A Novel SPECT-Based Approach Reveals Early Mechanisms of Central and Peripheral Inflammation after Cerebral Ischemia

Szigeti, Krisztián; Horváth, Ildikó; Veres, Dániel Sándor; Martinecz, Bernadett; Lénárt, Nikolett; Kovács, Noémi; Bakcsa, Erika; Marta, Alexa; Semjeni, M.; Máthé, Domokos; Dénes, Ádám

doi:10.1038/jcbfm.2015.174

Cited by 32 publications

(18 citation statements)

References 41 publications

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“…Our observation that ischemic strokes are associated with a significant increase in DAD score and lung ultrastructural changes might be explained by higher levels of TNF-α and IL-6 in the plasma and lungs, and of TNF-α in BALF. These data are consistent with experimental [ 37 ] and clinical [ 38 ] reports of increased systemic inflammation after stroke. The fact that total protein levels in BALF were higher in Stroke animals likely reflects increased permeability of the pulmonary capillary membrane due to inflammation [ 39 , 40 ].…”

Section: Discussionsupporting

confidence: 92%

Focal ischemic stroke leads to lung injury and reduces alveolar macrophage phagocytic capability in rats

Samary¹,

Ramos²,

Maia³

et al. 2018

Crit Care

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BackgroundIschemic stroke causes brain inflammation, which we postulate may result in lung damage. Several studies have focused on stroke-induced immunosuppression and lung infection; however, the possibility that strokes may trigger lung inflammation has been overlooked. We hypothesized that even focal ischemic stroke might induce acute systemic and pulmonary inflammation, thus altering respiratory parameters, lung tissue integrity, and alveolar macrophage behavior.MethodsForty-eight Wistar rats were randomly assigned to ischemic stroke (Stroke) or sham surgery (Sham). Lung function, histology, and inflammation in the lung, brain, bronchoalveolar lavage fluid (BALF), and circulating plasma were evaluated at 24 h. In vitro, alveolar macrophages from naïve rats (unstimulated) were exposed to serum or BALF from Sham or Stroke animals to elucidate possible mechanisms underlying alterations in alveolar macrophage phagocytic capability. Alveolar macrophages and epithelial and endothelial cells of Sham and Stroke animals were also isolated for evaluation of mRNA expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α.ResultsTwenty-four hours following ischemic stroke, the tidal volume, expiratory time, and mean inspiratory flow were increased. Compared to Sham animals, the respiratory rate and duty cycle during spontaneous breathing were reduced, but this did not affect lung mechanics during mechanical ventilation. Lungs from Stroke animals showed clear evidence of increased diffuse alveolar damage, pulmonary edema, and inflammation markers. This was associated with an increase in ultrastructural damage, as evidenced by injury to type 2 pneumocytes and endothelial cells, cellular infiltration, and enlarged basement membrane thickness. Protein levels of proinflammatory mediators were documented in the lung, brain, and plasma (TNF-α and IL-6) and in BALF (TNF-α). The phagocytic ability of macrophages was significantly reduced. Unstimulated macrophages isolated from naïve rats only upregulated expression of TNF-α and IL-6 following exposure to serum from Stroke rats. Exposure to BALF from Stroke or Sham animals did not change alveolar macrophage behavior, or gene expression of TNF-α and IL-6. IL-6 expression was increased in macrophages and endothelial cells from Stroke animals.ConclusionsIn rats, focal ischemic stroke is associated with brain–lung crosstalk, leading to increased pulmonary damage and inflammation, as well as reduced alveolar macrophage phagocytic capability, which seems to be promoted by systemic inflammation.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2164-0) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Focal ischemic stroke leads to lung injury and reduces alveolar macrophage phagocytic capability in rats

Samary¹,

Ramos²,

Maia³

et al. 2018

Crit Care

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“…Next, we determined the brain uptake of circulating 99mTc-DTPA to indicate whether disruption to the BBB occurs. 99m Tc-DTPA is a small molecular weight marker that has been used to measure BBB disruption in rodents and humans via SPECT imaging [ 23 – 26 ]. 99m Tc-DTPA has a molecular weight of 487 Da, which is comparable to that of 14 C-sucrose (342.3 Da) that we have used in previous studies [ 3 , 27 ].…”

