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

Janet L Funk, Arthur H. Moser, Gordon J. Strewler, Kenneth R. Feingold, Carl Grünfeld

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)204-210
Number of pages7
JournalMolecular Medicine
Volume2
Issue number2
StatePublished - 1996

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Parathyroid Hormone-Related Protein
Endotoxemia
Endotoxins
Rodentia
Mortality
Cytokines
Immunoradiometric Assay
Messenger RNA
Passive Immunization
Poisons
Survival Analysis
Septic Shock
Northern Blotting
Immunoglobulins
Immune Sera
Spleen
Tumor Necrosis Factor-alpha
Kidney
Lung
Peptides

ASJC Scopus subject areas

  • Genetics

Cite this

Parathyroid hormone-related protein is induced during lethal endotoxemia and contributes to endotoxin-induced mortality in rodents. / Funk, Janet L; Moser, Arthur H.; Strewler, Gordon J.; Feingold, Kenneth R.; Grünfeld, Carl.

In: Molecular Medicine, Vol. 2, No. 2, 1996, p. 204-210.

Research output: Contribution to journalArticle

Funk, Janet L ; Moser, Arthur H. ; Strewler, Gordon J. ; Feingold, Kenneth R. ; Grünfeld, Carl. / Parathyroid hormone-related protein is induced during lethal endotoxemia and contributes to endotoxin-induced mortality in rodents. In: Molecular Medicine. 1996 ; Vol. 2, No. 2. pp. 204-210.
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