甲状旁腺激素相关蛋白在致死性内毒素血症期间被诱导产生，并导致啮齿动物内毒素诱导的死亡。

Parathyroid hormone-related protein is induced during lethal endotoxemia and contributes to endotoxin-induced mortality in rodents.

作者信息

Funk J L, Moser A H, Strewler G J, Feingold K R, Grünfeld C

机构信息

Department of Medicine, University of California, San Francisco, USA.

出版信息

Mol Med. 1996 Mar;2(2):204-10.

PMID:8726463

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2230122/

Abstract

BACKGROUND

Parathyroid hormone-related protein (PTHrP) is a ubiquitous and highly conserved vasoactive peptide whose role and regulation in normal physiology remain an enigma. Recently, we demonstrated that low-dose endotoxin (LPS) induces intrasplenic, but not systemic, levels of PTHrP; and that tumor necrosis factor, a pro-inflammatory cytokine, is the major mediator of this effect. We have therefore hypothesized that, with higher, lethal doses of endotoxin, PTHrP could be induced in multiple tissues to such a degree that it could contribute to the lethality of septic shock.

MATERIALS AND METHODS

Northern blot analysis was used to measure PTHrP mRNA levels in vital organs of rats after administration of a near lethal dose (5 mg/250 g) of LPS (or vehicle alone). Plasma levels of PTHrP were also measured by immunoradiometric assay. The ability of the immunoglobulin fraction of two different PTHrP(1-34) antisera to protect from LPS-induced lethality was also studied in mice using survival analysis.

RESULTS

In response to a near-lethal dose of endotoxin, PTHrP mRNA levels increased acutely in every vital organ examined (spleen, lung, heart, kidney, and liver). Circulating levels of PTHrP also increased, peaking 2 hr after administration of high-dose endotoxin. Passive immunization of mice with anti-PTHrP(1-34) antibody 6 hr prior to administration of a lethal dose of LPS protected mice from endotoxin-induced death (p < 0.00005).

CONCLUSIONS

These results suggest that PTHrP belongs to the cascade of pro-inflammatory cytokines induced during lethal endotoxemia that is responsible for the toxic effects of LPS.

摘要

背景

甲状旁腺激素相关蛋白（PTHrP）是一种广泛存在且高度保守的血管活性肽，其在正常生理学中的作用和调节机制仍是一个谜。最近，我们发现低剂量内毒素（LPS）可诱导脾脏内而非全身的PTHrP水平升高；并且促炎细胞因子肿瘤坏死因子是这种效应的主要介导因子。因此，我们推测，在更高的致死剂量内毒素作用下，PTHrP可能在多个组织中被诱导到一定程度，从而导致脓毒症休克的致死性。

材料与方法

采用Northern印迹分析来测定给予接近致死剂量（5mg/250g）LPS（或仅给予载体）后大鼠重要器官中PTHrP mRNA水平。还通过免疫放射测定法测量血浆中PTHrP水平。在小鼠中使用生存分析研究了两种不同的PTHrP（1 - 34）抗血清的免疫球蛋白部分保护小鼠免受LPS诱导的致死性的能力。

结果

在给予接近致死剂量的内毒素后每个检测的重要器官（脾脏、肺、心脏、肾脏和肝脏）中，PTHrP mRNA水平急剧升高。循环中的PTHrP水平也升高，在给予高剂量内毒素后2小时达到峰值。在给予致死剂量LPS前6小时用抗PTHrP（1 - 34）抗体对小鼠进行被动免疫可保护小鼠免于内毒素诱导的死亡（p < 0.00005）。