis after stroke, leading to impaired perivascular CSF distribution and poor functional recovery in aged animals. We found that CSF entered the aged brain along perivascular tracts; this process was reduced by experimental stroke and was rescued by TGF-ß receptor inhibition. Brain fibronectin levels increased with experimental stroke, which was reversed with inhibitor treatment. Exogenous TGF-ß stimulation increased fibronectin expression, both in vivo and in primary cultured astrocytes. Oxygen-glucose deprivation of cultured astrocytes induced multiple changes in genes related to astrocyte activation and extracellular matrix production. Finally, in stroke patients, we found that serum TGF-ß levels correlated with poorer functional outcomes, suggesting that serum levels may act as a biomarker for functional recovery. These results support a potential new treatment strategy to enhance recovery in elderly stroke patients.
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Membrana Basal/patologia , Líquido Cefalorraquidiano/metabolismo , Recuperação de Função Fisiológica/fisiologia , Acidente Vascular Cerebral/fisiopatologia , Fator de Crescimento Transformador beta/farmacologia , Idoso , Animais , Benzamidas/farmacologia , Biomarcadores/sangue , Encéfalo/metabolismo , Feminino , Fibronectinas/metabolismo , Fibrose , Humanos , Masculino , Camundongos Endogâmicos C57BL , Pirazóis/farmacologia , Receptores de Fatores de Crescimento Transformadores beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/sangueRESUMO
BACKGROUND: Ischemic stroke results in a robust inflammatory response within the central nervous system. As the immune-inhibitory CD200-CD200 receptor 1 (CD200R1) signaling axis is a known regulator of immune homeostasis, we hypothesized that it may play a role in post-stroke immune suppression after stroke. METHODS: In this study, we investigated the role of CD200R1-mediated signaling in stroke using CD200 receptor 1-deficient mice. Mice were subjected to a 60-min middle cerebral artery occlusion and evaluated at days 3 and 7, representing the respective peak and early resolution stages of neuroinflammation in this model of ischemic stroke. Infarct size and behavioral deficits were assessed at both time points. Central and peripheral cellular immune responses were measured using flow cytometry. Bacterial colonization was determined in lung tissue homogenates both after acute stroke and in an LPS model of systemic inflammation. RESULTS: In wild-type (WT) animals, CD200R1 was expressed on infiltrating monocytes and lymphocytes after stroke but was absent on microglia. Early after ischemia (72 h), CD200R1-knockout (KO) mice had significantly poorer survival rates and an enhanced susceptibility to spontaneous bacterial colonization of the respiratory tract compared to wild-type (WT) controls, despite no difference in infarct or neurological deficits. While the CNS inflammation was resolved by day 7 post-stroke in WT mice, brain-resident microglia and monocyte activation persisted in CD200R1-KO mice, accompanied by a delayed, augmented lymphocyte response. At this time point, CD200R1-KO mice displayed greater weight loss, more severe neurological deficits, and impaired motor function compared to WT. Systemically, CD200R1-KO mice exhibited signs of persistent infection including lymphopenia, T cell activation and memory conversion, and narrowing of the TCR repertoire. These findings were confirmed in a second model of acute neuroinflammation induced by systemic endotoxin challenge. CONCLUSION: This study defines an essential role of CD200-CD200R1 signaling in stroke. Loss of CD200R1 led to high mortality, increased rates of post-stroke infection, and enhanced entry of peripheral leukocytes into the brain after ischemia, with no increase in infarct size. This suggests that the loss of CD200 receptor leads to enhanced peripheral inflammation that is triggered by brain injury.
