Strong V E, Mackrell P J, Concannon E M, Naama H A, Schaefer P A, Shaftan G W, Stapleton P P, Daly J M
Department of Surgery, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York 10021, USA.
Shock. 2000 Sep;14(3):374-9. doi: 10.1097/00024382-200014030-00023.
Major injury leads to impaired immune responses and increases the risk of infectious complications. Following trauma, increased prostaglandin E2 (PGE2) levels may be important in immunodysregulation. We hypothesized that blocking PGE2 with NS-398, a selective COX-2 inhibitor, during the first 24 h after injury may modify the immune response and protect the host from a subsequent septic challenge. BALB/c mice were given NS-398 (10 mg/kg) immediately after injury, at 12, and at 24 h after sham injury or trauma (femur fracture and 40% hemorrhage). On day 7 after injury, splenic macrophages were evaluated for cytokine production and COX-2 mRNA. In a separate study mice were injured, then given 3 doses of NS-398. After 7 days, cecal ligation and puncture was performed and mice were followed for survival. Traumatized mice given NS-398 had a significant survival advantage compared with trauma mice alone (P < 0.001). Macrophages from traumatized mice showed increased COX-2 mRNA and proinflammatory cytokines compared with controls (P < 0.05), whereas treatment of injured mice with NS-398 significantly decreased proinflammatory cytokine production (P < 0.05) and COX-2 mRNA. Therefore NS-398 given within 24 h of injury suppressed PGE2 through inhibition of cyclooxygenase, in addition to decreasing proinflammatory cytokines, and providing a survival advantage to the host.
严重损伤会导致免疫反应受损，并增加感染性并发症的风险。创伤后，前列腺素E2（PGE2）水平升高可能在免疫失调中起重要作用。我们假设，在损伤后的最初24小时内，用选择性环氧化酶-2（COX-2）抑制剂NS-398阻断PGE2，可能会改变免疫反应，并保护宿主免受随后的脓毒症攻击。对BALB/c小鼠在假手术或创伤（股骨骨折和40%出血）后立即、12小时和24小时给予NS-398（10毫克/千克）。在损伤后第7天，评估脾巨噬细胞的细胞因子产生和COX-2 mRNA水平。在另一项研究中，小鼠先受伤，然后给予3剂NS-398。7天后，进行盲肠结扎和穿刺，并观察小鼠的存活情况。与仅受创伤的小鼠相比，给予NS-398的创伤小鼠具有显著的生存优势（P<0.001）。与对照组相比，受创伤小鼠的巨噬细胞显示COX-2 mRNA和促炎细胞因子增加（P<0.05），而用NS-398治疗受伤小鼠可显著降低促炎细胞因子的产生（P<0.05）和COX-2 mRNA水平。因此，在损伤后24小时内给予NS-398，除了减少促炎细胞因子并为宿主提供生存优势外，还通过抑制环氧化酶抑制了PGE2。
