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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) ameliorates fetal growth restriction and neonatal brain weight loss following maternal exposure to lipopolysaccharide (LPS). (A) Birth weight. Data are presented as the means ± SD (n=46–59 per group); *P<0.01 vs. LPS group. (B) Neonatal brain weight on postnatal day (P)1, P3, P7, P10 and P14. The round, tetragonum and triangle symbols refer to the control, LPS and LPS + APC group, respectively. (C) Ratios of brain/body weight on P1, P3, P7, P10 and P14. The white, black, and gray bars refer to the control, LPS and LPS + APC group, respectively,. *P<0.05, **P<0.01 control vs. LPS group; †P<0.05, ‡P<0.01 APC vs. LPS group. Data are presented as the means ± SD (n=5).
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f12-ijmm-35-05-1199: Activated protein C (APC) ameliorates fetal growth restriction and neonatal brain weight loss following maternal exposure to lipopolysaccharide (LPS). (A) Birth weight. Data are presented as the means ± SD (n=46–59 per group); *P<0.01 vs. LPS group. (B) Neonatal brain weight on postnatal day (P)1, P3, P7, P10 and P14. The round, tetragonum and triangle symbols refer to the control, LPS and LPS + APC group, respectively. (C) Ratios of brain/body weight on P1, P3, P7, P10 and P14. The white, black, and gray bars refer to the control, LPS and LPS + APC group, respectively,. *P<0.05, **P<0.01 control vs. LPS group; †P<0.05, ‡P<0.01 APC vs. LPS group. Data are presented as the means ± SD (n=5).

Mentions: To determine whether a mild LPS challenge can restrict fetal growth or affect neonatal brain development, we evaluated the birth weight, as well as the brain and body weight of the rats on P1, P3, P7, P10 and P14. There was a significant decrease in the birth weight of the rats in the LPS group compared with the control group (P<0.001, Fig. 12A). The birth weight of the pups in the LPS + APC group was significantly higher than that of the pups in the LPS group (P<0.001, Fig. 12A). The brain weight of the pups from either the control or the LPS + APC group were significantly higher and kept increasing above those of the pups from the LPS group on P1 to P14 (Fig. 12B). Accordingly, the brain/body weight ratios of the pups in the LPS group were significantly lower than those of the pups in the control or LPS + APC group (Fig. 12C).


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) ameliorates fetal growth restriction and neonatal brain weight loss following maternal exposure to lipopolysaccharide (LPS). (A) Birth weight. Data are presented as the means ± SD (n=46–59 per group); *P<0.01 vs. LPS group. (B) Neonatal brain weight on postnatal day (P)1, P3, P7, P10 and P14. The round, tetragonum and triangle symbols refer to the control, LPS and LPS + APC group, respectively. (C) Ratios of brain/body weight on P1, P3, P7, P10 and P14. The white, black, and gray bars refer to the control, LPS and LPS + APC group, respectively,. *P<0.05, **P<0.01 control vs. LPS group; †P<0.05, ‡P<0.01 APC vs. LPS group. Data are presented as the means ± SD (n=5).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f12-ijmm-35-05-1199: Activated protein C (APC) ameliorates fetal growth restriction and neonatal brain weight loss following maternal exposure to lipopolysaccharide (LPS). (A) Birth weight. Data are presented as the means ± SD (n=46–59 per group); *P<0.01 vs. LPS group. (B) Neonatal brain weight on postnatal day (P)1, P3, P7, P10 and P14. The round, tetragonum and triangle symbols refer to the control, LPS and LPS + APC group, respectively. (C) Ratios of brain/body weight on P1, P3, P7, P10 and P14. The white, black, and gray bars refer to the control, LPS and LPS + APC group, respectively,. *P<0.05, **P<0.01 control vs. LPS group; †P<0.05, ‡P<0.01 APC vs. LPS group. Data are presented as the means ± SD (n=5).
Mentions: To determine whether a mild LPS challenge can restrict fetal growth or affect neonatal brain development, we evaluated the birth weight, as well as the brain and body weight of the rats on P1, P3, P7, P10 and P14. There was a significant decrease in the birth weight of the rats in the LPS group compared with the control group (P<0.001, Fig. 12A). The birth weight of the pups in the LPS + APC group was significantly higher than that of the pups in the LPS group (P<0.001, Fig. 12A). The brain weight of the pups from either the control or the LPS + APC group were significantly higher and kept increasing above those of the pups from the LPS group on P1 to P14 (Fig. 12B). Accordingly, the brain/body weight ratios of the pups in the LPS group were significantly lower than those of the pups in the control or LPS + APC group (Fig. 12C).

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