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Antígenos CD/metabolismo , Infecções Bacterianas/etiologia , Encefalite/etiologia , Infarto da Artéria Cerebral Média/fisiopatologia , Receptores de Orexina/metabolismo , Recuperação de Função Fisiológica/fisiologia , Transdução de Sinais/fisiologia , Animais , Encéfalo/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/fisiologia , Comportamento de Doença/efeitos dos fármacos , Comportamento de Doença/fisiologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/fisiologia , Comportamento de Nidação/fisiologia , Receptores de Orexina/genética , Fagocitose/fisiologia , Transtornos Psicomotores/etiologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: MicroRNAs (miRNA) are a class of small, endogenous (17-25 nucleotide) noncoding ribonucleic acids implicated in the transcriptional and post-transcriptional regulation of gene expression. This study examines stroke-specific miRNA expression in large vessel territory cardioembolic stroke. METHODS: Peripheral blood was collected from controls and ischemic stroke patients 24 hours after stroke onset. Whole blood miRNA was isolated and analyzed for differential expression. A total of 16 patients with acute middle cerebral artery territory strokes of cardioembolic origin were included in this pilot study. MiRNA profiling was conducted by miRCURY LNA™ microRNA Array. RESULTS: In patients with cardioembolic stroke, significant differential expression of 14 miRNAs was observed when compared to controls. Ten of these miRNA had not previously been associated with ischemic stroke (miR-664a-3p, -2116-5pp, -4531, -4765-5p, -647, -4709-3p, -4742-3p, -5584-3p, -4756-3p, and -5187-3p). Subanalysis of severe strokes (NIHSS > 10) identified an additional 5 differentially expressed miRNA. No significant effects of sex or tissue plasminogen activator treatment were seen on miRNA expression. CONCLUSIONS: Ischemic stroke patients show a differential miRNA expression profile as compared to controls. These new associations between circulating miRNAs and ischemic stroke may help to refine stroke subtype diagnosis and identify novel therapeutic miRNA targets for the treatment of ischemic stroke.
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Isquemia Encefálica/sangue , Embolia/sangue , MicroRNAs/sangue , Acidente Vascular Cerebral/sangue , Idoso , Biomarcadores/sangue , Isquemia Encefálica/etiologia , Embolia/complicações , Feminino , Cardiopatias/sangue , Cardiopatias/complicações , Humanos , Masculino , Projetos Piloto , Acidente Vascular Cerebral/etiologiaRESUMO
Ischemic stroke is a devastating brain injury resulting in high mortality and substantial loss of function. Understanding the pathophysiology of ischemic stroke risk, mortality, and functional loss is critical to the development of new therapies. Age and sex have a complex and interactive effect on ischemic stroke risk and pathophysiology. Aging is the strongest nonmodifiable risk factor for ischemic stroke, and aged stroke patients have higher mortality and morbidity and poorer functional recovery than their young counterparts. Importantly, patient age modifies the influence of patient sex in ischemic stroke. Early in life, the burden of ischemic stroke is higher in men, but stroke becomes more common and debilitating for women in elderly populations. The profound effects of sex and age on clinical ischemic stroke are mirrored in the results of experimental in vivo and in vitro studies. Here, we review current knowledge on the influence of age and sex in the incidence, mortality, and functional outcome of ischemic stroke in clinical populations. We also discuss the experimental evidence for sex and age differences in stroke pathophysiology and how a better understanding of these biological variables can improve clinical care and enhance development of novel therapies.
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Isquemia Encefálica/fisiopatologia , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/fisiopatologia , Fatores Etários , Animais , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/mortalidade , Feminino , Humanos , Incidência , Masculino , Prognóstico , Fatores Sexuais , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/mortalidadeRESUMO
The prevalence of cardiovascular disease has increased among middle-aged women in the United States, yet has declined in middle-aged men. In experimental stroke, middle-aged females have larger strokes and greater inflammation than age-matched males or younger females. The mechanism underlying this shift from an "ischemia-protected" to an "ischemia-sensitive" phenotype in aging females is unknown. One potential factor is an age-related increase in systemic factors that induce inflammation. Increased abdominal fat deposition is seen in women during middle age. Adipose tissue plays a key role in obesity-induced systemic inflammation, including increased pro-inflammatory cytokines. We hypothesized that age and sex differences in adipose immune cells promote an augmented pro-inflammatory milieu in middle-aged females driven by a balance shift between pro-inflammatory and anti-inflammatory T cells. Abdominal adipose tissue immune cells from young (3-4 months) and middle-aged (15-16 months) male and female C57BL/6J mice were analyzed by flow cytometry. Plasma triglyceride (TG), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) levels were determined with colorimetric assays. Middle-aged mice had higher adipose tissue mass compared to young mice. Lipid profiling showed no sex differences in TG and LDL, but middle-aged females had lower HDL (0.84 ± 0.07 µg/µl) than middle-aged males (1.35 ± 0.06 µg/µl). Flow cytometry data demonstrated an age-associated increase in adipose tissue CD8+ T cells that was augmented by female sex, with middle-aged females having a higher percentage of CD8+ cells (34.4 ± 3.2% of CD3+ T cells) than middle-aged males (24.4 ± 2.2%). This increase in CD8+ T-cell proportion was adipose tissue-specific, as this change was not observed in blood. Middle-aged females had higher numbers of activated (CD69+) CD8+ T cells than males. In addition, female CD8+ T cells produced higher levels of IFN-γ, TNF-α, and granzyme B ex vivo, and females had higher adipose levels of IFN-γ, RANTES and MIP-1ß than middle-aged males. In parallel, females had lower levels of regulatory T cells (Tregs), an anti-inflammatory T-cell subtype, compared to age-matched males. In conclusion, middle-aged females have a detrimental combination of elevated pro-inflammatory T cells and decreased anti-inflammatory Tregs in adipose tissue, which may promote a pro-inflammatory milieu and contribute to increased cardiovascular disease burden in aging females.
