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Bone Fracture Pre-Ischemic Stroke Exacerbates Ischemic Cerebral Injury in Mice.

Wang L, Kang S, Zou D, Zhan L, Li Z, Zhu W, Su H - PLoS ONE (2016)

Bottom Line: Behavior was tested 3 days after pMCAO.Our data showed that bone fracture shortly before stroke also increases neuroinflammation and exacerbates ischemic cerebral injury.Our findings suggest that inhibition of neuroinflammation or management of stroke risk factors before major bone surgery would be beneficial for patients who are likely to suffer from stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
Ischemic stroke is a devastating complication of bone fracture. Bone fracture shortly after stroke enhances stroke injury by augmenting inflammation. We hypothesize that bone fracture shortly before ischemic stroke also exacerbates ischemic cerebral injury. Tibia fracture was performed 6 or 24 hours before permanent middle cerebral artery occlusion (pMCAO) on C57BL/6J mice or Ccr2RFP/+Cx3cr1GFP/+ mice that have the RFP gene knocked into one allele of Ccr2 gene and GFP gene knocked into one allele of Cx3cr1 gene. Behavior was tested 3 days after pMCAO. Infarct volume, the number of CD68+ cells, apoptotic neurons, bone marrow-derived macrophages (RFP+), and microgila (GFP+) in the peri-infarct region were quantified. Compared to mice subjected to pMCAO only, bone fracture 6 or 24 hours before pMCAO increased behavioral deficits, the infarct volume, and the number of CD68+ cells and apoptotic neurons in the peri-infarct area. Both bone marrow-derived macrophages (CCR2+) and microglia (CX3CR1+) increased in the peri-infarct regions of mice subjected to bone fracture before pMCAO compared to stroke-only mice. The mice subjected to bone fracture 6 hours before pMCAO had more severe injury than mice that had bone fracture 24 hours before pMCAO. Our data showed that bone fracture shortly before stroke also increases neuroinflammation and exacerbates ischemic cerebral injury. Our findings suggest that inhibition of neuroinflammation or management of stroke risk factors before major bone surgery would be beneficial for patients who are likely to suffer from stroke.

No MeSH data available.


Related in: MedlinePlus

IL1ß and IL-6 levels increased in the peri-infarct brain of stroke mice.(A) Quantification of IL-1ß expression. *: P<0.05 vs. WT group; #: P = 0.001 vs. BF 3-day group; $: P<0.001 vs. BF 4-day group; &: P<0.01. (B) Quantification of IL-6 expression. *: P<0.05 vs. WT group; #: P<0.05 vs. BF 3-day group; $: P<0.05 vs. BF 4-day group. N = 6. BF 3 Days: Samples were collected 3 days after tibia fracture, which served as control for mice subjected to tibia fracture 6 hours before pMCAO. BF 4 Days: Samples were collected 4 days after tibia fracture, which served as control for mice subjected to tibia fracture 24 hours before pMCAO; BF 6h Stroke: tibia fracture 6 hours before pMCAO; BF 1 Day Stroke: tibia fracture 24 hours before pMCAO.
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pone.0153835.g007: IL1ß and IL-6 levels increased in the peri-infarct brain of stroke mice.(A) Quantification of IL-1ß expression. *: P<0.05 vs. WT group; #: P = 0.001 vs. BF 3-day group; $: P<0.001 vs. BF 4-day group; &: P<0.01. (B) Quantification of IL-6 expression. *: P<0.05 vs. WT group; #: P<0.05 vs. BF 3-day group; $: P<0.05 vs. BF 4-day group. N = 6. BF 3 Days: Samples were collected 3 days after tibia fracture, which served as control for mice subjected to tibia fracture 6 hours before pMCAO. BF 4 Days: Samples were collected 4 days after tibia fracture, which served as control for mice subjected to tibia fracture 24 hours before pMCAO; BF 6h Stroke: tibia fracture 6 hours before pMCAO; BF 1 Day Stroke: tibia fracture 24 hours before pMCAO.

Mentions: Previous studies have shown that tibia fracture increases interleukin 1ß (IL-1 ß), IL-6, and tumor necrosis factor α (TNFα) in the blood and hippocampus. It would be interesting to determine whether these cytokine levels are higher in the peri-infarct region of mice subjected to tibia fracture plus stroke vs. mice subjected to stroke only. TNF α expression increases in plasma shortly after tibia fracture, peaks at 30 minutes and returns to normal 12 hours later [16]. In this study, the brain samples were collected 3 days (group with tibia fracture 6 hours before the stroke group) or 4 days (group with tibia fracture 24 hours before stroke) after tibia fracture. It is unlikely to detect bone fracture induced increase of TNFα expression at these time points. The increase of IL-1ß and IL-6 lasts longer [17,18]. Therefore, we analyzed IL1-ß and IL-6 levels in the peri-infarct tissues. We found that the IL-1ß level was significantly higher in mice with both tibia fracture and stroke than in uninjured mice (WT) and mice with stroke alone. The IL-1ß in mice that have been subjected to tibia fracture 6 hours before stroke was also higher than in mice with tibia fracture or stroke only (Fig 7A). IL-6 levels were higher in mice subjected to both injuries than in WT and mice subjected to tibia fracture alone (Fig 7B).


