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Decreased progranulin levels in patients and rats with subarachnoid hemorrhage: a potential role in inhibiting inflammation by suppressing neutrophil recruitment.

Zhou C, Xie G, Wang C, Zhang Z, Chen Q, Zhang L, Wu L, Wei Y, Ding H, Hang C, Zhou M, Shi J - J Neuroinflammation (2015)

Bottom Line: These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1.In addition, neuronal apoptosis and BBB permeability were alleviated by r-PGRN.These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Jinling Hospital, Medical School of Nanjing University, 210002, No. 305 Zhongshan East Road, Nanjing, Jiangsu Province, China. zhouchenhui1989@126.com.

ABSTRACT

Background: Subarachnoid hemorrhage (SAH) is a devastating neurological injury with high morbidity and mortality that is mainly caused by early brain injury (EBI). Progranulin (PGRN) is known to be involved in various biological functions, such as anti-inflammation and tissue repair. This study aimed to investigate the change of PGRN in the brain after SAH and its role on EBI.

Methods: The levels of PGRN, myeloperoxidase (MPO), interleukin1β (IL-1β), and tumor necrosis factor-α (TNF-α) were detected in the cerebrospinal fluid (CSF) from SAH patients by enzyme-linked immunosorbent assay (ELISA). In addition, PGRN levels were also detected in the cerebral cortex after experimental SAH in rats by western blotting and immunohistochemistry (IHC). Recombinant human PGRN (r-PGRN) or an equal volume of phosphate-buffered saline (PBS) was administrated at 30 min after SAH. All rats were subsequently sacrificed at 24 h after SAH. Neurological score and brain water content were assessed. For mechanistic studies, the changes of MPO, matrix metalloproteinase-9 (MMP-9), zonula occludens 1 (ZO-1), Bcl-2, and cleaved caspase-3 were examined by western blotting and the levels of pro-inflammatory cytokines (IL-1β and TNF-α) were determined by ELISA. In addition, neuronal apoptosis and blood brain barrier (BBB) permeability were examined.

Results: The levels of PGRN significantly decreased, and the levels of MPO, IL-1β, and TNF-α were markedly elevated in the CSF from SAH patients. In rats, PGRN levels in the brain also decreased after SAH. Administration of r-PGRN decreased brain water content and improved neurological scores at 24 h after SAH. These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1. In addition, neuronal apoptosis and BBB permeability were alleviated by r-PGRN.

Conclusions: These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH.

No MeSH data available.


Related in: MedlinePlus

Effect of PGRN on neural cell apoptosis 24 h after SAH. Western blotting revealed Bcl-2 levels in the SAH group were significantly reduced compared with sham. R-PGRN treatment increased the levels of Bcl-2 (a). Cleaved caspase-3 levels in the SAH group were significantly higher than the sham group. Treatment with r-PGRN markedly reduced cleaved caspase-3 levels (b). The number of TUNEL-positive cells increased after SAH and reduced after r-PGRN treatment (c). No difference was detected between the untreated SAH group and the PBS-treated SAH group. Data are expressed as the mean ± SEM from six rats. ***p < 0.001 and **p < 0.01 compared with the sham group, nsp > 0.05 compared with the SAH group, ##p < 0.01 and #p < 0.05 compared with the SAH group
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Fig8: Effect of PGRN on neural cell apoptosis 24 h after SAH. Western blotting revealed Bcl-2 levels in the SAH group were significantly reduced compared with sham. R-PGRN treatment increased the levels of Bcl-2 (a). Cleaved caspase-3 levels in the SAH group were significantly higher than the sham group. Treatment with r-PGRN markedly reduced cleaved caspase-3 levels (b). The number of TUNEL-positive cells increased after SAH and reduced after r-PGRN treatment (c). No difference was detected between the untreated SAH group and the PBS-treated SAH group. Data are expressed as the mean ± SEM from six rats. ***p < 0.001 and **p < 0.01 compared with the sham group, nsp > 0.05 compared with the SAH group, ##p < 0.01 and #p < 0.05 compared with the SAH group

Mentions: To illustrate the effects of PGRN on neural cell apoptosis, the levels of apoptosis-related proteins (bcl-2 and cleaved caspase-3) and extent of TUNEL were monitored at 24 h after SAH in our study. As shown in Fig. 8a, b, Bcl-2 levels decreased after SAH (p < 0.01) and were upregulated by r-PGRN treatment (p < 0.05). In contrast, cleaved caspase-3 levels increased after SAH (p < 0.01) and reduced after treatment with r-PGRN (p < 0.05). In addition, TUNEL (Fig. 8c) revealed that there were few TUNEL-positive cells in the sham group, whereas the apoptotic index in the SAH group was significantly higher than that of rats in the sham group (p < 0.001). The percentage of TUNEL-positive cells reduced after r-PGRN treatment (p < 0.01).Fig. 8


Decreased progranulin levels in patients and rats with subarachnoid hemorrhage: a potential role in inhibiting inflammation by suppressing neutrophil recruitment.

