Endotoxin removal by polymyxin B immobilized cartridge inactivates circulating proapoptotic factors.
OBJECTIVE
Severe sepsis and septic shock continue to be major clinical challenges due to high associated mortality. Lipopolysaccharide (LPS) is a component of the cell membrane of Gram-negative bacteria, and is believed to initiate septic-induced signaling, inflammation and organ damage, including acute renal failure. Polymyxin B (PMX-B) hemoperfusion of septic patients can improve survival and decreasing organ dysfunction by removing circulating LPS. Unfortunately, some clinicians have been slow to adopt this novel therapy due to the lack of understanding of the cellular mechanisms involved in this treatment. Apoptosis, or programmed cell death, is known to contribute to acute renal failure and overall organ dysfunction during sepsis, and can be activated by LPS-initiated signaling pathways. Therefore, the protective renal effects associated with PMX-B hemoperfusion of septic patients may result from alterations in cellular apoptosis. This chapter will review recent data regarding the role of apoptosis prevention in the mechanism leading to the improved outcome and decreased acute renal failure associated with PMX-B hemoperfusion during sepsis.


METHODS
Blood was collected, upon inclusion and following 72 h, from conventionally treated patients and patients receiving two PMX-B hemoperfusion treatments. Plasma was subsequently used to stimulate renal tubule cells or glomerular podocytes to assess their ability to induce apoptosis.


RESULTS
All plasma collected upon inclusions, as well as plasma from conventionally treated patients at 72 h, significantly increased apoptosis, while plasma collected from patients following PMX-B treatment induced significantly less apoptosis than time 0 or conventionally treated controls. This decreased proapoptotic signal resulted from decreased extrinsic and intrinsic apoptotic signaling determined by decreased caspase activity, Fas expression and Bax/Bcl-2 balance.


CONCLUSIONS
The protective effects of extracorporeal therapy with PMX-B on the development of acute renal failure result, in part, through its ability to reduce the systemic proapoptotic activity of septic patients on renal cells.
Martin
Erica L
EL
Ranieri
V Marco
VM
D058186:Acute Kidney Injury / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D017209:Apoptosis / Q000187:drug effects; D001775:Blood Circulation; D004731:Endotoxins / Q000097:blood* / Q000302:isolation & purification; D005112:Extracorporeal Circulation / Q000379:methods; D053222:Fas Ligand Protein / Q000502:physiology; D006464:Hemoperfusion / Q000379:methods; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology; D008070:Lipopolysaccharides / Q000097:blood / Q000302:isolation & purification; D011112:Polymyxin B / Q000627:therapeutic use*; D018805:Sepsis / Q000097:blood* / Q000188:drug therapy; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D019014:fas Receptor / Q000502:physiology
D004731:Endotoxins; D053222:Fas Ligand Protein; D008070:Lipopolysaccharides; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D011112:Polymyxin B