Abstract TP266: Ischemic Stroke Induces Striking Heterogeneity in the Inflammatory Leukocyte Infiltrate Across the Core and Penumbra

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Neil A Nadkarni ◽  
Ayush Batra ◽  
William A Muller ◽  
David P Sullivan
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Response ◽  
Therapeutic Interventions ◽  
Wide Field ◽  
Exact Nature ◽  
Leukocyte Infiltration ◽  
Tetrazolium Chloride ◽  
Leukocyte Extravasation ◽  
Spatio Temporal ◽  
Infarcted Tissue

Background: Current therapies for ischemic stroke focus on reperfusion but do not address the acute inflammatory response. Previous clinical trials aimed at modulating the inflammatory milieu by disrupting leukocyte infiltration failed to show clinical efficacy. One possible explanation for this unexpected shortcoming is an incomplete understanding of the precise spatio-temporal underpinnings of leukocyte extravasation and infiltration. Methods: Here we describe the evolution of the inflammatory response in a mouse transient middle cerebral artery occlusion (tMCAO) stroke model at 0, 1, 2 and 3 days post reperfusion. We used wide field and confocal immunofluorescence microscopy to examine the exact nature and location of the invading myelomonocytic populations, with close examination of the leukocyte position with regard to the brain vasculature and the perivascular space. Results: Our findings suggest that the vast majority of infiltrating myelomonocytic cells escape the perivascular compartment and enter the parenchyma. Interestingly, leukocyte extravasation and accumulation in the subcortex occurred over several days. Dramatic heterogeneity in the inflammatory infiltrate was observed across the infarcted tissue, but also in the surrounding penumbra and adjacent cortical surface. In addition, triphenyl tetrazolium chloride staining, a common indicator for infarcted tissue, did not correlate with the amount or location of leukocyte infiltration. Conclusion: Taken together our findings demonstrate that the infiltration of leukocytes dynamically evolves over several days following reperfusion. Furthermore, leukocytes infiltrate in a heterogeneous pattern that does not correlate well with traditional markers of cellular dysfunction. A better understating of the precise spatio-temporal infiltration of inflammatory cells could help inform the next generation of therapeutic interventions.

scholarly journals Simulating Spatio-Temporal Patterns of Bicycle Flows with an Agent-Based Model

2021 ◽  
Vol 10 (2) ◽  
pp. 88
Author(s):  
Dana Kaziyeva ◽  
Martin Loidl ◽  
Gudrun Wallentin
Keyword(s):  
Regional Scale ◽  
Evidence Base ◽  
Wide Field ◽  
Traffic Patterns ◽  
Agent Based Model ◽  
Validation Data ◽  
Agent Based ◽  
Mobility Behavior ◽  
Spatio Temporal ◽  
Models Validation

Transport planning strategies regard cycling promotion as a suitable means for tackling problems connected with motorized traffic such as limited space, congestion, and pollution. However, the evidence base for optimizing cycling promotion is weak in most cases, and information on bicycle patterns at a sufficient resolution is largely lacking. In this paper, we propose agent-based modeling to simulate bicycle traffic flows at a regional scale level for an entire day. The feasibility of the model is demonstrated in a use case in the Salzburg region, Austria. The simulation results in distinct spatio-temporal bicycle traffic patterns at high spatial (road segments) and temporal (minute) resolution. Scenario analysis positively assesses the model’s level of complexity, where the demographically parametrized behavior of cyclists outperforms stochastic null models. Validation with reference data from three sources shows a high correlation between simulated and observed bicycle traffic, where the predictive power is primarily related to the quality of the input and validation data. In conclusion, the implemented agent-based model successfully simulates bicycle patterns of 186,000 inhabitants within a reasonable time. This spatially explicit approach of modeling individual mobility behavior opens new opportunities for evidence-based planning and decision making in the wide field of cycling promotion

scholarly journals Oral Glucosylceramide Reduces 2,4-Dinitrofluorobenzene Induced Inflammatory Response in Mice by Reducing TNF-Alpha Levels and Leukocyte Infiltration