Bone Fracture Pre-Ischemic Stroke Exacerbates Ischemic Cerebral Injury in Mice.

Wang L, Kang S, Zou D, Zhan L, Li Z, Zhu W, Su H - PLoS ONE (2016)

IL1ß and IL-6 levels increased in the peri-infarct brain of stroke mice.(A) Quantification of IL-1ß expression. *: P<0.05 vs. WT group; #: P = 0.001 vs. BF 3-day group; $: P<0.001 vs. BF 4-day group; &: P<0.01. (B) Quantification of IL-6 expression. *: P<0.05 vs. WT group; #: P<0.05 vs. BF 3-day group; $: P<0.05 vs. BF 4-day group. N = 6. BF 3 Days: Samples were collected 3 days after tibia fracture, which served as control for mice subjected to tibia fracture 6 hours before pMCAO. BF 4 Days: Samples were collected 4 days after tibia fracture, which served as control for mice subjected to tibia fracture 24 hours before pMCAO; BF 6h Stroke: tibia fracture 6 hours before pMCAO; BF 1 Day Stroke: tibia fracture 24 hours before pMCAO.
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pone.0153835.g007: IL1ß and IL-6 levels increased in the peri-infarct brain of stroke mice.(A) Quantification of IL-1ß expression. *: P<0.05 vs. WT group; #: P = 0.001 vs. BF 3-day group; $: P<0.001 vs. BF 4-day group; &: P<0.01. (B) Quantification of IL-6 expression. *: P<0.05 vs. WT group; #: P<0.05 vs. BF 3-day group; $: P<0.05 vs. BF 4-day group. N = 6. BF 3 Days: Samples were collected 3 days after tibia fracture, which served as control for mice subjected to tibia fracture 6 hours before pMCAO. BF 4 Days: Samples were collected 4 days after tibia fracture, which served as control for mice subjected to tibia fracture 24 hours before pMCAO; BF 6h Stroke: tibia fracture 6 hours before pMCAO; BF 1 Day Stroke: tibia fracture 24 hours before pMCAO.
Mentions: Previous studies have shown that tibia fracture increases interleukin 1ß (IL-1 ß), IL-6, and tumor necrosis factor α (TNFα) in the blood and hippocampus. It would be interesting to determine whether these cytokine levels are higher in the peri-infarct region of mice subjected to tibia fracture plus stroke vs. mice subjected to stroke only. TNF α expression increases in plasma shortly after tibia fracture, peaks at 30 minutes and returns to normal 12 hours later [16]. In this study, the brain samples were collected 3 days (group with tibia fracture 6 hours before the stroke group) or 4 days (group with tibia fracture 24 hours before stroke) after tibia fracture. It is unlikely to detect bone fracture induced increase of TNFα expression at these time points. The increase of IL-1ß and IL-6 lasts longer [17,18]. Therefore, we analyzed IL1-ß and IL-6 levels in the peri-infarct tissues. We found that the IL-1ß level was significantly higher in mice with both tibia fracture and stroke than in uninjured mice (WT) and mice with stroke alone. The IL-1ß in mice that have been subjected to tibia fracture 6 hours before stroke was also higher than in mice with tibia fracture or stroke only (Fig 7A). IL-6 levels were higher in mice subjected to both injuries than in WT and mice subjected to tibia fracture alone (Fig 7B).

Bottom Line: Behavior was tested 3 days after pMCAO.Our data showed that bone fracture shortly before stroke also increases neuroinflammation and exacerbates ischemic cerebral injury.Our findings suggest that inhibition of neuroinflammation or management of stroke risk factors before major bone surgery would be beneficial for patients who are likely to suffer from stroke.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, California, United States of America.

ABSTRACT
Ischemic stroke is a devastating complication of bone fracture. Bone fracture shortly after stroke enhances stroke injury by augmenting inflammation. We hypothesize that bone fracture shortly before ischemic stroke also exacerbates ischemic cerebral injury. Tibia fracture was performed 6 or 24 hours before permanent middle cerebral artery occlusion (pMCAO) on C57BL/6J mice or Ccr2RFP/+Cx3cr1GFP/+ mice that have the RFP gene knocked into one allele of Ccr2 gene and GFP gene knocked into one allele of Cx3cr1 gene. Behavior was tested 3 days after pMCAO. Infarct volume, the number of CD68+ cells, apoptotic neurons, bone marrow-derived macrophages (RFP+), and microgila (GFP+) in the peri-infarct region were quantified. Compared to mice subjected to pMCAO only, bone fracture 6 or 24 hours before pMCAO increased behavioral deficits, the infarct volume, and the number of CD68+ cells and apoptotic neurons in the peri-infarct area. Both bone marrow-derived macrophages (CCR2+) and microglia (CX3CR1+) increased in the peri-infarct regions of mice subjected to bone fracture before pMCAO compared to stroke-only mice. The mice subjected to bone fracture 6 hours before pMCAO had more severe injury than mice that had bone fracture 24 hours before pMCAO. Our data showed that bone fracture shortly before stroke also increases neuroinflammation and exacerbates ischemic cerebral injury. Our findings suggest that inhibition of neuroinflammation or management of stroke risk factors before major bone surgery would be beneficial for patients who are likely to suffer from stroke.

No MeSH data available.


Related in: MedlinePlus