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Increased expression of the chemokines CXCL1 and MIP-1α by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats.

Johnson EA, Dao TL, Guignet MA, Geddes CE, Koemeter-Cox AI, Kan RK - J Neuroinflammation (2011)

Bottom Line: Chemokines with significantly increased protein levels were localized to resident brain cells (i.e. neurons, astrocytes, microglia and endothelial cells).We observed significant concentration increases for CXCL1 and MIP-1α after seizure onset.This process may play a key role in the progressive secondary brain pathology observed in this model though further study is warranted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Division, Pharmacology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA. erik.a.johnson1@us.army.mil

ABSTRACT

Background: Exposure to the nerve agent soman (GD) causes neuronal cell death and impaired behavioral function dependent on the induction of status epilepticus (SE). Little is known about the maturation of this pathological process, though neuroinflammation and infiltration of neutrophils are prominent features. The purpose of this study is to quantify the regional and temporal progression of early chemotactic signals, describe the cellular expression of these factors and the relationship between expression and neutrophil infiltration in damaged brain using a rat GD seizure model.

Methods: Protein levels of 4 chemokines responsible for neutrophil infiltration and activation were quantified up to 72 hours in multiple brain regions (i.e. piriform cortex, hippocampus and thalamus) following SE onset using multiplex bead immunoassays. Chemokines with significantly increased protein levels were localized to resident brain cells (i.e. neurons, astrocytes, microglia and endothelial cells). Lastly, neutrophil infiltration into these brain regions was quantified and correlated to the expression of these chemokines.

Results: We observed significant concentration increases for CXCL1 and MIP-1α after seizure onset. CXCL1 expression originated from neurons and endothelial cells while MIP-1α was expressed by neurons and microglia. Lastly, the expression of these chemokines directly preceded and positively correlated with significant neutrophil infiltration in the brain. These data suggest that following GD-induced SE, a strong chemotactic response originating from various brain cells, recruits circulating neutrophils to the injured brain.

Conclusions: A strong induction of neutrophil attractant chemokines occurs following GD-induced SE resulting in neutrophil influx into injured brain tissues. This process may play a key role in the progressive secondary brain pathology observed in this model though further study is warranted.

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Related in: MedlinePlus

CXCL1 increases in rat brain after GD-induced SE. Concentrations of CXCL1 peak at 6 hours in the piriform cortex (solid gray line) and 12 hours in the hippocampus (solid black line) and thalamus (open gray line). Data are given as pg/ml of tissue lysate and reported as mean ± SEM. Data were analyzed using a one-way ANOVA with a post-hoc Dunnett's analysis comparing to vehicle control. (## p < 0.01 hippocampus, * p < 0.05, ** p < 0.01 piriform cortex, $$ p < 0.01 thalamus).
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Figure 1: CXCL1 increases in rat brain after GD-induced SE. Concentrations of CXCL1 peak at 6 hours in the piriform cortex (solid gray line) and 12 hours in the hippocampus (solid black line) and thalamus (open gray line). Data are given as pg/ml of tissue lysate and reported as mean ± SEM. Data were analyzed using a one-way ANOVA with a post-hoc Dunnett's analysis comparing to vehicle control. (## p < 0.01 hippocampus, * p < 0.05, ** p < 0.01 piriform cortex, $$ p < 0.01 thalamus).

Mentions: CXCL1 concentrations significantly increased in all three brain regions (Figure 1). The highest concentrations were in the hippocampus, where concentrations significantly increased by 6 hours (4674 ± 1504 pg/ml) and peaked by 12 hours (8441 ± 2152 pg/ml vs. 58 ± 6 pg/ml in vehicle controls) following GD-induced SE. In the piriform cortex, CXCL1 levels peaked at 6 hours (1164 ± 195 pg/ml) and remained significantly elevated up to 24 hours (501 ± 176 pg/ml) compared to vehicle controls (49 ± 9 pg/ml). In the thalamus, CXCL1 concentration became significant at 12 hours compared to controls (4571 ± 643 pg/ml vs. 50 ± 3 pg/ml).


Increased expression of the chemokines CXCL1 and MIP-1α by resident brain cells precedes neutrophil infiltration in the brain following prolonged soman-induced status epilepticus in rats.

