It has demonstrated histone deacetylase inhibitor to be protective in preclinical and early clinical studies for the therapy of cancer,central nervous system degenerative diseases and immune system diseases.Strikingly,Recent studies have shown that it has emerged as a potent prosurvival and anti-inflammatory drug,offering new lines of therapeutic intervention for sepsis shock,and can reverse the changes of genes expression at the molecular level,caused by sepsis shock and its follow-up of fluid resuscitation.What' s more,it has slight impact on hemodynamics,ultimately alleviates lesions to systemic inflammatory response syndrome and multiple organ failure syndrome and simultaneously lays a good foundation to win the golden time for treatment.On the other hand,with the development of second hit theory,it will also set up a bridge between hemorrhagic shock and septic shock,resulting in expansioning the breadth and depth of understanding of shock.In brief,histone deacetylase inhibitors are the extension and challenges of the traditional therapy of anti-sepsis shock.

BACKGROUND:Studies have shown that suberoylanilide hydroxamic acid (SAHA) has protective effects in some vital organs in animals after hemorrhagic shock, and 7.5% hypertonic saline (HS) exerts significant effects on stabilizing the hemodynamics of hemorrhagic shock animals. OBJECTIVE:To evaluate the effect of SAHA combined with HS on the hemodynamics of hemorrhagic shock rats. METHODS: Fifty rats were randomly and equaly divided into five groups: sham, shock non-resuscitation, SAHA, 7.5% HS, and 7.5% HS + SAHA. Each group contained 10 rats. Except the sham group, rats in the remaining four groups were applied to establish hemorrhagic shock models. In the sham group, rats were given anesthesia catheter, not bleeding; in the shock non-resuscitation group, the bleeding was found, but rats were not resuscitated and were kiled after 60 minutes of observations; in the other three groups, rats were respectively resuscitated at 60 minutes after bleeding, through intravenous administration of SAHA within 5 minutes, 7.5% HS and SAHA + 7.5% HS within 20 minutes. Heart rate, mean arterial pressure and left ventricular systolic pressure were monitored through the femoral artery and the right common carotid artery catheter in each group. RESULTS AND CONCLUSION:At 3 hours after resuscitation, the heart rate was the highest in the 7.5% HS + SAHA group, compared with the SAHA and 7.5% HS groups (P < 0.05). After resuscitation, the mean arterial pressure and left ventricular systolic pressure were increased, with long-lasting effect and less fluctuation (P < 0.05). Experimental results show that 7.5% HS combined with SAHA has a superiority than traditional HS and simple drugs for resuscitation after hemorrhagic shock.

Objective To explore the pathogenesis of acute lung injury in rats suffering hemorrhagic shock at plateau.Methods Seventy-two male Wistar rats, weighing 280-320 g, were randomized into 6 groups (n=12): sham group (group Sham), hemorrhagic shock for 15 min (group HS15), hemorrhagic shock for 30 min group (group HS30), hemorrhagic shock for 45 min group (group HS45), hemorrhagic shock for 60 min group (group HS60) and 90 min group (group HS90).Hemorrhagic shock model of Wistar rats was reproduced at plateau.The rats were only anesthetized, no shock and were sacrificed after 90 min in group Sham.The other groups were different in bleeding time and then were respectively sacrificed at 15, 30, 45, 60 and 90 min after shock.The pathological changes in the lungs were observed with light microscope.Wet to dry weight ratio (W/D), lung permeability index (LPI), myeloperoxidase (MPO) activity, malondialdehyde (MDA) and superoxide dismutase (SOD) in lung were measured.Enzyme-linked immunosorbent assay was used to detect the TNF-α and IL-10 in lung tissue, the expression and distribution of claudin-3 and claudin-4 in lung tissue was verified by immunohistochemistry method.Results Compared with group Sham, shock causes acute lung injury at different degree, and was positively correlated with the duration of shock, during the period of 15 to 30 min, it merely rendered a slight change in lung W/D, LPI, MPO, MDA, TNF-α, T-SOD and IL-10.Subsequently, along with time prolonged, lung W/D, neutrophils in BALF, LPI, MPO, MDA, TNF-α were significantly elevated, while T-SOD and IL-10 were notably reduced (P<0.05).Immunohistochemical results showed that claudin-3 and claudin-4 expression in lung epithelial cells and endothelial cells expressed at low levels and dislocated (P<0.05).Conclusion After a short time compensatory lesions, the change of rats' hemodynamic stability suffering severe hemorrhagic shock showed a spiral downward.Along with the extension of the shock, hemorrhagic shock at plateau results into the disturbance of inflammatory response and oxidative stress, the loss of claudin-3 and claudin-4 in lung epithelial cells, which triggers the acute lung injury.

