Costantini Todd W, Peterson Carrie Y, Kroll Lauren, Loomis William H, Putnam James G, Wolf Paul, Eliceiri Brian P, Baird Andrew, Bansal Vishal, Coimbra Raul
Division of Trauma, Surgical Critical Care, and Burns, Department of Surgery, University of California-San Diego School of Medicine, San Diego, California, USA.
J Trauma. 2009 Dec;67(6):1162-8. doi: 10.1097/TA.0b013e3181ba3577.
Intestinal barrier breakdown after severe burn can lead to intestinal inflammation, which may act as the source of the systemic inflammatory response. In vitro intestinal cell studies have shown that mitogen-activated protein kinase (MAPK) signaling is an important modulator of intestinal inflammation. We have previously observed that pentoxifylline (PTX) attenuates burn-induced intestinal permeability and tight junction breakdown. We hypothesized that PTX would limit intestinal barrier breakdown and attenuate inflammatory signaling via the MAPK pathway.
Male balb/c mice underwent 30% total body surface area full-thickness steam burn. Immediately after burn, animals received an intraperitoneal injection of PTX (12.5 mg/kg) in normal saline or normal saline alone. In vivo intestinal permeability to 4 kDa fluorescein isothiocyanate-dextran was measured. Intestinal extracts were obtained to measure interleukin-6 by enzyme-linked immunosorbent assay, and phosphorylated p38 MAPK, p38 MAPK, phosphorylated extracellular signal-related kinase (1/2) (ERK (1/2)), and ERK (1/2) by immunoblotting. Acute lung injury was assessed by histology at 24 hours after burn.
Administration of PTX immediately after injury attenuated burn-induced intestinal permeability. PTX also decreased the burn-induced phosphorylation of p38 MAPK and decreased phosphorylation of ERK (1/2) at 2 hours and 24 hours after injury. Animals given PTX had decreased intestinal interleukin-6 levels. A single dose of PTX also decreased histologic lung injury at 24 hours after burn.
PTX attenuates burn-induced intestinal permeability and subsequent intestinal inflammation. Use of PTX after burn was also associated with decreased acute lung injury. Because of its compelling anti-inflammatory effects, PTX may be an ideal candidate for use as an immunomodulatory adjunct to resuscitation fluid.
严重烧伤后肠道屏障破坏可导致肠道炎症，这可能是全身炎症反应的来源。体外肠道细胞研究表明，丝裂原活化蛋白激酶（MAPK）信号传导是肠道炎症的重要调节因子。我们之前观察到己酮可可碱（PTX）可减轻烧伤诱导的肠道通透性和紧密连接破坏。我们推测PTX会限制肠道屏障破坏并通过MAPK途径减轻炎症信号传导。
雄性balb/c小鼠接受30%体表面积的全层蒸汽烧伤。烧伤后立即给动物腹腔注射溶于生理盐水的PTX（12.5mg/kg）或仅注射生理盐水。测量体内肠道对4kDa异硫氰酸荧光素葡聚糖的通透性。获取肠道提取物，通过酶联免疫吸附测定法测量白细胞介素-6，并通过免疫印迹法测量磷酸化p38 MAPK、p38 MAPK、磷酸化细胞外信号调节激酶（1/2）（ERK（1/2））和ERK（1/2）。在烧伤后24小时通过组织学评估急性肺损伤。
损伤后立即给予PTX可减轻烧伤诱导的肠道通透性。PTX还降低了烧伤诱导的p38 MAPK磷酸化，并在损伤后2小时和24小时降低了ERK（1/2）的磷酸化。给予PTX的动物肠道白细胞介素-6水平降低。单次给予PTX还可减轻烧伤后24小时的组织学肺损伤。
PTX可减轻烧伤诱导的肠道通透性及随后的肠道炎症。烧伤后使用PTX还与急性肺损伤减轻有关。由于其显著的抗炎作用，PTX可能是用作复苏液免疫调节辅助药物的理想候选物。
