[Changes in adrenal cortex function and protective effect of dexamethasone in septic rats during early phases].
OBJECTIVE
To affirm the presence of relative adrenal insufficiency (RAI) in the early phases of sepsis and its probable mechanisms, and to study the optimal time for glucocorticoid replacement therapy.


METHODS
A total of 260 healthy male Wistar rats were randomized into five groups (each group n=52), including normal control group, sham operation group, cecal ligation and puncture (CLP) group, dexamethasone prevention group (with 10 mg/kg dexamethasone injection into the abdominal cavity before CLP) and dexamethasone treatment group (with 10 mg/kg dexamethasone injection into the abdominal cavity 7 hours after CLP). Each group was subdivided into five subgroups according to five time points: 2, 4, 6, 8 and 12 hours. Adrenocorticotrophic hormone (ACTH) test was conducted at 8 hours and 12 hours, and before and after 30 minutes of ACTH administration, the cortisol content in serum was determined with radioimmunoassay (RIA) and the expressions of Toll-like receptor 4 (TLR4), tumor necrosis factor-alpha (TNF-alpha) mRNA in adrenal glands were detected with semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Ultrastructure of adrenal cortex was observed with transmission electron microscope. The survival rats was recorded in all groups.


RESULTS
(1) The levels of cortisol in CLP group, dexamethasone prevention group and dexamethasone treatment group were respectively higher than those of normal control and sham operation groups (all P<0.05). But there was no marked change in the levels of cortisol between pre-and post-ACTH in rats with sepsis in the early phases. (2)The expressions of TLR4, TNF-alpha mRNA in adrenal both were significantly increased in CLP group, and they were higher than those in sham operation group (P<0.05 or P<0.01). The expressions of TLR4, TNF-alpha mRNA in dexamethasone prevention group and treatment group were significantly lower than those in CLP group, and those in the dexamethasone prevention group were lower than those in sham operation group. (3)In the groups of CLP, dexamethasone prevention and treatment, ultrastructure changes were observed in the adrenal, especially in CLP group. (4)The survival rate of the dexamethasone prevention and treatment groups at 12 hours were higher than that of CLP group (76.92%, 40.00% vs. 33.33%, P<0.01 and P<0.05). The survival rate of dexamethasone prevention group was higher than that of dexamethasone treatment group (P<0.05).


CONCLUSIONS
(1)RAI occurs during the early stage of sepsis. (2)The expressions of TLR4, TNF-alpha mRNA in adrenal and changes in corticoadrenal ultrastructure participates in the pathogenesis of RAI in the early stage of sepsis in rat. (3) Dexamethasone therapy could effectively increase the survival rate and improve outcome through down-regulating the expression changes in TLR4, TNF-alpha mRNA and alleviating changes in ultrastructure of adrenal glands. Early administration of dexamethasone may give good result in the treatment of sepsis.
Hu
Zhen-jie
ZJ
Intensive Care Unit, Forth Hospital Affiliated to Hebei Medical University, Shijiazhuang 050011, Hebei, China.
Tian
Hui-yu
HY
Wang
Lan-tao
LT
Tian
Hui-yan
HY
D000302:Adrenal Cortex / Q000503:physiopathology* / Q000648:ultrastructure; D000818:Animals; D003907:Dexamethasone / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005938:Glucocorticoids / Q000627:therapeutic use*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000188:drug therapy / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D005938:Glucocorticoids; D012333:RNA, Messenger; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone