A murine model of inflammation-induced cerebral microbleeds

Sumbria, Rachita K.; Grigoryan, Mher Mahoney; Vasilevko, Vitaly; Krasieva, Tatiana B.; Scadeng, Miriam; Dvornikova, Alexandra; Paganini‐Hill, Annlia; Kim, Ronald; Cribbs, David H.; Fisher, Mark

doi:10.1186/s12974-016-0693-5

Cited by 68 publications

(67 citation statements)

References 37 publications

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“…Interestingly, LPS‐treated mice did more often present with intra‐AV iron deposits, indicative for intraleaflet haemorrhages. LPS‐induced haemorrhage was previously observed in both brain and lung tissue in C57BL/6 mice, which was attributed to increased microvascular permeability . Neovascularization is induced in atherosclerotic plaques in arteries and AV leaflets .…”

Section: Discussionmentioning

confidence: 86%

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Short‐term LPS induces aortic valve thickening in ApoE*3Leiden mice

Broekhoven

Krijnen

Fuijkschot

et al. 2019

Eur J Clin Investigation

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Background Recently, it was shown that 12 weeks of lipopolysaccharide (LPS) administration to nonatherosclerotic mice induced thickening of the aortic heart valve (AV). Whether such effects may also occur even earlier is unknown. As most patients with AV stenosis also have atherosclerosis, we studied the short‐term effect of LPS on the AVs in an atherosclerotic mouse model. Methods ApoE*3Leiden mice, on an atherogenic diet, were injected intraperitoneally with either LPS or phosphate buffered saline (PBS), and sacrificed 2 or 15 days later. AVs were assessed for size, fibrosis, glycosaminoglycans (GAGs), lipids, calcium deposits, iron deposits and inflammatory cells. Results LPS injection caused an increase in maximal leaflet thickness at 2 days (128.4 µm) compared to PBS‐injected mice (67.8 µm; P = 0.007), whereas at 15 days this was not significantly different. LPS injection did not significantly affect average AV thickness on day 2 (37.8 µm), but did significantly increase average AV thickness at day 15 (41.6 µm; P = 0.038) compared to PBS‐injected mice (31.7 and 32.3 µm respectively). LPS injection did not affect AV fibrosis, GAGs and lipid content. Furthermore, no calcium deposits were found. Iron deposits, indicative for valve haemorrhage, were observed in one AV of the PBS‐injected group (a day 2 mouse; 9.1%) and in five AVs of the LPS‐injected group (both day 2‐ and 15 mice; 29.4%). No significant differences in inflammatory cell infiltration were observed upon LPS injection. Conclusion Short‐term LPS apparently has the potential to increase AV thickening and haemorrhage. These results suggest that systemic inflammation can acutely compromise AV structure.

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Section: Discussionmentioning

confidence: 86%

“…LPS-induced haemorrhage was previously observed in both brain and lung tissue in C57BL/6 mice, which was attributed to increased microvascular permeability. 43,44 Neovascularization is induced in atherosclerotic plaques in arteries and AV leaflets. 32 However, these intra-plaque microvessels are prone to haemorrhage.…”

Section: Discussionmentioning

confidence: 99%

Short‐term LPS induces aortic valve thickening in ApoE*3Leiden mice

Broekhoven

Krijnen

Fuijkschot

et al. 2019

Eur J Clin Investigation

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“…Immunohistochemical analyses [16] were performed using one coronal 40-μm section per mouse approximately −2 to −2.4 mm posterior to the bregma, and identical coordinate sections per staining from the analyzed groups were incubated in 0.5% hydrogen peroxide in 0.1 M PBS (pH 7.4) containing 0.3% Triton X-100 (PBST) for 30 min at room temperature to block endogenous peroxidase activity. After washing with PBST, sections were incubated for 30 min with PBST containing 2% bovine serum albumin (BSA) to block non-specific protein binding.…”