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Gordura Abdominal/imunologia , Tecido Adiposo/imunologia , Envelhecimento/fisiologia , Linfócitos T CD8-Positivos/imunologia , Doenças Cardiovasculares/imunologia , Fatores Sexuais , Linfócitos T Reguladores/imunologia , Animais , Feminino , Granzimas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Interferon gama/metabolismo , Lipoproteínas HDL/metabolismo , Ativação Linfocitária , Masculino , Camundongos , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND AND PURPOSE: Intracerebral hemorrhage (ICH) is a devastating disease with a 30-day mortality of ~50%. There are no effective therapies for ICH. ICH results in brain damage in 2 major ways: through the mechanical forces of extravasated blood and then through toxicity of the intraparenchymal blood components including hemoglobin/iron. LTF (lactoferrin) is an iron-binding protein, uniquely abundant in polymorphonuclear neutrophils (PMNs). After ICH, circulating blood PMNs enter the ICH-afflicted brain where they release LTF. By virtue of sequestrating iron, LTF may contribute to hematoma detoxification. METHODS: ICH in mice was produced using intrastriatal autologous blood injection. PMNs were depleted with intraperitoneal administration of anti-Ly-6G antibody. Treatment of mouse brain cell cultures with lysed RBC or iron was used as in vitro model of ICH. RESULTS: LTF mRNA was undetectable in the mouse brain, even after ICH. Unlike mRNA, LTF protein increased in ICH-affected hemispheres by 6 hours, peaked at 24 to 72 hours, and remained elevated for at least a week after ICH. At the single cell level, LTF was detected in PMNs in the hematoma-affected brain at all time points after ICH. We also found elevated LTF in the plasma after ICH, with a temporal profile similar to LTF changes in the brain. Importantly, mrLTF (recombinant mouse LTF) reduced the cytotoxicity of lysed RBC and FeCl3 to brain cells in culture. Ultimately, in an ICH model, systemic administration of mrLTF (at 3, 24, and 48 hours after ICH) reduced brain edema and ameliorated neurological deficits caused by ICH. mrLTF retained the benefit in reducing behavioral deficit even with 24-hour treatment delay. Interestingly, systemic depletion of PMNs at 24 hours after ICH worsened neurological deficits, suggesting that PMN infiltration into the brain at later stages after ICH could be a beneficial response. CONCLUSIONS: LTF delivered to the ICH-affected brain by infiltrating PMNs may assist in hematoma detoxification and represent a powerful potential target for the treatment of ICH.
