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首页> 外文期刊>American Journal of Physiology >Mechanisms and pathophysiological implications of sinusoidal endothelial cell gap formation following treatment with galactosamine/endotoxin in mice.
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Mechanisms and pathophysiological implications of sinusoidal endothelial cell gap formation following treatment with galactosamine/endotoxin in mice.

机译：小鼠半乳糖胺/内毒素治疗后正弦内皮细胞间隙形成的机制和病理生理意义。

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摘要

Neutrophil extravasation from sinusoids is a critical step for acute inflammatory tissue injury. However, the role of sinusoidal endothelial cells (SECs) in this process remains unclear. Matrix metalloproteinases (MMPs) have been shown to involve gap formation in SECs in several liver diseases. Therefore, the present study examined SEC modifications elicited by galactosamine (Gal)/endotoxin (ET). Treatment of male C3Heb/FeJ mice with Gal/ET or Gal/TNF caused the formation of numerous gaps in SECs at 4 h when no neutrophil extravasation occurred. Six hours after Gal/ET or Gal/TNF treatment, blood elements started to penetrate to the extrasinusoidal space through large gaps. Treatment with ET alone caused sinusoidal neutrophil accumulation but no gap formation, neutrophil extravasation, or hemorrhage. Gal/ET treatment increased hepatic MMP-2 and MMP-9 mRNA expression (6.7- and 11-fold, respectively). Pretreatment with 2-[(4-biphenylsulfonyl) amino]-3-phenyl-propionic acid, an MMP-2/MMP-9 inhibitor (5 mg/kg), minimized gap formation after Gal/ET and Gal/TNF treatment. The MMP inhibitor reduced injury only in the Gal/ET model mainly due to reduced TNF formation. The MMP inhibitor attenuated sinusoidal neutrophil accumulation at 6 h but failed to attenuate Gal/TNF-induced liver injury at 7 h due to excessive apoptosis. These results suggest that Gal/ET or Gal/TNF activates MMPs, which are responsible for SEC gap formation. Although the initial appearance of gap formation is independent of neutrophils, the gaps allow initial contact of neutrophils with damaged hepatocytes. In addition, MMP activation promotes neutrophil accumulation in sinusoids.
机译：从正弦曲线中性粒细胞外渗是急性炎性组织损伤的关键步骤。但是，在此过程中，正弦血管内皮细胞（SEC）的作用仍不清楚。基质金属蛋白酶（MMP）已显示在几种肝病中涉及SEC中的缺口形成。因此，本研究检查了半乳糖胺（Gal）/内毒素（ET）引起的SEC修饰。用Gal / ET或Gal / TNF处理雄性C3Heb / FeJ小鼠时，在4小时内未发生嗜中性粒细胞外渗时，在SEC中形成了许多缺口。 Gal / ET或Gal / TNF治疗六小时后，血液元素开始通过大间隙渗透到窦外空间。单独使用ET进行治疗会引起窦性中性粒细胞积聚，但不会形成缝隙，中性粒细胞外渗或出血。 Gal / ET治疗可增加肝MMP-2和MMP-9 mRNA表达（分别为6.7和11倍）。用2-[（4-联苯磺酰基）氨基] -3-苯基-丙酸（一种MMP-2 / MMP-9抑制剂）（5 mg / kg）进行预处理，可最大程度地减少Gal / ET和Gal / TNF处理后的空位形成。 MMP抑制剂仅在Gal / ET模型中减少了损伤，这主要是由于减少了TNF的形成。 MMP抑制剂在6 h减弱了窦性中性粒细胞的积累，但由于过度的细胞凋亡在7 h未能减弱Gal / TNF诱导的肝损伤。这些结果表明，Gal / ET或Gal / TNF激活了MMP，而这些MMP是SEC缺口形成的原因。尽管间隙形成的最初外观与嗜中性粒细胞无关，但是间隙允许嗜中性粒细胞与受损的肝细胞进行初始接触。此外，MMP激活促进中性粒细胞在正弦波中的积累。

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