Johnson EA, Dao TL, Guignet MA, Geddes CE, Koemeter-Cox AI, Kan RK - J Neuroinflammation (2011)

CXCL1 increases in rat brain after GD-induced SE. Concentrations of CXCL1 peak at 6 hours in the piriform cortex (solid gray line) and 12 hours in the hippocampus (solid black line) and thalamus (open gray line). Data are given as pg/ml of tissue lysate and reported as mean ± SEM. Data were analyzed using a one-way ANOVA with a post-hoc Dunnett's analysis comparing to vehicle control. (## p < 0.01 hippocampus, * p < 0.05, ** p < 0.01 piriform cortex, $$ p < 0.01 thalamus).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3104356&req=5

Figure 1: CXCL1 increases in rat brain after GD-induced SE. Concentrations of CXCL1 peak at 6 hours in the piriform cortex (solid gray line) and 12 hours in the hippocampus (solid black line) and thalamus (open gray line). Data are given as pg/ml of tissue lysate and reported as mean ± SEM. Data were analyzed using a one-way ANOVA with a post-hoc Dunnett's analysis comparing to vehicle control. (## p < 0.01 hippocampus, * p < 0.05, ** p < 0.01 piriform cortex, $$ p < 0.01 thalamus).
Mentions: CXCL1 concentrations significantly increased in all three brain regions (Figure 1). The highest concentrations were in the hippocampus, where concentrations significantly increased by 6 hours (4674 ± 1504 pg/ml) and peaked by 12 hours (8441 ± 2152 pg/ml vs. 58 ± 6 pg/ml in vehicle controls) following GD-induced SE. In the piriform cortex, CXCL1 levels peaked at 6 hours (1164 ± 195 pg/ml) and remained significantly elevated up to 24 hours (501 ± 176 pg/ml) compared to vehicle controls (49 ± 9 pg/ml). In the thalamus, CXCL1 concentration became significant at 12 hours compared to controls (4571 ± 643 pg/ml vs. 50 ± 3 pg/ml).

Bottom Line: Chemokines with significantly increased protein levels were localized to resident brain cells (i.e. neurons, astrocytes, microglia and endothelial cells).We observed significant concentration increases for CXCL1 and MIP-1α after seizure onset.This process may play a key role in the progressive secondary brain pathology observed in this model though further study is warranted.

View Article: PubMed Central - HTML - PubMed

Affiliation: Research Division, Pharmacology Branch, US Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, MD 21010, USA. erik.a.johnson1@us.army.mil

ABSTRACT

Background: Exposure to the nerve agent soman (GD) causes neuronal cell death and impaired behavioral function dependent on the induction of status epilepticus (SE). Little is known about the maturation of this pathological process, though neuroinflammation and infiltration of neutrophils are prominent features. The purpose of this study is to quantify the regional and temporal progression of early chemotactic signals, describe the cellular expression of these factors and the relationship between expression and neutrophil infiltration in damaged brain using a rat GD seizure model.

Methods: Protein levels of 4 chemokines responsible for neutrophil infiltration and activation were quantified up to 72 hours in multiple brain regions (i.e. piriform cortex, hippocampus and thalamus) following SE onset using multiplex bead immunoassays. Chemokines with significantly increased protein levels were localized to resident brain cells (i.e. neurons, astrocytes, microglia and endothelial cells). Lastly, neutrophil infiltration into these brain regions was quantified and correlated to the expression of these chemokines.

Results: We observed significant concentration increases for CXCL1 and MIP-1α after seizure onset. CXCL1 expression originated from neurons and endothelial cells while MIP-1α was expressed by neurons and microglia. Lastly, the expression of these chemokines directly preceded and positively correlated with significant neutrophil infiltration in the brain. These data suggest that following GD-induced SE, a strong chemotactic response originating from various brain cells, recruits circulating neutrophils to the injured brain.

Conclusions: A strong induction of neutrophil attractant chemokines occurs following GD-induced SE resulting in neutrophil influx into injured brain tissues. This process may play a key role in the progressive secondary brain pathology observed in this model though further study is warranted.

Show MeSH
Related in: MedlinePlus