Zhou C, Xie G, Wang C, Zhang Z, Chen Q, Zhang L, Wu L, Wei Y, Ding H, Hang C, Zhou M, Shi J - J Neuroinflammation (2015)

Effect of PGRN on neural cell apoptosis 24 h after SAH. Western blotting revealed Bcl-2 levels in the SAH group were significantly reduced compared with sham. R-PGRN treatment increased the levels of Bcl-2 (a). Cleaved caspase-3 levels in the SAH group were significantly higher than the sham group. Treatment with r-PGRN markedly reduced cleaved caspase-3 levels (b). The number of TUNEL-positive cells increased after SAH and reduced after r-PGRN treatment (c). No difference was detected between the untreated SAH group and the PBS-treated SAH group. Data are expressed as the mean ± SEM from six rats. ***p < 0.001 and **p < 0.01 compared with the sham group, nsp > 0.05 compared with the SAH group, ##p < 0.01 and #p < 0.05 compared with the SAH group
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4630923&req=5

Fig8: Effect of PGRN on neural cell apoptosis 24 h after SAH. Western blotting revealed Bcl-2 levels in the SAH group were significantly reduced compared with sham. R-PGRN treatment increased the levels of Bcl-2 (a). Cleaved caspase-3 levels in the SAH group were significantly higher than the sham group. Treatment with r-PGRN markedly reduced cleaved caspase-3 levels (b). The number of TUNEL-positive cells increased after SAH and reduced after r-PGRN treatment (c). No difference was detected between the untreated SAH group and the PBS-treated SAH group. Data are expressed as the mean ± SEM from six rats. ***p < 0.001 and **p < 0.01 compared with the sham group, nsp > 0.05 compared with the SAH group, ##p < 0.01 and #p < 0.05 compared with the SAH group
Mentions: To illustrate the effects of PGRN on neural cell apoptosis, the levels of apoptosis-related proteins (bcl-2 and cleaved caspase-3) and extent of TUNEL were monitored at 24 h after SAH in our study. As shown in Fig. 8a, b, Bcl-2 levels decreased after SAH (p < 0.01) and were upregulated by r-PGRN treatment (p < 0.05). In contrast, cleaved caspase-3 levels increased after SAH (p < 0.01) and reduced after treatment with r-PGRN (p < 0.05). In addition, TUNEL (Fig. 8c) revealed that there were few TUNEL-positive cells in the sham group, whereas the apoptotic index in the SAH group was significantly higher than that of rats in the sham group (p < 0.001). The percentage of TUNEL-positive cells reduced after r-PGRN treatment (p < 0.01).Fig. 8

Bottom Line: These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1.In addition, neuronal apoptosis and BBB permeability were alleviated by r-PGRN.These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurosurgery, Jinling Hospital, Medical School of Nanjing University, 210002, No. 305 Zhongshan East Road, Nanjing, Jiangsu Province, China. zhouchenhui1989@126.com.

ABSTRACT

Background: Subarachnoid hemorrhage (SAH) is a devastating neurological injury with high morbidity and mortality that is mainly caused by early brain injury (EBI). Progranulin (PGRN) is known to be involved in various biological functions, such as anti-inflammation and tissue repair. This study aimed to investigate the change of PGRN in the brain after SAH and its role on EBI.

Methods: The levels of PGRN, myeloperoxidase (MPO), interleukin1β (IL-1β), and tumor necrosis factor-α (TNF-α) were detected in the cerebrospinal fluid (CSF) from SAH patients by enzyme-linked immunosorbent assay (ELISA). In addition, PGRN levels were also detected in the cerebral cortex after experimental SAH in rats by western blotting and immunohistochemistry (IHC). Recombinant human PGRN (r-PGRN) or an equal volume of phosphate-buffered saline (PBS) was administrated at 30 min after SAH. All rats were subsequently sacrificed at 24 h after SAH. Neurological score and brain water content were assessed. For mechanistic studies, the changes of MPO, matrix metalloproteinase-9 (MMP-9), zonula occludens 1 (ZO-1), Bcl-2, and cleaved caspase-3 were examined by western blotting and the levels of pro-inflammatory cytokines (IL-1β and TNF-α) were determined by ELISA. In addition, neuronal apoptosis and blood brain barrier (BBB) permeability were examined.

Results: The levels of PGRN significantly decreased, and the levels of MPO, IL-1β, and TNF-α were markedly elevated in the CSF from SAH patients. In rats, PGRN levels in the brain also decreased after SAH. Administration of r-PGRN decreased brain water content and improved neurological scores at 24 h after SAH. These changes were associated with marked reductions in MPO, MMP-9, and proinflammation cytokine levels, as well as increased levels of Bcl-2 and ZO-1. In addition, neuronal apoptosis and BBB permeability were alleviated by r-PGRN.

Conclusions: These results indicate that the levels of PGRN decreased after SAH and that r-PGRN alleviates EBI after SAH possibly via inhibition of neutrophil recruitment, providing a new target for the treatment of SAH.

No MeSH data available.


Related in: MedlinePlus