Section: Methodsmentioning

confidence: 99%

Effects of phosphodiesterase 3A modulation on murine cerebral microhemorrhages

Sumbria

Vasilevko

Grigoryan

et al. 2017

J Neuroinflammation

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BackgroundCerebral microbleeds (CMB) are MRI-demonstrable cerebral microhemorrhages (CMH) which commonly coexist with ischemic stroke. This creates a challenging therapeutic milieu, and a strategy that simultaneously protects the vessel wall and provides anti-thrombotic activity is an attractive potential approach. Phosphodiesterase 3A (PDE3A) inhibition is known to provide cerebral vessel wall protection combined with anti-thrombotic effects. As an initial step in the development of a therapy that simultaneously treats CMB and ischemic stroke, we hypothesized that inhibition of the PDE3A pathway is protective against CMH development.MethodsThe effect of PDE3A pathway inhibition was studied in the inflammation-induced and cerebral amyloid angiopathy (CAA)-associated mouse models of CMH. The PDE3A pathway was modulated using two approaches: genetic deletion of PDE3A and pharmacological inhibition of PDE3A by cilostazol. The effects of PDE3A pathway modulation on H&E- and Prussian blue (PB)-positive CMH development, BBB function (IgG, claudin-5, and fibrinogen), and neuroinflammation (ICAM-1, Iba-1, and GFAP) were investigated.ResultsRobust development of CMH in the inflammation-induced and CAA-associated spontaneous mouse models was observed. Inflammation-induced CMH were associated with markers of BBB dysfunction and inflammation, and CAA-associated spontaneous CMH were associated primarily with markers of neuroinflammation. Genetic deletion of the PDE3A gene did not alter BBB function, microglial activation, or CMH development, but significantly reduced endothelial and astrocyte activation in the inflammation-induced CMH mouse model. In the CAA-associated CMH mouse model, PDE3A modulation via pharmacological inhibition by cilostazol did not alter BBB function, neuroinflammation, or CMH development.ConclusionsModulation of the PDE3A pathway, either by genetic deletion or pharmacological inhibition, does not alter CMH development in an inflammation-induced or in a CAA-associated mouse model of CMH. The role of microglial activation and BBB injury in CMH development warrants further investigation.

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“…Atherosclerosis and hypertension related vessel damage impair autoregulation of brain blood circulation, which may rapidly decompensate in systemic inflammation and MODS. This is particularly evident in ischemic-reperfusional and hemorrhagic damage over the most vulnerable regions of the brain [193,194].…”

Section: Role Of Astroglia In Bbb Abnormalities In Systemic Inflammationmentioning

confidence: 99%

Astroglia in Sepsis Associated Encephalopathy

Shulyatnikova

Verkhratsky

2019

Neurochem Res

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Cellular pathophysiology of sepsis associated encephalopathy (SAE) remains poorly characterised. Brain pathology in SAE, which is manifested by impaired perception, consciousness and cognition, results from multifactorial events, including high levels of systemic cytokines, microbial components and endotoxins, which all damage the brain barriers, instigate neuroinflammation and cause homeostatic failure. Astrocytes, being the principal homeostatic cells of the central nervous system contribute to the brain defence against infection. Forming multifunctional anatomical barriers, astroglial cells maintain brain-systemic interfaces and restrict the damage to the nervous tissue. Astrocytes detect, produce and integrate inflammatory signals between immune cells and cells of brain parenchyma, thus regulating brain immune response. In SAE astrocytes are present in both reactive and astrogliopathic states; balance between these states define evolution of pathology and neurological outcomes. In humans pathophysiology of SAE is complicated by frequent presence of comorbidities, as well as age-related remodelling of the brain tissue with senescence of astroglia; these confounding factors further impact upon SAE progression and neurological deficits.

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A murine model of inflammation-induced cerebral microbleeds

Cited by 68 publications

References 37 publications

Short‐term LPS induces aortic valve thickening in ApoE*3Leiden mice

Short‐term LPS induces aortic valve thickening in ApoE*3Leiden mice

Effects of phosphodiesterase 3A modulation on murine cerebral microhemorrhages

Astroglia in Sepsis Associated Encephalopathy

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