Hsp90 regulation affects the treatment of glucocorticoid for pancreatitis-induced lung injury

Abstract

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.

Xiaoyaosan (Tiaogan-Liqi therapy) protects peritoneal macrophages from corticosterone-induced stress by regulating the interaction between glucocorticoid receptor and ABCA1

“…These data suggested XYS could protect PMs from CORT-induced stress by inhibiting the elevated GR protein level from being transported into the nucleus. Previous reports also showed that HSP90 could assist the internuclear transfer of GC-GR complex, then GC-GR complex could bind to the GR element (GRE) and induce C D E F the expression of the target genes (13,28). When released from HSP90, the activity of GR's transportation into the nucleus was enhanced.…”

Corticosteroid treatment for acute/acute-on-chronic experimental and naturally occurring pancreatitis in several species: a scoping review to inform possible use in dogs

“…Performance, detection and reporting bias: No blinding, no stated histopathology scoring system, no statistical evaluation, seems to be conclusions based on subjective evaluation. No drop-outs Very small (6/6) Zhao et al [ 64 ] Mice Controlled trial III Good, all male, similar age mice of 2 genotypes High Selection bias: No randomisation stated. Performance, detection and reporting bias: No blinding stated, histopathological changes of the pancreas was not included in the aims, but shown by photos and not commented on.…”

“…Only 1 study [ 38 ] described the method of randomisation. Eight studies were categorised as nonrandomised controlled trials, with 4 involving canines [ 57 – 60 ] and 4 involving rodents [ 61 – 64 ]. Two human studies were categorised as retrospective case control studies [ 37 , 65 ], and 1 human study was categorised as a case series [ 66 ] (Tables 1 and 2 ).…”

“…Rodents and dogs subjected to induced AP were generally not treated or only treated with IV or SC fluids. Few were treated with analgesics [ 47 , 62 ] or antimicrobials [ 58 , 64 ]. In addition, test subjects (GC groups) were given corticosteroids while model controls were not.…”

“…Prednisolone was used in 1 canine study [ 57 ] and 2 rodent studies [ 44 , 50 ], while methylprednisolone was used in 6 rodent studies [ 42 , 46 , 51 , 52 , 55 , 63 ]. Cortisone acetate was used in just 1 canine study [ 59 ], whereas dexamethasone was used in 1 canine study [ 58 ], 3 human studies [ 38 , 40 , 66 ] and 10 rodent studies [ 36 , 41 , 45 , 47 – 49 , 54 , 56 , 62 , 64 ]. The type of corticosteroid used for treatment was not specified in one of the rodent studies [ 53 ].…”