Objective To evaluate the effect of suberoylanilide hydroxamic acid (SAHA) on liver injury induced by lethal hemorrhagic shock in rats first entering high altitude.Methods Forty healthy male SpragueDawley rats,aged 2-3 months,weighing 240-280 g,transported from breeding grounds at an altitude of 1520 meters to the experimental station at an altitude of 3780 meters,were randomly divided into 4 groups (n =10each):sham operation group (group S),lethal hemorrhagic shock group (group LHS),normal saline group (group NS),and SAHA group.Anesthesia was induced with inhalation of 3% isoflurane and maintained with inhalation of 0.5%-1.0% isoflurane.Lethal hemorrhagic shock was induced by withdrawing blood from the femoral artery in groups LHS,NS and SAHA.Normal saline 0.25 ml and SAHA 7.5 mg/kg (0.25 ml) were injected intravenously over 2 min after completion of blood-letting in groups NS and SAHA,respectively.The survival rates with 3 h were recorded.Blood samples from femoral veins were taken before blood-letting,immediately after completion of blood-letting and at 3 h after completion of blood-letting (immediately after death if the survival time was less than 3 h) for determination of serum aspartate aminotransferase (AST),alanine aminotransferase (ALT) and lactic dehydrogenase (LDH) activities by the colorimetric method.Liver specimens were taken at 3 h after completion of blood-letting or immediately after death for examination of the pathological changes of the liver and for determination of c-Jun N-terminal kinase (JNK),phosphorylated-JNK (p-JNK) and caspase-3 expression and acetylation of H3K9 in liver tissues by Western blot.Results Compared with group S,the activities of serum AST,ALT and LDH were significantly increased in the other three groups (P ＜ 0.01).Compared with LHS and NS groups,the activities of serum AST,ALT and LDH were significantly decreased,the survival rate within 3 h and acetylation of H3K9 were increased,caspase-3 expression was down-regulated,and p-JNK/JNK ratio was decreased in group SAHA (P ＜ 0.05 or 0.01).The pathological changes of the liver were severe in LHS and NS groups and attenuated in SAHA group.Conclusion Administration of SAHA in early shock can significantly protect the liver after lethal hemorrhage in rats first entering high altitude,and increased acetylation of H3K9 and inhibition of the JNK/caspase-3 apoptotic pathway in liver tissues are involved in the mechanism.

