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


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.
Funk
J L
JL
Department of Medicine, University of California, San Francisco, USA.
Moser
A H
AH
Strewler
G J
GJ
Feingold
K R
KR
Grünfeld
C
C
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015152:Blotting, Northern; D003643:Death; D004731:Endotoxins / Q000633:toxicity*; D004926:Escherichia coli; D008070:Lipopolysaccharides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D010281:Parathyroid Hormone / Q000096:biosynthesis; D044162:Parathyroid Hormone-Related Protein; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014115:Toxemia / Q000503:physiopathology*; D014158:Transcription, Genetic
D000906:Antibodies; D004731:Endotoxins; D008070:Lipopolysaccharides; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D012333:RNA, Messenger