| Objective Sepsis is a systemic inflammatory response to infection, which is the most common cause of death in intensive care units[1-3]. Studies suggested that intestinal barrier dysfunction and increased intestinal permeability are morbid states that often accompany developing of sepsis. Increased intestinal permeability may contribute to bacterial translocation and the development of multiple organ failure. Intestinal barrier function has become an important indicator to determine the prognosis of critically ill patients, the intestinal tract is not only the multiple organ dysfunction(MODS) of the target organ, but also the start of MODS. Therefore, research on the prevention and controlling of intestinal barrier function from failure has become an important topic in current field of medicine.Parecoxib, a non-steroidal anti-inflammatory drugs(NSAIDs), which is a cyclooxygenase-2 specific inhibitor can be injected by intravenous or intramuscular. It is hydrolyzed into valdecoxib by carboxylesterase in liver. The specific inhibition of cyclooxygenase-2 exert anti-inflammatory and analgesic effect by blocking the prostaglandins production. High levels of prostanoids damage the gut barrier, inhibition of prostanoid production may seem an obvious treatment strategy. Cyclooxygenase-2 inhibitors have been reported to protect the intestinal barrier by inhibition of prostanoid production.This study was designed to investigate the protective effects of parecoxib and molecular mechanisms in rats model of sepsis.Methods Part 1:Cecal ligation and puncture procedure(CLP) was applied to induce sepsis. 72 Wistar rats were randomly dividedinto 6 groups(n=12/ each group): Sham, Sham+10mg/kg parecoxib, CLP, CLP+0.1mg/kg parecoxib, CLP+1.0mg/kg parecoxib, CLP +10mg/kg parecoxib. Different dose of parecoxib was given. Rats were injected parecoxib by intraperitoneal at 20 min after CLP or sham operation, twice a day. Observed the survival rate 1 day、2 day、3 day、5 day and 7 day after CLP or sham operation. The intestine damage was measured. Furthermore, the changes of DAO and D-lactate reflecting intestinal permeability were detected and the activity level of intestinal tissue myeloperoxidase(MPO) was measured. The expression of intestinal tight junction protein including Claudin-1and ZO-1were detected.Part 2: Sepsis was induced by cecal ligation and puncture(CLP). 32 Wistar rats were randomly assigned to 4 groups(n=8/ each group): Sham, Sham+10mg/kg parecoxib, CLP, CLP +10mg/kg parecoxib. Rats were injected parecoxib by intraperitoneal at 20 min after CLP or sham operation, twice a day. The changes of hemodynamics and blood gas were measured. Moreover, the mesenteric microcirculation(including perfused vessel density, total vessel density, proportion of perfused and microcirculation flow index) of rats with sepsis were detected after CLP or sham operation.Part 3:Cecal ligation and puncture was adopted to induce sepsis. 48 Wistar rats were randomly assigned to 6 groups(n=8/ each group): Sham, Sham+10mg/kg parecoxib, CLP, CLP +10mg/kg parecoxib, CLP+NS-398,CLP+NS-398+parecoxib. CLP+NS-398 and CLP+NS-398+parecoxib were injected NS-398 10mg/kg intraperitoneal 2h before operation. The level of tumor necrosis factor α [TNF-α], anti-inflammatory cytokine interleukin-6 [IL-6] and pro-inflammatory cytokine interleukin-10 [IL-10] in serum and intestinal tissue were measured. In addition, the expression of prostanoid E2,m PGES-1(microsomal prostaglandin E synthase 1) and EP4(E-prostanoid receptor 4) were detected.Results Part 1:Intraperitoneal injection 10mg/kg Parecoxib sodium can effectively improve the survival rate of rats with sepsis(P <0.05);Parecoxib treatment reduced the activity of myeloperoxidase(MPO) in intestinal tissue, decreased the plasma level of DAO and D-lactate, andattenuated the damage of the intestinal tissuesignificantly(P<0.05); Parecoxib upregulated the expression of ZO-1 and Claudin-1protein which may be associated with maintaining the intestinal barrier function(P<0.05).Part 2: Parecoxib treatment markedly improved the hemodynamics in rat with sepsis(P <0.05); Parecoxib treatment could significantly improve the arterial blood gas and reduce the level of serum lactate in rats with sepsis(P <0.05); Parecoxib treatment could markedly improve the mesenteric microcirculation and increase the total vascular density and perfusion vascular density and microcirculation blood flow index in rats with sepsis(P <0.05).Part 3:Parecoxib treatment improved the intestinal barrier function might be associated with the decreased levels of pro-inflammatory cytokines(TNF-α and IL-6) and the increased level of anti-inflammatory cytokine(IL-10) in serum and tissue(P <0.05); Parecoxib treatment inhibited the expression of prostanoid E2、m PGES-1 and EP4 as well as the level of m RNA, which may play a protective role in sepsis(P <0.05).Conclusion Parecoxib treatment improves intestine injury,reduces the intestinal mucosal permeability and improves mesenteric microcirculationin rats with sepsis, the mechanism might be associated with inhibiting the prostanoid E2 activation. |
PDF Full Text Request