Objective To evaluate the role of haeme oxygenase-1 (HO-1) in remote limb ischemic preconditioning (RLIP)-induced attenuation of lung ischemia-reperfusion (I/R) injury in rabbits.Methods Twenty-four Japanese White Rabbits,aged 4-5 months,weighing 2.0-2.5 kg,were randomly divided into 4 groups (n =6 each) using a random number table:sham operation group (S group),I/R group,RLIP group and zinc protoporphyrin (ZnPP,an inhibitor of HO-1) plus RLIP group (ZnPP + RLIP group).Lung I/R was produced by 60 min occlusion of the left lung hilum followed by 180 min of reperfusion in I/R,RLIP and ZnPP + RLIP groups.RLIP and ZnPP + RLIP groups received 3 cycles of 10 min ischemia followed by 10 min reperfusion in the bilateral hind limbs immediately before occlusion of the left lung hilum.In ZnPP + RLIP group,ZnPP 10 μmol/kg was injected intravenously 10 min prior to hind limb ischemia and the rest of the procedures were similar to those previously described in RLIP group.At the end of reperfusion,arterial blood samples were collected for blood gas analysis.The animals were then sacrificed and pulmonary specimens were obtained for microscopic examination of the pathological changes which were scored (lung injury score,LIS) and for determination of wet/dry lung weight ratio (W/D ratio),myleoperoxidase (MPO) activity,malondialdehyde (MDA) content and expression and activity of HO-1 in the lung tissues.Results Compared with group S,PaO2 was significantly decreased,and LIS,W/D ratio,MPO activity,MDA content,and HO-1 expression and activity were increased in I/R group (P ＜ 0.01).Compared with I/R group,PaO2 and HO-1 expression and activity were significantly increased,and LIS,W/D ratio,MPO activity and MDA content were decreased in RLIP group (P ＜ 0.01).Compared with RLIP group,PaO2 and HO-1 expression and activity were significantly decreased,and LIS,W/D ratio,MPO activity and MDA content were increased in ZnPP + RLIP group (P ＜ 0.01).Conclusion RLIP up-regulates HO-1 expression and enhances HO-1 activity,thus reducing lung I/R injury in rabbits.

AIM: To investigate the effects of rosiglitazone(ROSI),an agonist of peroxisome proliferator-activated receptor ?(PPAR?),on the lung expression of intercellular adhesion molecule-1(ICAM-1) and cytokine-induced neutrophil chemoattractant(CINC) in rats with acute lung injury. METHODS: Thirty-six male Wistar rats were randomly divided into six groups: control group,ROSI group,GW9662(a PPAR? antagonist) group,lipopolysaccharide(LPS,6 mg/kg,iv) group,ROSI-LPS group(0.3 mg/kg ROSI iv 30 min prior to LPS) and GW9662-ROSI-LPS group(0.3 mg/kg GW9662,iv,20 min before ROSI).Four hours after LPS injection,wet/dry weight(W/D) ratio,myeloperoxidase (MPO) activity,malondialdehyde(MDA) and CINC-1 concentrations were assayed in the lung tissues.Immunohistochemical analysis of ICAM-1 expression was also studied.RESULTS: Pretreatment with ROSI significantly attenuated LPS-induced increases in W/D ratio,MPO activity,MDA and CINC-1 concentrations as well as ICAM-1 expression in the lung tissues.The specific PPAR? antagonist GW9662 antagonized the effects of ROSI.CONCLUSION: Pretreatment with ROSI reduces LPS-induced lung injury in rats.The mechanism involves inhibition of the lung expression of ICAM-1 and CINC-1 by the activation of PPAR?.

Objective To investigate the effects of remote preconditioning on inflammatory cytokines and respiratory index of rabbit lung injured by ischemia/reperfusion.Methods Eighteen rabbits were randomly divided into three groups(6 each):control group(C),ischemia-reperfusion group(I/R)and remote preconditioning group(R).The plasma concentrations of interleukin-6(IL-6),tumor necrosis factor-?(TNF-?)and interleukin-10(IL-10)were measured before ischemia and 60,120 and 180 min after reperfusion.Respiratory index(A-aO2/PaO2)was calculated before ischemia and 15,30,60,120 and 180 min after reperfusion.The animals were sacrificed after reperfusion,and the left lung was removed for calculation of wet/dry(W/D)ratio and lung permeability index,histological examination was done with light microscope,and diffuse alveolar damage(DAD)scores was estimated.Results The plasma concentrations of IL-6 and TNF-? were significantly higher in I/R group than in C group(P

