Hsp90 regulation affects the treatment of glucocorticoid for pancreatitis-induced lung injury
- 94 Downloads
Glucocorticoids are commonly used for the treatment of pancreatitis and complicated acute lung injury and help to reduce the mortality rates of both. The effect of gene variants in heat shock protein 90 (Hsp90), a key chaperone molecule of the glucocorticoid receptor (GR), on the therapeutic effect of glucocorticoids is unclear. Our study aims to investigate the different susceptibility to glucocorticoid treatment in BALB/c and C57BL/6 mice carrying different Hsp90 genotypes in an animal model of pancreatitis-induced lung injury. Compared with BALB/c mice, C57BL/6 mice have lower mortality rates, decreased water content in their lungs, and a lower level of IL-1 beta in an animal model of acute pancreatitis. C57BL/6 mice show a greater therapeutic effect and increased GR binding activities with glucocorticoid responsive element compared to BALB/c mice after a 0.4 mg/kg dexamethasone (DEX) treatment. Treatment with a higher dose of DEX (4 mg/kg) significantly reduced mortality rates and increased GR-GRE binding activity in both strains of mice, and there was no significant difference between the two strains. DEX did not exert a protective role after geldanamycin, a specific inhibitor of Hsp90, was administered in both strains of mice. Our study revealed that Hsp90 gene variants are responsible for the greater therapeutic effect of DEX in C57BL/6 mice compared to BALB/c mice, which implies that combining DEX treatment with Hsp90 regulation would promote the efficiency of DEX and would be an effective way to alleviate the side effects of hormone therapy.
KeywordsAcute pancreatitis Acute lung injury Glucocorticoid receptor Heat shock protein 90
This work was supported by the National Natural Science Foundation of China [Grant 30470988] and the Foundation for the Author of National Excellent Doctoral Dissertation of China [Grant 200156].
Compliance with ethical standards
Conflict of interest
The authors have declared that no conflict of interest exists.
- 4.Jibard N, Meng X, Leclerc P, Rajkowski K, Fortin D, Schweizer-Groyer G, Catelli MG, Baulieu EE, Cadepond F (1999) Delimitation of two regions in the 90-kDa heat shock protein (Hsp90) able to interact with the glucocorticosteroid receptor (GR). Exp Cell Res 247:461–474. doi: 10.1006/excr.1998.4375 CrossRefPubMedGoogle Scholar
- 13.Cadepond F, Jibard N, Binart N, Schweizer-Groyer G, Segard-Maurel I, Baulieu EE (1994) Selective deletions in the 90 kDa heat shock protein (hsp90) impede hetero-oligomeric complex formation with the glucocorticosteroid receptor (GR) or hormone binding by GR. J Steroid Biochem Mol Biol 48:361–367CrossRefPubMedGoogle Scholar
- 16.Zhang S, Lv C, Yang X, Han Z, Zhang S, Zhang J, Zong C, Gao L, Li L, Zhao Q, Li R, Yang Y, Yu F, Li X, Zhang P, Wei L (2015) Corticosterone mediates the inhibitory effect of restraint stress on the migration of mesenchymal stem cell to carbon tetrachloride-induced fibrotic liver by downregulating CXCR4/7 expression. Stem Cells Dev 24:587–596. doi: 10.1089/scd.2014.0243 CrossRefPubMedGoogle Scholar
- 19.Ramudo L, Yubero S, Manso MA, Sanchez-Recio J, Weruaga E, De Dios I (2010) Effects of dexamethasone on intercellular adhesion molecule 1 expression and inflammatory response in necrotizing acute pancreatitis in rats. Pancreas 39:1057–1063. doi: 10.1097/MPA.0b013e3181da0f3e CrossRefPubMedGoogle Scholar
- 26.Li YY, Li XJ, Lv S, Li K, Li YN, Gao ZR, Feng JY, Chen CJ, Schaefer C (2010) Ascitic fluid and serum from rats with acute pancreatitis injure rat pancreatic tissues and alter the expression of heat shock protein 60. Cell Stress Chaperones 15:583–591. doi: 10.1007/s12192-010-0170-5 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Ye R, Mareninova OA, Barron E, Wang M, Hinton DR, Pandol SJ, Lee AS (2010) Grp78 heterozygosity regulates chaperone balance in exocrine pancreas with differential response to cerulein-induced acute pancreatitis. Am J Pathol 177:2827–2836. doi: 10.2353/ajpath.2010.100368 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Moretti AI, Rios EC, Soriano FG, de Souza HP, Abatepaulo F, Barbeiro DF, Velasco IT (2009) Acute pancreatitis: hypertonic saline increases heat shock proteins 70 and 90 and reduces neutrophil infiltration in lung injury. Pancreas 38:507–514. doi: 10.1097/MPA.0b013e31819fef75 CrossRefPubMedGoogle Scholar
- 33.Nakada S, Tsuneyama K, Kato I, Tabuchi Y, Takasaki I, Furusawa Y, Kawaguchi H, Fujimoto M, Goto H, Hikiami H, Kondo T, Takano Y, Shimada Y (2010) Identification of candidate genes involved in endogenous protection mechanisms against acute pancreatitis in mice. Biochem Biophys Res Commun 391:1342–1347. doi: 10.1016/j.bbrc.2009.12.047 CrossRefPubMedGoogle Scholar
- 34.Szabolcs A, Biczo G, Rakonczay Z, Tiszlavicz L, Halm G, Wittmann T, Takacs T (2009) Simultaneous proteosome inhibition and heat shock protein induction by bortezomib is beneficial in experimental pancreatitis. Eur J Pharmacol 616:270–274. doi: 10.1016/j.ejphar.2009.05.019 CrossRefPubMedGoogle Scholar