Inhibition of Janus kinase 2 and signal transduction and activator of transcription 3 protect against cecal ligation and puncture-induced multiple organ damage and mortality.
BACKGROUND
Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway plays an important role in sepsis, transducing a multitude of inflammatory signals. To date, knowledge of JAK/STAT pathway in sepsis is limited. This study was to investigate the potential role of JAK/STAT pathway in mediating multiple organ damage and mortality in septic rats. Our data showed that inhibition of JAK2/STAT3 attenuated cecal ligation and puncture-induced multiple organ damage and mortality in 48 hours in rats.


METHODS
A total of 98 male Wistar rats were randomly divided into 4 groups as follows: (1) normal control group (n = 10); (2) cecal ligation and puncture (CLP) group (n = 40), which was further divided into 2, 6, 24, 48-hour post-CLP groups; (3) AG490 (8.0 mg/kg, Calbiochem, La Jolla, CA) treatment group (n = 24), which was further divided into 2, 6, 24, 48-hour post-CLP groups; (4) rapamycin (0.4 mg/kg, Calbiochem, Calbiochem, La Jolla, CA) treatment group (n = 24), which was further divided into 2, 6, 24, 48-hour post-CLP groups; CLP was performed to induce experimental sepsis. AG490 (8 mg/kg) or rapamycin (0.4 mg/kg) was injected subcutaneously 0.5 hour before CLP in respective group. Animals were killed at destined time after CLP (not including the death rate observation group), and specimens of serum, liver, and lungs were harvested and stored in liquid nitrogen for subsequent analyses. In an additional experiment, 88 animals were randomly divided into three groups to compare the survival rate, including CLP group (n = 40), AG490 treatment group (8 mg/kg, n = 24), and rapamycin treatment group (0.4 mg/kg, n = 24). Mortality of rats in each group was recorded up to 48 hours after the procedure.


RESULTS
After CLP challenge, myeloperoxidase (MPO), aspartate transaminase, and alanine aminotransferase levels, as well as activation of JAK2 and STAT3, were markedly increased. Administration of AG490 or rapamycin significantly decreased activation of JAK2 and STAT3, as well as high mobility group box-1 protein, MPO, alanine aminotransferase levels (p < 0.05 or p < 0.01). In addition, treatment with AG490 or rapamycin significantly improved the 48-hour survival rate from 37.5% (15 of 40) to 66.7% (16 of 24) and 70.8% (17 of 24), respectively (both p < 0.05).


CONCLUSIONS
JAK2/STAT3 pathway might play a role in the development of multiple organ damage in septic rats, which suggested a potential strategy to control sepsis.
Hui
Liu
L
Department of Microbiology and Immunology, Burns Institute, First Hospital Affiliated to Chinese PLA General Hospital (formerly 304th Hospital), Beijing 100037, People's Republic of China.
Yao
Yongming
Y
Wang
Songbai
S
Yu
Yan
Y
Dong
Ning
N
Li
Hongyun
H
Sheng
Zhiyong
Z
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002432:Cecum / Q000293:injuries*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000097:blood; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D008297:Male; D009102:Multiple Organ Failure / Q000235:genetics* / Q000401:mortality; D009195:Peroxidase / Q000097:blood; D051381:Rats; D017208:Rats, Wistar; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics*; D020123:Sirolimus / Q000494:pharmacology*; D015996:Survival Rate; D020032:Tyrphostins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D024243:HMGB1 Protein; C104200:Hbp1 protein, rat; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D009195:Peroxidase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D020123:Sirolimus