Dalli Jesmond, Kraft Bryan D, Colas Romain A, Shinohara Masakazu, Fredenburgh Laura E, Hess Dean R, Chiang Nan, Welty-Wolf Karen, Choi Augustine M, Piantadosi Claude A, Serhan Charles N
1 Department of Anesthesiology, Perioperative and Pain Medicine, and.
2 Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham, North Carolina.
Am J Respir Cell Mol Biol. 2015 Sep;53(3):314-25. doi: 10.1165/rcmb.2014-0299OC.
Strategies for the treatment of bacterial pneumonia beyond traditional antimicrobial therapy have been limited. The recently discovered novel genus of lipid mediators, coined "specialized proresolving mediators" (SPMs), which orchestrate clearance of recruited leukocytes and restore epithelial barrier integrity, have offered new insight into the resolution of inflammation. We performed lipid mediator (LM) metabololipidomic profiling and identification of LMs on peripheral blood leukocytes and plasma from a baboon model of Streptococcus pneumoniae pneumonia. Leukocytes and plasma were isolated from whole blood of S. pneumoniae-infected (n = 5-6 per time point) and control, uninfected baboons (n = 4 per time point) at 0, 24, 48, and 168 hours. In a subset of baboons with pneumonia (n = 3), we administered inhaled carbon monoxide (CO) at 48 hours (200-300 ppm for 60-90 min). Unstimulated leukocytes from control animals produced a proresolving LM signature with elevated resolvins and lipoxins. In contrast, serum-treated, zymosan-stimulated leukocytes and leukocytes from baboons with S. pneumoniae pneumonia produced a proinflammatory LM signature profile with elevated leukotriene B4 and prostaglandins. Plasma from baboons with S. pneumoniae pneumonia also displayed significantly reduced LM-SPM levels, including eicosapentaenoic acid-derived E-series resolvins (RvE) and lipoxins. CO inhalation increased levels of plasma RvE and lipoxins relative to preexposure levels. These results establish the leukocyte and plasma LM profiles biosynthesized during S. pneumoniae pneumonia in baboons and provide evidence for pneumonia-induced dysregulation of these proresolution programs. Moreover, these SPM profiles are partially restored with inhaled low-dose CO and SPM, which may shorten the time to pneumonia resolution.
除传统抗菌治疗外，细菌性肺炎的治疗策略一直有限。最近发现的一类新的脂质介质，即“特殊促消退介质”（SPM），可协调募集的白细胞清除并恢复上皮屏障完整性，为炎症消退提供了新的见解。我们对肺炎链球菌肺炎狒狒模型的外周血白细胞和血浆进行了脂质介质（LM）代谢脂质组学分析和LM鉴定。在0、24、48和168小时从感染肺炎链球菌的狒狒（每个时间点n = 5 - 6）和对照未感染狒狒（每个时间点n = 4）的全血中分离白细胞和血浆。在一部分患有肺炎的狒狒（n = 3）中，我们在48小时给予吸入一氧化碳（CO）（200 - 300 ppm，持续60 - 90分钟）。来自对照动物的未刺激白细胞产生具有升高的消退素和脂氧素的促消退LM特征。相比之下，血清处理的、酵母聚糖刺激的白细胞以及患有肺炎链球菌肺炎的狒狒的白细胞产生具有升高的白三烯B4和前列腺素的促炎LM特征谱。患有肺炎链球菌肺炎的狒狒的血浆中LM - SPM水平也显著降低，包括二十碳五烯酸衍生的E系列消退素（RvE）和脂氧素。与暴露前水平相比，吸入CO可增加血浆RvE和脂氧素水平。这些结果确定了狒狒肺炎链球菌肺炎期间生物合成的白细胞和血浆LM谱，并为肺炎诱导的这些促消退程序失调提供了证据。此外，这些SPM谱通过吸入低剂量CO和SPM部分恢复，这可能缩短肺炎消退时间。
