Transient changes in erythrocyte membrane permeability are induced by sublytic amounts of the complement membrane attack complex (C5b-9)

Abstract

We have previously shown that sublytic heterologous complement induces large but transient increases in erythrocyte membrane permeability. We now report that when erythrocytes are bystanders in zymosan-activated autologous serum, they increase their Na+ permeability 10-fold, indicating that autologous complement can also induce transient membrane lesions. When we isolated the effect of the C5b-9 membrane attack complex of complement by using human C5b-9 assembled from purified components, we found there was minimal lysis but efficient Na+ uptake. Suspension of the sublytically damaged erythrocytes in K+ medium caused the cells to lyse, which is consistent with the cells recruiting a compensatory K+ efflux similar to that observed when human erythrocytes were exposed to heterologous complement. Sublytic C5b-9 exposure also became lytic when extracellular Ca2+ was limited and when the cells were exposed to charybdotoxin, an inhibitor of the Ca(2+)- activated K+ channel. This indicates that Ca2+ is required for the functional termination of the C5b-9 lesion. We also show that the membrane hyperpolarization resulting from activation of the Ca(2+)- dependent K+ efflux does not influence the termination of the C5b-9 lesion. Thus, the influx of Ca2+ through the complement lesion initiates at least two apparently independent adaptive responses: (1) a process that terminates the leak; and (2) a K+ efflux that has a volume regulatory function. Our data support the potential of the sublytic C5b- 9 lesion to act as a physiologic mediator for autologous erythrocytes.

Experimental murine acid aspiration injury is mediated by neutrophils and the alternative complement pathway

“…Third, C activation can directly damage cells by formation of the membrane attack complex (C5b-9), which is a porelike structure that inserts itself into plasma membranes and allows indiscriminate movement of water and ions such as calcium. This results in a membrane perturbation, resulting in second messenger signaling, enzyme activation, and possible osmotic lysis (12). To study whether C acts through PMN recruitment/activation or independently by direct injury to cells, we inhibited C activation with sCR1 in neutropenic mice.…”

Skeletal muscle reperfusion injury is mediated by neutrophils and the complement membrane attack complex

“…Second, covalently deposited iC3b on endothelial cell membranes acts as a chemoactivator signaling for a neutrophil oxidative burst via CD11b (12). Third, integration of the membrane attack complex C5b-9 into the endothelial cell membrane can act as a pore, leading to unchecked ion flux, which in turn could lead to second messenger signaling, enzyme (4,19). This possibility is supported by evidence showing deposition of the C5b-9 membrane attack complex in infarcted regions of human myocardium as well as reperfused areas of gut and skeletal muscle following experimental rat gut and hindlimb ischemia, respectively (3,7,25).…”

Deficiency of the Mouse Complement Regulatory Protein mCd59b Results in Spontaneous Hemolytic Anemia with Platelet Activation and Progressive Male Infertility

“…The MAC pore can also open trantivation comparable to the hemolytic anemia seen in siently, generating significant but non-lytic changes in patients with PNH (for this reason we also call these the cell membrane permeability, and release of some features in mCd59b Ϫ/Ϫ mice a PNH-like phenotype). In intracellular cytokines of molecular weight Ͻ20-30 kd addition, mCd59b Ϫ/Ϫ , which initially are normally fertile, such as bFGF or IL-1 (Acosta et al, 1996; Benzaquen progressively lose their fertility; this acquired infertility et al, 1994; Halperin et al, 1993aHalperin et al, , 1993bShankland et is associated with intriguing sperm cell abnormalities including decreased number, abnormal shape, and loss of mobility. Together, the hemolytic anemia and the ac- quired reproductive problems observed in mCd59b Ϫ/Ϫ resulted in mCd59 ϩ/Ϫ mice (Figure 1B).…”