Lipids ◽  
2011 ◽  
Vol 46 (6) ◽  
pp. 505-512 ◽  
Author(s):  
Jingjing Duan ◽  
Tatsuya Sugawara ◽  
Shota Sakai ◽  
Kazuhiko Aida ◽  
Takashi Hirata
Keyword(s):  
Inflammatory Response ◽  
Tnf Alpha ◽  
Leukocyte Infiltration

scholarly journals Roles of Specialized Pro-Resolving Lipid Mediators in Autophagy and Inflammation

2020 ◽  
Vol 21 (18) ◽  
pp. 6637 ◽  
Author(s):  
Antonio Recchiuti ◽  
Elisa Isopi ◽  
Mario Romano ◽  
Domenico Mattoscio
Keyword(s):  
Inflammatory Response ◽  
Cytokine Production ◽  
Lipid Mediators ◽  
Tissue Homeostasis ◽  
Leukocyte Infiltration ◽  
Catabolic Pathway ◽  
Resolution Of Inflammation ◽  
Endogenous Lipid ◽  
Inflammation Resolution ◽  
Cellular Components

Autophagy is a catabolic pathway that accounts for degradation and recycling of cellular components to extend cell survival under stress conditions. In addition to this prominent role, recent evidence indicates that autophagy is crucially involved in the regulation of the inflammatory response, a tightly controlled process aimed at clearing the inflammatory stimulus and restoring tissue homeostasis. To be efficient and beneficial to the host, inflammation should be controlled by a resolution program, since uncontrolled inflammation is the underlying cause of many pathologies. Resolution of inflammation is an active process mediated by a variety of mediators, including the so-called specialized pro-resolving lipid mediators (SPMs), a family of endogenous lipid autacoids known to regulate leukocyte infiltration and activities, and counterbalance cytokine production. Recently, regulation of autophagic mechanisms by these mediators has emerged, uncovering unappreciated connections between inflammation resolution and autophagy. Here, we summarize mechanisms of autophagy and resolution, focusing on the contribution of autophagy in sustaining paradigmatic examples of chronic inflammatory disorders. Then, we discuss the evidence that SPMs can restore dysregulated autophagy, hypothesizing that resolution of inflammation could represent an innovative approach to modulate autophagy and its impact on the inflammatory response.

scholarly journals Kininogen deficiency protects from ischemic neurodegeneration in mice by reducing thrombosis, blood-brain barrier damage, and inflammation

Blood ◽  
2012 ◽  
Vol 120 (19) ◽  
pp. 4082-4092 ◽  
Author(s):  
Friederike Langhauser ◽  
Eva Göb ◽  
Peter Kraft ◽  
Christian Geis ◽  
Joachim Schmitt ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Blood Brain Barrier ◽  
Thrombus Formation ◽  
Therapeutic Interventions ◽  
Brain Barrier ◽  
Edema Formation ◽  
Kinin System ◽  
Local Inflammatory Response ◽  
Blood Brain ◽  
Blood Brain Barrier Damage

Abstract Thrombosis and inflammation are hallmarks of ischemic stroke still unamenable to therapeutic interventions. High-molecular-weight kininogen (KNG) is a central constituent of the contact-kinin system which represents an interface between thrombotic and inflammatory circuits and is critically involved in stroke development. Kng−/− mice are protected from thrombosis after artificial vessel wall injury and lack the proinflammatory mediator bradykinin. We investigated the consequences of KNG deficiency in models of ischemic stroke. Kng−/− mice of either sex subjected to transient middle cerebral artery occlusion developed dramatically smaller brain infarctions and less severe neurologic deficits without an increase in infarct-associated hemorrhage. This protective effect was preserved at later stages of infarction as well as in elderly mice. Targeting KNG reduced thrombus formation in ischemic vessels and improved cerebral blood flow, and reconstitution of KNG-deficient mice with human KNG or bradykinin restored clot deposition and infarct susceptibility. Moreover, mice deficient in KNG showed less severe blood-brain barrier damage and edema formation, and the local inflammatory response was reduced compared with controls. Because KNG appears to be instrumental in pathologic thrombus formation and inflammation but dispensable for hemostasis, KNG inhibition may offer a selective and safe strategy for combating stroke and other thromboembolic diseases.

