Valdés-Ferrer Sergio I, Papoin Julien, Dancho Meghan E, Olofsson Peder S, Li Jianhua, Lipton Jeffrey M, Avancena Patricia, Yang Huan, Zou Yong-Rui, Chavan Sangeeta S, Volpe Bruce T, Gardenghi Sara, Rivella Stefano, Diamond Betty, Andersson Ulf, Steinberg Bettie M, Blanc Lionel, Tracey Kevin J
Elmezzi Graduate School of Molecular Medicine, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
Mol Med. 2016 May;21(1):951-958. doi: 10.2119/molmed.2015.00243. Epub 2015 Dec 29.
Patients surviving sepsis develop anemia, but the molecular mechanism is unknown. Here we observed that mice surviving polymicrobial gram-negative sepsis develop hypochromic, microcytic anemia with reticulocytosis. The bone marrow of sepsis survivors accumulates polychromatophilic and orthochromatic erythroblasts. Compensatory extramedullary erythropoiesis in the spleen is defective during terminal differentiation. Circulating tumor necrosis factor (TNF) and interleukin (IL)-6 are elevated for 5 d after the onset of sepsis, and serum high-mobility group box 1 (HMGB1) levels are increased from d 7 until at least d 28. Administration of recombinant HMGB1 to healthy mice mediates anemia with extramedullary erythropoiesis and significantly elevated reticulocyte counts. Moreover, administration of anti-HMGB1 monoclonal antibodies after sepsis significantly ameliorates the development of anemia (hematocrit 48.5 ± 9.0% versus 37.4 ± 6.1%, p < 0.01; hemoglobin 14.0 ± 1.7 versus 11.7 ± 1.2 g/dL, p < 0.01). Together, these results indicate that HMGB1 mediates anemia by interfering with erythropoiesis, suggesting a potential therapeutic strategy for anemia in sepsis.
脓毒症幸存者会出现贫血，但分子机制尚不清楚。在此我们观察到，多重微生物革兰氏阴性脓毒症存活小鼠会出现低色素性、小细胞性贫血并伴有网织红细胞增多。脓毒症幸存者的骨髓中会积聚多染性和正染性成红细胞。在终末分化过程中，脾脏中的代偿性髓外造血存在缺陷。脓毒症发作后5天，循环肿瘤坏死因子（TNF）和白细胞介素（IL）-6水平升高，血清高迁移率族蛋白B1（HMGB1）水平从第7天开始升高，至少持续到第28天。给健康小鼠注射重组HMGB1会导致伴有髓外造血的贫血，并使网织红细胞计数显著升高。此外，脓毒症发作后注射抗HMGB1单克隆抗体可显著改善贫血的发展（血细胞比容48.5±9.0%对37.4±6.1%，p<0.01；血红蛋白14.0±1.7对11.7±1.2 g/dL，p<0.01）。总之，这些结果表明HMGB1通过干扰红细胞生成来介导贫血，提示脓毒症贫血可能的治疗策略。
