Geranylgeranylacetone attenuates septic diaphragm dysfunction by induction of heat shock protein 70.

Abstract

OBJECTIVE:

The purposes of the present study were to evaluate the induction of heat shock protein (HSP) 70 expression in the diaphragm by geranylgeranylacetone (GGA) administration and to determine the effect of HSP70 induction on diaphragm contractility measured in vitro and the production of oxygen-derived free radicals during experimental septic peritonitis.

DESIGN:

Prospective laboratory study.

SETTING:

University laboratory.

SUBJECTS:

One-hundred sixty male Wistar rats.

INTERVENTIONS:

In experiment 1, rats received GGA intragastrically, and time-dependent induction of HSP70 expression in the diaphragm was determined at 0, 12, 24, and 36 hrs after GGA administration. To evaluate dose-dependent inhibition of GGA-induced HSP70 expression by quercetin, rats were pretreated with progressive doses of quercetin before GGA administration. In experiment 2, rats received gum arabic solution (vehicle), 100, 200, or 400 mg/kg of GGA. In experiment 3, rats were pretreated with quercetin or glycerol before GGA or vehicle administration. Intra-abdominal sepsis was induced by cecal ligation and perforation (CLP) under inhalation anesthesia after GGA or vehicle administration in experiments 2 and 3.

MEASUREMENTS AND MAIN RESULTS:

Western blot analysis using diaphragm homogenates obtained from normal rats showed that HSP70 expression peaked at 24 or 36 hrs after GGA administration and that pretreatment with >10 mg/kg of quercetin blocked the induction of HSP70 expression by GGA. CLP induced diaphragmatic dysfunction and increased diaphragmatic malondialdehyde concentrations and superoxide dismutase and glutathione peroxidase activities. GGA attenuated CLP-induced diaphragm dysfunction and increased malondialdehyde concentrations in a dose-dependent manner but did not affect superoxide dismutase and glutathione peroxidase activities after CLP. Diaphragm dysfunction and increased diaphragmatic malondialdehyde concentrations after CLP were maintained on quercetin pretreatment despite GGA administration.

CONCLUSIONS:

GGA induces HSP70 expression in the diaphragm, and this induction attenuates septic diaphragm impairment by inhibiting the production of oxygen-derived free radicals.

• Authors: Yoshiki Masuda, Shinzoh Sumita, Naoyuki Fujimura, Akiyoshi Namiki
• Journal: Critical care medicine (Crit Care Med) Vol. 31 Issue 11 Pg. 2585-91 (Nov 2003) ISSN: 0090-3493 [Print] United States
• PMID: 14605528 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Ulcer Agents
• Diterpenes
• HSP70 Heat-Shock Proteins
• Superoxide Dismutase
• geranylgeranylacetone

Topics

• Animals
• Anti-Ulcer Agents (therapeutic use)
• Diaphragm (drug effects, metabolism)
• Diterpenes (therapeutic use)
• HSP70 Heat-Shock Proteins (biosynthesis)
• Male
• Muscle Contraction (drug effects)
• Rats
• Rats, Wistar
• Sepsis (drug therapy, metabolism)
• Superoxide Dismutase (metabolism)