Found in Translation

Dirnagl, Ulrich; Endres, Matthias

doi:10.1161/strokeaha.113.004075

Cited by 129 publications

(51 citation statements)

References 136 publications

(120 reference statements)

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“…by guest on May 11, 2018 http://stroke.ahajournals.org/ mechanisms of increased susceptibility to infection and to develop preventive treatment strategies. 23 However, it remained unclear whether cerebral ischemia affects resident lung cells, which mediate first-line pulmonary immune responses during respiratory infections. Our data suggest that lung innate immune responses are suppressed after stroke by increased cholinergic signaling, which is relayed by the parasympathetic vagus nerve and the α7nAChR expressed on AEC and MΦ.…”

Section: Strokementioning

confidence: 99%

Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke

Engel¹,

Akyüz

Gonçalves

et al. 2015

Stroke

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T he management of medical complications is one of the most critical factors in the therapy of stroke because 95% of stroke patients experience at least one relevant medical complication in the first 3 months after stroke. 1 In both experimental and clinical studies, infections are the most common complication after stroke.2 Among these, pneumonia is the most relevant poststroke infection, 3 accounting for the highest attributable mortality after stroke. 4 To maintain body homeostasis in response to challenges from the environment, the nervous and immune systems are closely interconnected in an intense bidirectional communication. 5 Recent experimental and clinical evidence indicates that central nervous system injuries like stroke, spinal cord injury, or traumatic brain injury disturb the normally well-balanced interplay between these 2 supersystems, resulting in a profound and long-lasting immunodepression. 6,7 Overactivation of the sympathetic nervous system after stroke was shown to mediate suppression of peripheral cellular immune responses and to contribute to development of poststroke bacterial lung infections. [8][9][10] However, changes in the pulmonary immune compartment and the underlying mechanisms of impaired antibacterial lung immune responses after stroke are currently not understood.Besides resident lung immune cells, such as alveolar macrophages (MΦ), alveolar epithelial cells (AEC) express Background and Purpose-Temporary immunosuppression has been identified as a major risk factor for the development of pneumonia after acute central nervous system injury. Although overactivation of the sympathetic nervous system was previously shown to mediate suppression of systemic cellular immune responses after stroke, the role of the parasympathetic cholinergic anti-inflammatory pathway in the antibacterial defense in lung remains largely elusive. Methods-The middle cerebral artery occlusion model in mice was used to examine the influence of the parasympathetic nervous system on poststroke immunosuppression. We used heart rate variability measurement by telemetry, vagotomy, α7 nicotinic acetylcholine receptor-deficient mice, and parasympathomimetics (nicotine, PNU282987) to measure and modulate parasympathetic activity. Results-Here, we demonstrate a rapidly increased parasympathetic activity in mice after experimental stroke. Inhibition of cholinergic signaling by either vagotomy or by using α7 nicotinic acetylcholine receptor-deficient mice reversed pulmonary immune hyporesponsiveness and prevented pneumonia after stroke. In vivo and ex vivo studies on the role of α7 nicotinic acetylcholine receptor on different lung cells using bone marrow chimeric mice and isolated primary cells indicated that not only macrophages but also alveolar epithelial cells are a major cellular target of cholinergic antiinflammatory signaling in the lung. 12 Both MΦ and lung epithelial cells have been shown to express the α7 nicotinergic acetylcholine receptor (α7nAChR), 13 which has been identified as a crucial downstre...