Section: Resultsmentioning

confidence: 99%

Genetics and sex influence peripheral and central innate immune responses and blood-brain barrier integrity

et al. 2018

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Lipopolysaccharide (LPS) is a stimulator of the innate immune system and is routinely used in animal models to study blood-brain barrier (BBB) dysfunction under inflammatory conditions. It is appreciated that both humans and mice have sexually dimorphic immune responses, which could influence the brain’s response to a systemic inflammatory insult. Mouse strain is also an important factor that can contribute to pathophysiological responses to inflammatory stimuli. Therefore, we aimed to test whether BBB disruption and the associated cytokine profiles in response to LPS differed in male and female mice from two mouse strains most commonly used in blood-brain barrier studies: CD-1 and C57BL6/J (C57). Mice were treated with saline, a single injection of 0.3, or 3mg/kg LPS, or three injections of 3mg/kg LPS, and studied 28 hours after the first LPS injection. To assay BBB disruption, we utilized the tracer 99mTc-DTPA. A 23-plex panel of cytokines was assayed in brain and blood of the same cohort of mice, which allowed us to compare differences in the levels of individual cytokines as well as correlations among cytokines and 99mTc-DTPA uptake. We found that only the three-injection dose of LPS induced significant BBB disruption in all sexes and strains. The treatment, strain, and sex, as well as treatment-by- strain and treatment-by-sex interactions significantly contributed to the variance. The mean brain/serum ratios of 99mTc-DTPA in the three-injection LPS group were ranked CD-1 male < CD-1 female < C57 male < C57 female. There were significant sex and strain differences in cytokine profiles in brain and blood, and pro-inflammatory cytokines and chemokines in brain were most strongly correlated with 99mTc-DTPA brain/serum ratios.

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“…In response to ischemic stroke, the integrity of BBB compromises promptly and changes dynamically, which can be observed by magnetic resonance imaging (MRI) and other imaging techniques . During the early phase, cytoskeletal alterations in brain ECs can be initiated by actin polymerization followed by translocation of tight junctions (TJs) within 30‐60 minutes of reperfusion through activation of the Rho‐associated protein kinase (ROCK)/myosin .…”

Section: Dynamic Changes Of Blood‐brain Barrier Integrity (Bbb) Aftermentioning

confidence: 99%

The peripheral immune response after stroke—A double edge sword for blood‐brain barrier integrity

Zhu

Huang

et al. 2018

CNS Neurosci Ther

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Summary The blood‐brain barrier (BBB) is a highly regulated interface that separates the peripheral circulation and the brain. It plays a vital role in regulating the trafficking of solutes, fluid, and cells at the blood‐brain interface and maintaining the homeostasis of brain microenvironment for normal neuronal activity. Growing evidence has led to the realization that ischemic stroke elicits profound immune responses in the circulation and the activation of multiple subsets of immune cells, which in turn affect both the early disruption and the later repair of the BBB after stroke. Distinct phenotypes or subsets of peripheral immune cells along with diverse intracellular mechanisms contribute to the dynamic changes of BBB integrity after stroke. This review focuses on the interaction between the peripheral immune cells and the BBB after ischemic stroke. Understanding their reciprocal interaction may generate new directions for stroke research and may also drive the innovation of easy accessible immune modulatory treatment strategies targeting BBB in the pursuit of better stroke recovery.

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A Novel SPECT-Based Approach Reveals Early Mechanisms of Central and Peripheral Inflammation after Cerebral Ischemia

Cited by 32 publications

References 41 publications

Focal ischemic stroke leads to lung injury and reduces alveolar macrophage phagocytic capability in rats

Focal ischemic stroke leads to lung injury and reduces alveolar macrophage phagocytic capability in rats

Genetics and sex influence peripheral and central innate immune responses and blood-brain barrier integrity

The peripheral immune response after stroke—A double edge sword for blood‐brain barrier integrity

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