TNF-α antagonist attenuates systemic lipopolysaccharide-induced brain white matter injury in neonatal rats.

BACKGROUND: Systemic inflammation is an important risk factor for neurodevelopmental impairments in preterm infants. Premyelinating oligodendrocytes are main building blocks of white matter in preterm infants and vulnerable to oxidative stress and excitotoxic stress. Tumour necrosis factor-α (TNF-α) plays important roles in systemic inflammation and local inflammation leading to apoptosis of premyelinating oligodendrocytes and white matter injury (WMI) in brain tissue. This study was conducted to investigate whether etanercept, a TNF-α antagonist, could attenuate systemic lipopolysaccharide (LPS)-induced WMI in the immature brain. RESULTS: We found that intraperitoneal LPS administration caused systemic and local inflammation in brain tissue. Subsequent etanercept treatment significantly attenuated LPS-induced inflammation in brain tissue as well as in systemic circulation. Intraperitoneal LPS also induced microgliosis and astrocytosis in the cingulum and etanercept treatment reduced LPS-induced microgliosis and astrocytosis. Additionally, systemic LPS-induced apoptosis of oligodendrocyte precursor cells was observed, which was lessened by etanercept treatment. The concentration of etanercept in the CSF was higher when it was administrated with LPS than when administrated with a vehicle. CONCLUSIONS: It appears that etanercept reduce WMI in the neonatal rat brain via attenuation of systemic and local inflammation. This study provides preclinical data suggesting etanercept-mediated modulation of inflammation as a promising approach to reduce WMI caused by sepsis or necrotizing enterocolitis in preterm infants.

Alteration of TGF-ß-ALK-Smad signaling in hyperoxia-induced bronchopulmonary dysplasia model of newborn rats.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a main chronic lung disease commonly occurs in preterm infants. BPD is characterized by impaired alveolarization and vascularization of the developing lung. Transforming growth factor-ß (TGF-ß) signaling pathway is known to play an important role during lung vascular development. In the present study, we examined whether the regulation of TGF-ß-ALK-Smad signaling pathway influence on the disruption of pulmonary vascular development in newborn rats as hyperoxia-induced BPD model. MATERIALS AND METHODS: Newborn rats were continuously exposed to 21% or 85% O2 for 7 days, and subsequently kept in normoxic condition for another 14 days. Lung tissues harvested at each time point were evaluated for the expression of TGF-ß1, ALK1, ALK5, phosphorylated Smad1/5, phosphorylated Smad2/3, VEGF, and endoglin, as accessed by both biochemical and immunohistological analyses. RESULTS: Double-fluorescence immunohistochemical staining indicated these molecules were mainly expressed in pulmonary endothelial cells. The expression of TGF-ß1 and ALK5 mRNA and protein were significantly increased in D5 hyperoxia group, while that of ALK1 mRNA and protein were significantly decreased. The level of phosphorylated Smad1/5 was significantly decreased in D7 hyperoxia group, whereas that of phosphorylated Smad2/3 was oppositely increased. In addition, the expression of vascular endothelial growth factor (VEGF) mRNA was increased at D1 with subsequent decrease in D7 hyperoxia group. There was no significantly difference in endoglin expression in entire experimental period. CONCLUSION: These results indicate that exposure to hyperoxia altered the balance between TGF-ß-ALK1-Smad1/5 and TGF-ß-ALK5-Smad2/3 pathways in pulmonary endothelial cells, which may ultimately lead to the development of BPD.