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Neuroprotective effects of activated protein C on intrauterine inflammation-induced neonatal white matter injury are associated with the downregulation of fibrinogen-like protein 2/fibroleukin prothrombinase and the inhibition of pro-inflammatory cytokine expression.

Jin SJ, Liu Y, Deng SH, Liao LH, Lin TL, Ning Q, Luo XP - Int. J. Mol. Med. (2015)

Bottom Line: The results revealed that APC markedly reduced the LPS-induced increase in fgl2 expression and fibrin deposition, as well as the production of the pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, in the placentas and fetal brains.In addition, APC attenuated cerebral apoptosis and brain edema, downregulated PAR1 and NF-κB p65 expression in the fetal brains, and improved hypomyelination and structural disturbances in the periventricular area of the neonatal rat brains.Our observations provide evidence that APC attenuates fetal neuroinflammation and the associated secondary WMI in the developing brain by inhibiting the expression of fgl2 and pro-inflammatory mediators, suggesting that APC may be a potential therapeutic approach for intrauterine inflammation-induced neonatal brain injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

ABSTRACT
Maternal intrauterine inflammation or infection is an important risk factor for neonatal cerebral white matter injury (WMI) and future neurological deficits. Activated protein C (APC), a natural anticoagulant, has been shown to exhibit anti-inflammatory, anti-apoptotic, profibrinolytic and cytoprotective activities. Recent studies have demonstrated that the novel prothrombinase, fibrinogen-like protein 2 (fgl2), contributes to the pathogenesis of a number of inflammatory diseases through the generation of fibrin. Thus, we hypothesized that APC may regulate coagulant and inflammatory processes and improve brain injury in an experimental rat model of intrauterine inflammation-induced WMI. The animal model was established by the administration of an intraperitoneal injection of lipopolysaccharide (LPS) to pregnant Sprague-Dawley rats on embryonic day (E)17 and E18. APC was administered intraperitoneally 30 min after the second LPS injection. The expression of fgl2 and the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β expression in the placentas and fetal brains was determined on E19. Nerve cell death, the brain water content and protease-activated receptor 1 (PAR1) and nuclear factor κB (NF-κB) p65 expression was detected in the fetal brains. WMI in the neonatal rat brains was evaluated by hematoxylin and eosin (H&E) staining and immunohistochemistry for myelin basic protein (MBP). The results revealed that APC markedly reduced the LPS-induced increase in fgl2 expression and fibrin deposition, as well as the production of the pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, in the placentas and fetal brains. In addition, APC attenuated cerebral apoptosis and brain edema, downregulated PAR1 and NF-κB p65 expression in the fetal brains, and improved hypomyelination and structural disturbances in the periventricular area of the neonatal rat brains. Our observations provide evidence that APC attenuates fetal neuroinflammation and the associated secondary WMI in the developing brain by inhibiting the expression of fgl2 and pro-inflammatory mediators, suggesting that APC may be a potential therapeutic approach for intrauterine inflammation-induced neonatal brain injury.

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Activated protein C (APC) attenuates periventricular white matter cell death and brain edema on embryonic day (E)19. (A) Apoptotic index (AI) of periventricular white matter cells. The area counted in each photomicrograph is 0.6 mm2. Values are presented as the means ± SD (n=6). **P<0.001 vs. lipopolysaccharide (LPS) group. (B) Brain water content. Values are presented as the means ± SD (n=6). **P<0.001 vs. LPS group.
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f5-ijmm-35-05-1199: Activated protein C (APC) attenuates periventricular white matter cell death and brain edema on embryonic day (E)19. (A) Apoptotic index (AI) of periventricular white matter cells. The area counted in each photomicrograph is 0.6 mm2. Values are presented as the means ± SD (n=6). **P<0.001 vs. lipopolysaccharide (LPS) group. (B) Brain water content. Values are presented as the means ± SD (n=6). **P<0.001 vs. LPS group.

Mentions: For the evaluation of fetal brain injury following maternal exposure to LPS, apoptotic cell death was measured by TUNEL staining (Fig. 5A). The apoptotic index (AI) was calculated to quantify the number of TUNEL-positive cells. The number of TUNEL-positive cells in the periventricular white matter was significantly increased in the LPS group (AI = 10.63±1.88%) compared with the control group (AI = 0.05±0.05%; P<0.001, Fig. 5A). Treatment wit APC significantly reduced the number of TUNEL-positive cells in the periventricular white matter (AI = 1.33±0.44%; P<0.001, Fig. 5A) compared with the LPS group.


