Introduction: Ischemic stroke is becoming a primary cause of disability and death worldwide. To date, therapeutic options remain limited focusing on mechanical thrombolysis or administration of thrombolytic agents. However, these therapies do not promote neuroprotection and neuro-restoration of the ischemic area of the brain.
Areas covered: This review highlights the option of minimal invasive, intra-arterial, administration of biological agents for stroke therapy. The authors provide an update of all available studies, discuss issues that influence outcomes and describe future perspectives which aim to improve clinical outcomes. New therapeutic options based on cellular and molecular interactions following an ischemic brain event, will be highlighted.
Expert opinion: Intra-arterial administration of biological agents during trans-catheter thrombolysis or thrombectomy could limit neuronal cell death and facilitate regeneration or neurogenesis following ischemic brain injury. Despite the initial progress, further meticulous studies are needed in order to establish the clinical use of stem cell-induced neuroprotection and neuroregeneration. 相似文献
Resistin is an immunometabolic mediator that is elevated in several inflammatory disorders. A ligand for Toll-like receptor 4, resistin modulates the recruitment and activation of myeloid cells, notably neutrophils. Neutrophils are major drivers of cystic fibrosis (CF) lung disease, in part due to the release of human neutrophil elastase- and myeloperoxidase-rich primary granules, leading to tissue damage. Here we assessed the relationship of resistin to CF lung disease.
Methods
Resistin levels were measured in plasma and sputum from three retrospective CF cohorts spanning a wide range of disease. We also assessed the ability of neutrophils to secrete resistin upon activation in vitro. Finally, we constructed a multivariate model assessing the relationship between resistin levels and lung function.
Results
Plasma resistin levels were only marginally higher in CF than in healthy control subjects. By contrast, sputum resistin levels were very high in CF, reaching 50–100 fold higher levels than in plasma. Among CF patients, higher plasma resistin levels were associated with allergic bronchopulmonary aspergillosis, and higher sputum resistin levels were associated with CF-related diabetes. Mechanistically, in vitro release of neutrophil primary granules was concomitant with resistin secretion. Overall, sputum resistin levels were negatively correlated with CF lung function, independently of other variables (age, sex, and genotype).
Conclusions
Our data establish relationships between resistin levels in the plasma and sputum of CF patients that correlate with disease status, and identify resistin as a novel mechanistic link between neutrophilic inflammation and lung disease in CF. 相似文献
Clinical trials are probably the most informative experiments to help an understanding of multiple sclerosis (MS) biology. Recent successes with CD20‐depleting antibodies have focused attention towards B cell subsets as important mediators in MS. The trial of tabalumab (NTC00882999), which inhibits B cell activation factor (BAFF), is reported and reviewed and this trial is contrasted with the trial on the inhibition of a proliferation‐inducing ligand (APRIL) and BAFF using atacicept (NCT00642902). Both tabalumab and atacicept induce depletion of mature B cells and inhibit antibody formation, but they fail to deplete memory B cells and do not inhibit relapsing MS. Atacicept is reported to augment memory B cell responses and may precipitate relapse, suggesting the importance of APRIL. However, BAFF inhibition can enhance peripheral blood memory B cell responses, which was not associated with augmented relapse. Although other interpretations are possible, these data further support the hypothesis that memory B cells may be of central importance in relapsing MS, as they are the major CD20+ B cell subset expressing APRIL receptors. They also suggest that quantitative and/or qualitative differences in B cell responses or other factors, such as an immune‐regulatory effect associated with APRIL, may be important in determining whether MS reactivates following neutralization of peripheral B cell maturation and survival factors. 相似文献