Objective To explore the neuroprotective effect of repeated preconditioning with cannabinoid receptor agonist WIN 55,212-2 on focal cerebral ischemia-reperfusion injury in rats.Methods Focal cerebral ischemia was induced by middle cerebral artery occlusion(MCAO)for 120min.Fifty male SD rats were randomly assigned to five groups(10 each):rats in control group and dimethyl sulphoxide group(DMSO group)were intraperitoneally administered 0.3ml normal saline and 0.3ml DMSO once a day for 5 days.Rats in WIN 55,212-2 preconditioning groups(including WIN1,WIN3 and WIN5 group)received intraperitoneal injection of 1mg/kg WIN 55,212-2(dissolved with 0.3ml DMSO)once a day for 1d,3d and 5d,respectively.All animals underwent MCAO operation 24h after last pretreatment to reproduce temporal(120min)focal cerebral ischemia model.The neurological function score(NFS)was evaluated at 24,48 and 72h after reperfusion.Brain infarct was identified with 2% 2,3,5-triphenyltetrazolium chloride(TTC)staining 72h after reperfusion,and the brain infarct volume was expressed as percentage of normal cerebral hemisphere volume.Results The NFSs of rats in WIN 55,212-2 preconditioning groups(WIN1,WIN3 and WIN5 group)were significantly higher,and the infarct volumes were significantly smaller than that in control group and DMSO group at 24h,48h and 72h after reperfusion(P0.05).Conclusion The neuroprotective effect of repeated preconditioning with cannabinoid receptor agonist WIN 55,212-2 may be enhanced by increased time of pretreatment.

Objective To investigate the role of astroglial glutamate-glutamine shuttle in the development of neuropathic pain (NP) in rats. Methods Forty-eight adult male SD rats weighing 200-230 g were randomly divided into 8 groups (n =6 each): Ⅰ control group (group C);Ⅱ sham operation group (group S);group ⅢNP;Ⅳ-Ⅶ 0.01, 0.03, 0.05 and 0.10 mmol/L methionine sulfoximine (MSO, an inhibitor of glutamine synthetase (GS)) group (group M1-4 );Ⅷ MSO + glutaminate group (group MG). In group C no operation was performed. In group S the sciatic nerve was only exposed but not ligated. NP was induced by ligation of the tibial nerve and commom peroneal nerve according to the technique described by Dixon. After the establishment of the model, intrathecal PBS 50 μl was injected in group NP, IT 0.01, 0.03, 0.05 and 0.10 mmol/L MSO 50 μl was injected intrathecally in group M1-4, and 0.05 mmol/L MSO 50 μl was injected intrathecally and then 0.25 mmol/L glutamine 50 μl was injected intrathecally 15 min later in group MG. Mechanical pain threshold was measured 1 week before ligation (T0 , baseline), 1 week after ligation (T1) and 15, 30, 45 and 60 min after injection of MSO (T2-5). Then rats were killed and the lumbar segment of the spinal cord was removed for determination of the expression of glial fibrillary acidic protein (GFAP) and GS and the co-expression (GFAP/GS) in the dorsal horn.Results Mechanical pain threshold was significantly lower at T1-5 in group MG and NP and at T2-4 in group M3.4 ,and the expression of GFAP, GS and GFAP/GS was significantly higher in group MG,NP and M3 than in group S and C ( P ＜ 0.05) .Conclusion Astroglial glutamate-glutamine shuttle in the spinal cord is involved in the development of neuropathic pain in rats.

Objective To investigate the analgesic efficacy of ultrasound?guided adductor canal blockade (ACB)after minor arthroscopic knee surgery. Methods Sixty patients undergone minor arthroscopic knee surgery were randomly divided into group ACB(n=20)and group Control(n=20). All patients received spinal anesthesia. The patients in group ACB received ultrasound?gGuided ACB with 20 ml 0.5% ropivacaine,and patients in group Control received 20 ml saline after the surgery. In addition ,all patients have a basic analgesic regimen with etoricoxib. Visual analogue scales(VAS) during rest and passive movement ,additional analgesic dose and side effects were recorded at 4,8,12,24 h Post?operation. At 24 h post?operation,the numbers of patients who can walk for 5 meters were recorded. Results VAS during rest and movement at 4 h,8 h and 12 h post?operation in group ACB were significantly lower than those in group Control. And all patients could walk 5m at 24 h post?operation. No headache,nausea and vomiting,urinary retention and other adverse reactions were observed in group ACB. There were four patients who received additional analgesic and one patient vomitted. Conclusions Significant analgesic effect of the ACB could be detected after minor arthroscopic knee surgery ,with less reduction in requirements for supplemental opioids.