Neuroprotective effects of activated protein C on intrauterine inflammation-induced neonatal white matter injury are associated with the downregulation of fibrinogen-like protein 2/fibroleukin prothrombinase and the inhibition of pro-inflammatory cytokine expression.

Jin SJ, Liu Y, Deng SH, Liao LH, Lin TL, Ning Q, Luo XP - Int. J. Mol. Med. (2015)

Activated protein C (APC) attenuates periventricular white matter cell death and brain edema on embryonic day (E)19. (A) Apoptotic index (AI) of periventricular white matter cells. The area counted in each photomicrograph is 0.6 mm2. Values are presented as the means ± SD (n=6). **P<0.001 vs. lipopolysaccharide (LPS) group. (B) Brain water content. Values are presented as the means ± SD (n=6). **P<0.001 vs. LPS group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4380123&req=5

f5-ijmm-35-05-1199: Activated protein C (APC) attenuates periventricular white matter cell death and brain edema on embryonic day (E)19. (A) Apoptotic index (AI) of periventricular white matter cells. The area counted in each photomicrograph is 0.6 mm2. Values are presented as the means ± SD (n=6). **P<0.001 vs. lipopolysaccharide (LPS) group. (B) Brain water content. Values are presented as the means ± SD (n=6). **P<0.001 vs. LPS group.
Mentions: For the evaluation of fetal brain injury following maternal exposure to LPS, apoptotic cell death was measured by TUNEL staining (Fig. 5A). The apoptotic index (AI) was calculated to quantify the number of TUNEL-positive cells. The number of TUNEL-positive cells in the periventricular white matter was significantly increased in the LPS group (AI = 10.63±1.88%) compared with the control group (AI = 0.05±0.05%; P<0.001, Fig. 5A). Treatment wit APC significantly reduced the number of TUNEL-positive cells in the periventricular white matter (AI = 1.33±0.44%; P<0.001, Fig. 5A) compared with the LPS group.

Bottom Line: The results revealed that APC markedly reduced the LPS-induced increase in fgl2 expression and fibrin deposition, as well as the production of the pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, in the placentas and fetal brains.In addition, APC attenuated cerebral apoptosis and brain edema, downregulated PAR1 and NF-κB p65 expression in the fetal brains, and improved hypomyelination and structural disturbances in the periventricular area of the neonatal rat brains.Our observations provide evidence that APC attenuates fetal neuroinflammation and the associated secondary WMI in the developing brain by inhibiting the expression of fgl2 and pro-inflammatory mediators, suggesting that APC may be a potential therapeutic approach for intrauterine inflammation-induced neonatal brain injury.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.

ABSTRACT
Maternal intrauterine inflammation or infection is an important risk factor for neonatal cerebral white matter injury (WMI) and future neurological deficits. Activated protein C (APC), a natural anticoagulant, has been shown to exhibit anti-inflammatory, anti-apoptotic, profibrinolytic and cytoprotective activities. Recent studies have demonstrated that the novel prothrombinase, fibrinogen-like protein 2 (fgl2), contributes to the pathogenesis of a number of inflammatory diseases through the generation of fibrin. Thus, we hypothesized that APC may regulate coagulant and inflammatory processes and improve brain injury in an experimental rat model of intrauterine inflammation-induced WMI. The animal model was established by the administration of an intraperitoneal injection of lipopolysaccharide (LPS) to pregnant Sprague-Dawley rats on embryonic day (E)17 and E18. APC was administered intraperitoneally 30 min after the second LPS injection. The expression of fgl2 and the pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β expression in the placentas and fetal brains was determined on E19. Nerve cell death, the brain water content and protease-activated receptor 1 (PAR1) and nuclear factor κB (NF-κB) p65 expression was detected in the fetal brains. WMI in the neonatal rat brains was evaluated by hematoxylin and eosin (H&E) staining and immunohistochemistry for myelin basic protein (MBP). The results revealed that APC markedly reduced the LPS-induced increase in fgl2 expression and fibrin deposition, as well as the production of the pro-inflammatory cytokines, TNF-α, IL-6 and IL-1β, in the placentas and fetal brains. In addition, APC attenuated cerebral apoptosis and brain edema, downregulated PAR1 and NF-κB p65 expression in the fetal brains, and improved hypomyelination and structural disturbances in the periventricular area of the neonatal rat brains. Our observations provide evidence that APC attenuates fetal neuroinflammation and the associated secondary WMI in the developing brain by inhibiting the expression of fgl2 and pro-inflammatory mediators, suggesting that APC may be a potential therapeutic approach for intrauterine inflammation-induced neonatal brain injury.

Show MeSH
Related in: MedlinePlus