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Section: Strokementioning

confidence: 99%

Cholinergic Pathway Suppresses Pulmonary Innate Immunity Facilitating Pneumonia After Stroke

Engel¹,

Akyüz

Gonçalves

et al. 2015

Stroke

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“…52,53 Unexpectedly, neuroprotective agents, which block molecular elaboration of ischemic insult on brain cells, have shown no clinical benefit in patients despite their preclinical efficacy. 54 Because recanalization of the occluded vessel is in essence associated with improved clinical outcome, 1 it makes sense to target proteins such as TAFI and PAI-1 that inhibit thrombolysis. 11 Indeed, when the diabody (0.8 mg/kg) was administered early after thrombin-mediated MCAo, a strong beneficial effect on lesion volume was observed ( Figure 3A).…”

Section: Blood 19 February 2015 X Volume 125 Number 8 Dual Tafi/paimentioning

confidence: 99%

Innovative thrombolytic strategy using a heterodimer diabody against TAFI and PAI-1 in mouse models of thrombosis and stroke

Wyseure

Rubio

Denorme

et al. 2015

Blood

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• Early thrombolytic treatment with a bispecific inhibitor against TAFI and PAI-1 is effective without exogenous tPA.• Even at the highest dose tested, the bispecific inhibitor against TAFI and PAI-1 does not prolong bleeding time.Circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) are causal factors for thrombolytic failure. Therefore, we evaluated an antibody-engineered bispecific inhibitor against TAFI and PAI-1 (heterodimer diabody, Db-TCK26D6x33H1F7) in several mouse models of thrombosis and stroke. Prophylactic administration of the diabody (0.8 mg/kg) in a thromboplastin-induced model of thromboembolism led to decreased lung fibrin deposition. In a model of cerebral ischemia and reperfusion, diabody administration (0.8 mg/kg, 1 hour postocclusion) led to a mitigated cerebral injury with a 2.3-fold reduced lesion and improved functional outcomes. In a mouse model of thrombin-induced middle cerebral artery occlusion, the efficacy of the diabody was compared to the standard thrombolytic treatment with recombinant tissuetype plasminogen activator (tPA). Early administration of diabody (0.8 mg/kg) caused a twofold decrease in brain lesion size, whereas that of tPA (10 mg/kg) had a much smaller effect. Delayed administration of diabody or tPA had no effect on lesion size, whereas the combined administration of diabody with tPA caused a 1.7-fold decrease in lesion size. In contrast to tPA, the diabody did not increase accumulative bleeding. In conclusion, administration of a bispecific inhibitor against TAFI and PAI-1 results in a prominent profibrinolytic effect in mice without increased bleeding. (Blood. 2015;125(8):1325-1332 IntroductionPlasminogen activators are the only thrombolytic agents approved to rapidly revascularize a thrombosed vessel. Reperfusion of the ischemiaaffected organ leads to an improved outcome in patients when applied within the first hours after ischemic onset.1 Despite this evidence-based beneficial effect, current thrombolytic agents remain widely underutilized due to life-threatening side effects such as cerebral hemorrhages and possible neurotoxicity.2,3 For acute ischemic stroke, in particular, the only licensed treatment option consists of a high systemic dose of recombinant tissue-type plasminogen activator (tPA), which is actually given to ,10% of the patients. Therefore, there is an unmet clinical need to explore novel therapeutic avenues to enhance fibrinolysis without plasminogen activator-associated adverse effects. Endogenous intravascular fibrinolysis is driven on the release of tPA from the endothelium, which in turn enzymatically activates plasminogen into the fibrin-degrading enzyme, plasmin.4 This activation step is attenuated by circulating thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1). Activated TAFI (TAFIa; encoded by the CPB2 gene) eliminates C-terminal Lys exposed on partially degraded fibrin, which ultimately leads to a diminished efficiency and localizati...

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“…Reasons for these failures and the predictive ability of stroke models have been discussed in many articles, as have suggested improvements for future research that might improve translation. [65][66][67][68] In respect of these previous experiences, it is important therefore to highlight gaps in current knowledge relating to inhibition of IL-1 in stroke. There remains limited data on the therapeutic window for IL-1 inhibition, although one recent study reports efficacy of IL-1Ra up to 12 hours after intravenous treatment in rat MCAO.…”

Section: Clinical Trials Of Il-1ra In Strokementioning

confidence: 99%