scholarly journals Dynamic capillary stalls in reperfused ischemic penumbra contribute to injury: A hyperacute role for neutrophils in persistent traffic jams

2020 ◽  
pp. 0271678X2091417 ◽  
Author(s):  
Şefik E Erdener ◽  
Jianbo Tang ◽  
Kıvılcım Kılıç ◽  
Dmitry Postnov ◽  
John T Giblin ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Cellular Damage ◽  
Ischemic Penumbra ◽  
Dynamic Flow ◽  
Traffic Jams ◽  
Activated Neutrophils ◽  
Resolution Imaging ◽  
Spatio Temporal ◽  
Capillary Circulation

Ever since the introduction of thrombolysis and the subsequent expansion of endovascular treatments for acute ischemic stroke, it remains to be identified why the actual outcomes are less favorable despite recanalization. Here, by high spatio-temporal resolution imaging of capillary circulation in mice, we introduce the pathological phenomenon of dynamic flow stalls in cerebral capillaries, occurring persistently in salvageable penumbra after reperfusion. These stalls, which are different from permanent cellular plugs of no-reflow, were temporarily and repetitively occurring in the capillary network, impairing the overall circulation like small focal traffic jams. In vivo microscopy in the ischemic penumbra revealed leukocytes traveling slowly through capillary lumen or getting stuck, while red blood cell flow was being disturbed in the neighboring segments under reperfused conditions. Stall dynamics could be modulated, by injection of an anti-Ly6G antibody specifically targeting neutrophils. Decreased number and duration of stalls were associated with improvement in penumbral blood flow within 2–24 h after reperfusion along with increased capillary oxygenation, decreased cellular damage and improved functional outcome. Thereby, dynamic microcirculatory stall phenomenon can be a contributing factor to ongoing penumbral injury and is a potential hyperacute mechanism adding on previous observations of detrimental effects of activated neutrophils in ischemic stroke.

scholarly journals Association Between Splenic Contraction and the Systemic Inflammatory Response After Acute Ischemic Stroke Varies with Age and Race

2017 ◽  
Vol 9 (5) ◽  
pp. 484-492 ◽  
Author(s):  
Alicia Zha ◽  
Farhaan Vahidy ◽  
Jaskaren Randhawa ◽  
Kaushik Parsha ◽  
Thanh Bui ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Inflammatory Response ◽  
Acute Ischemic Stroke ◽  
Systemic Inflammatory Response

scholarly journals Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases

2006 ◽  
Vol 290 (5) ◽  
pp. L797-L805 ◽  
Author(s):  
Gye Young Park ◽  
John W. Christman
Keyword(s):  
Lung Diseases ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Biological Research ◽  
Specific Cell ◽  
Exact Nature ◽  
Proinflammatory Response ◽  
Disease States ◽  
Inflammatory Models ◽  
Cox 2

Inducible cyclooxygenase (COX-2) and its metabolites have diverse and potent biological actions that are important for both physiological and disease states of lung. The wide variety of prostaglandin (PG) products are influenced by the level of cellular activation, the exact nature of the stimulus, and the specific cell type involved in their production. In turn, the anti- and proinflammatory response of PG is mediated by a blend of specific surface and intracellular receptors that mediate diverse cellular events. The complexity of this system is being at least partially resolved by the generation of specific molecular biological research tools that include cloning and characterization of the enzymes distal to COX-2 and the corresponding receptors to the final cellular products of arachidonic metabolism. The most informative of these approaches have employed genetically modified animals and specific receptor antagonists to determine the exact role of specific COX-2-derived metabolites on specific cell types of the lung in the context of inflammatory models. These data have suggested a number of cell-specific, pathway-specific, and receptor-specific approaches that could lead to effective therapeutic interventions for most inflammatory lung diseases.

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