气候变化领域集成服务门户(CCPortal): Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons

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DOI	10.1073/pnas.2104347118
	Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons
	Keshari R.S.; Popescu N.I.; Silasi R.; Regmi G.; Lupu C.; Simmons J.H.; Ricardo A.; Mark Coggeshall K.; Lupu F.
发表日期	2021
ISSN	0027-8424
卷号	118 期号:37
英文摘要	Late-stage anthrax infections are characterized by dysregulated immune responses and hematogenous spread of Bacillus anthracis, leading to extreme bacteremia, sepsis, multiple organ failure, and, ultimately, death. Despite the bacterium being nonhemolytic, some fulminant anthrax patients develop a secondary atypical hemolytic uremic syndrome (aHUS) through unknown mechanisms. We recapitulated the pathology in baboons challenged with cell wall peptidoglycan (PGN), a polymeric, pathogen-associated molecular pattern responsible for the hemostatic dysregulation in anthrax sepsis. Similar to aHUS anthrax patients, PGN induces an initial hematocrit elevation followed by progressive hemolytic anemia and associated renal failure. Etiologically, PGN induces erythrolysis through direct excessive activation of all three complement pathways. Blunting terminal complement activation with a C5 neutralizing peptide prevented the progressive deposition of membrane attack complexes on red blood cells (RBC) and subsequent intravascular hemolysis, heme cytotoxicity, and acute kidney injury. Importantly, C5 neutralization did not prevent immune recognition of PGN and shifted the systemic inflammatory responses, consistent with improved survival in sepsis. Whereas PGN-induced hemostatic dysregulation was unchanged, C5 inhibition augmented fibrinolysis and improved the thromboischemic resolution. Overall, our study identifies PGN-driven complement activation as the pathologic mechanism underlying hemolytic anemia in anthrax and likely other grampositive infections in which PGN is abundantly represented. Neutralization of terminal complement reactions reduces the hemolytic uremic pathology induced by PGN and could alleviate heme cytotoxicity and its associated kidney failure in gram-positive infections. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Acute kidney injury; Anthrax; Complement; Hemolysis; Peptidoglycan
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/238799
作者单位	Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States; Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, United States; Michale E. Keeling Center for Comparative Medicine and Research, University of Texas MD Anderson Cancer Center, Bastrop, TX 78602, United States; Ra Pharmaceuticals Inc., Cambridge, MA 02140, United States; Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States; Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, United States
推荐引用方式 GB/T 7714	Keshari R.S.,Popescu N.I.,Silasi R.,et al. Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons[J],2021,118(37).
APA	Keshari R.S..,Popescu N.I..,Silasi R..,Regmi G..,Lupu C..,...&Lupu F..(2021).Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons.Proceedings of the National Academy of Sciences of the United States of America,118(37).
MLA	Keshari R.S.,et al."Complement C5 inhibition protects against hemolytic anemia and acute kidney injury in anthrax peptidoglycan-induced sepsis in baboons".Proceedings of the National Academy of Sciences of the United States of America 118.37(2021).