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Encéfalo/metabolismo , Hemorragia Cerebral/metabolismo , Hematoma/metabolismo , Ferro/metabolismo , Lactoferrina/genética , Neutrófilos/metabolismo , RNA Mensageiro/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Edema Encefálico/metabolismo , Técnicas de Cultura de Células , Modelos Animais de Doenças , Eritrócitos , Técnicas In Vitro , Lactoferrina/metabolismo , Lactoferrina/farmacologia , CamundongosRESUMO
Objective: Patients with intracerebral hemorrhage (ICH) may elaborate varying degrees of perihematomal edema (PHE), requiring closer monitoring and a higher intensity of treatment. Here, we explore whether the soluble form of CD163, a scavenger receptor responsible for hemoglobin sequestration, can serve as a prognostic biomarker of PHE development and poor outcome after ICH. Methods: Our study cohort was comprised of 51 primary age- and sex-matched ICH patients with moderate-sized, hypertensive deep hemorrhages. Patients were part of a prospective ICH registry cataloguing admission data along with functional outcomes. We measured sCD163 levels in serial serum and cerebrospinal fluid (CSF) samples obtained at prespecified timepoints. Descriptive statistics, including a generalized estimating equation for longitudinal data, were used to analyze sCD163 in relation to ICH outcomes. Results: Acute serum sCD163 (<48 h postictus) was significantly elevated in ICH patients compared to both acute neurological event controls (P = <0.001) and healthy controls (P = 0.003). As predicted, acute serum sCD163 levels were significantly associated with both hematoma volume expansion (P = 0.009) and PHE expansion (P = 0.002). Further examination determined that patients with high PHE expansion had poorer modified Rankin Scale scores at discharge (P = 0.024), and circulating sCD163 levels were found to be significantly lower in patients with high-level PHE expansion. Interpretation: Acute sCD163 levels may be a useful biomarker for the acute identification of patients at risk for hematoma expansion, perihematomal edema expansion and poorer short-term outcomes.
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Shortly after intracerebral hemorrhage, neutrophils infiltrate the intracerebral hemorrhage-injured brain. Once within the brain, neutrophils degranulate, releasing destructive molecules that may exacerbate brain damage. However, neutrophils also release beneficial molecules, including iron-scavenging lactoferrin that may limit hematoma/iron-mediated brain injury after intracerebral hemorrhage. Here, we show that the immunoregulatory cytokine interleukin-27 is upregulated centrally and peripherally after intracerebral hemorrhage. Data from rodent models indicate that interleukin-27 modifies neutrophil maturation in the bone marrow, suppressing their production of pro-inflammatory/cytotoxic products while increasing their production of beneficial iron-scavenging molecules, including lactoferrin. Finally, interleukin-27 or lactoferrin administration results in reduced edema, enhanced hematoma clearance, and improved neurological outcomes in an animal model of intracerebral hemorrhage. These results suggest that interleukin-27/lactoferrin-mediated modulations of neutrophil function may represent a therapeutically viable concept for the modification of neutrophils toward a "beneficial" phenotype for the treatment of intracerebral hemorrhage.Neutrophils are important modulators of tissue damage after intracerebral hemorrhage (ICH), but how this function is regulated is not clear. Here, the authors show interleukin-27 promotes the tissue-protecting functions of neutrophils via, at least partly, the induction of lactoferrin to present a potential therapy for ICH.
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Hemorragia Cerebral/imunologia , Interleucina-27/imunologia , Neurônios/metabolismo , Infiltração de Neutrófilos/imunologia , Animais , Astrócitos , Edema Encefálico , Células Cultivadas , Córtex Cerebral/citologia , Hemorragia Cerebral/metabolismo , Citometria de Fluxo , Interleucina-27/farmacologia , Lactoferrina/metabolismo , Lactoferrina/farmacologia , Camundongos , Microglia , Neurônios/efeitos dos fármacos , Neutrófilos/imunologia , Oligodendroglia , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/metabolismoRESUMO
Circulating levels of the pro-inflammatory cytokine C-C motif chemokine 11 (CCL11, also known as eotaxin-1) are increased in several animal models of neuroinflammation, including traumatic brain injury and Alzheimer's disease. Increased levels of CCL11 have also been linked to decreased neurogenesis in mice. We hypothesized that circulating CCL11 levels would increase following ischemic stroke in mice and humans, and that higher CCL11 levels would correlate with poor long-term recovery in patients. As predicted, circulating levels of CCL11 in both young and aged mice increased significantly 24 h after experimental stroke. However, ischemic stroke patients showed decreased CCL11 levels compared to controls 24 h after stroke. Interestingly, lower post-stroke CCL11 levels were predictive of increased stroke severity and independently predictive of poorer functional outcomes in patients 12 months after ischemic stroke. These results illustrate important differences in the peripheral inflammatory response to ischemic stroke between mice and human patients. In addition, it suggests CCL11 as a candidate biomarker for the prediction of acute and long-term functional outcomes in ischemic stroke patients.