AimsWe previously showed that the protective effects of endothelial progenitor cells (EPCs)‐released exosomes (EPC‐EXs) on endothelium in diabetes. However, whether EPC‐EXs are protective in diabetic ischemic stroke is unknown. Here, we investigated the effects of EPC‐EXs on diabetic stroke mice and tested whether miR‐126 enriched EPC‐EXs (EPC‐EXsmiR126) have enhanced efficacy.MethodsThe db/db mice subjected to ischemic stroke were intravenously administrated with EPC‐EXs 2 hours after ischemic stroke. The infarct volume, cerebral microvascular density (MVD), cerebral blood flow (CBF), neurological function, angiogenesis and neurogenesis, and levels of cleaved caspase‐3, miR‐126, and VEGFR2 were measured on day 2 and 14.ResultsWe found that (a) injected EPC‐EXs merged with brain endothelial cells, neurons, astrocytes, and microglia in the peri‐infarct area; (b) EPC‐EXsmiR126 were more effective than EPC‐EXs in decreasing infarct size and increasing CBF and MVD, and in promoting angiogenesis and neurogenesis as well as neurological functional recovery; (c) These effects were accompanied with downregulated cleaved caspase‐3 on day 2 and vascular endothelial growth factor receptor 2 (VEGFR2) upregulation till day 14.ConclusionOur results indicate that enrichment of miR126 enhanced the therapeutic efficacy of EPC‐EXs on diabetic ischemic stroke by attenuating acute injury and promoting neurological function recovery. 相似文献
Central illustration: cumulative major adverse cardiac events (MACE) and bioresorbable vascular scaffold (BVS) thrombosis rates after 1, 2, 3, 4 and 5 years. 相似文献
In addition to providing pathogen-specific immunity, vaccines can also confer nonspecific effects (NSEs) on mortality and morbidity unrelated to the targeted disease. Immunisation with live vaccines, such as the BCG vaccine, has generally been associated with significantly reduced all-cause infant mortality. In contrast, some inactivated vaccines, such as the diphtheria, tetanus, whole-cell pertussis (DTPw) vaccine, have been controversially associated with increased all-cause mortality especially in female infants in high-mortality settings. The NSEs associated with BCG have been attributed, in part, to the induction of trained immunity, an epigenetic and metabolic reprograming of innate immune cells, increasing their responsiveness to subsequent microbial encounters. Whether non-live vaccines such as DTPw induce trained immunity is currently poorly understood. Here, we report that immunisation of mice with DTPw induced a unique program of trained immunity in comparison to BCG immunised mice. Altered monocyte and DC cytokine responses were evident in DTPw immunised mice even months after vaccination. Furthermore, splenic cDCs from DTPw immunised mice had altered chromatin accessibility at loci involved in immunity and metabolism, suggesting that these changes were epigenetically mediated. Interestingly, changing the order in which the BCG and DTPw vaccines were co-administered to mice altered subsequent trained immune responses. Given these differences in trained immunity, we also assessed whether administration of these vaccines altered susceptibility to sepsis in two different mouse models. Immunisation with either BCG or a DTPw-containing vaccine prior to the induction of sepsis did not significantly alter survival. Further studies are now needed to more fully investigate the potential consequences of DTPw induced trained immunity in different contexts and to assess whether other non-live vaccines also induce similar changes. 相似文献
Antibody-mediated rejection is a major complication in renal transplantation. The pathologic manifestations of acute antibody-mediated rejection that has progressed to functional impairment of a renal transplant have been defined in clinical biopsy specimens. However, the initial stages of the process are difficult to resolve with the unavoidable variables of clinical studies. We devised a model of renal transplantation to elucidate the initial stages of humoral rejection. Kidneys were orthotopically allografted to immunodeficient mice. After perioperative inflammation subsided, donor-specific alloantibodies were passively transferred to the recipient. Within 1 hour after a single transfer of antibodies, C4d was deposited diffusely on capillaries, and von Willebrand factor released from endothelial cells coated intravascular platelet aggregates. Platelet-transported inflammatory mediators platelet factor 4 and serotonin accumulated in the graft at 100- to 1000-fold higher concentrations compared with other platelet-transported chemokines. Activated platelets that expressed P-selectin attached to vascular endothelium and macrophages. These intragraft inflammatory changes were accompanied by evidence of acute endothelial injury. Repeated transfers of alloantibodies over 1 week sustained high levels of platelet factor 4 and serotonin. Platelet depletion decreased platelet mediators and altered the accumulation of macrophages. These data indicate that platelets augment early inflammation in response to donor-specific antibodies and that platelet-derived mediators may be markers of evolving alloantibody responses. 相似文献