Metabolic Response of Macrophages to Injury Promoted by the Activated Complement System R. F. P. BACURAU, 1 P. I. HOMEM DE BITTENCOURT JR., 2 P. NEWSHOLME 3 AND L. F. B. P. COSTA ROSA 1 * 1 Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, SP, Brazil 2 Department of Physiology, Federal University of Rio Grande do Sul, RS, Brazil 3 Department of Biochemistry, University College Dublin, Bel®eld, Dublin 4, Ireland In nucleated cells, the swelling promoted by a complement system (CS) attack is not enough to promote cell death, because unlike erythrocytes these cells are able to eliminate cytolytic complement channels from the plasma membrane, by processesthat include endocytosis. Several studies have demonstrated that the resistance of nucleated cellsto the injury promoted by the CS is related to the cellular metabolism. Despite this, to the present day, no study has clearly related cell survival capacity to injury by the CS to its energetic metabolic status. In macrophages, the challenge imposed by the CS provoked an increase in the total amount of glucose incorporated into fatty acids, including phospholipids and cholesterol; substrates for membrane synthesis. The inhibition of cholesterol synthesis promoted an increase of the cell death rate. These data support the importance of cholesterol metabolism for macrophage resistance to necrosis induced by the activated complement system. Copyright # 1999 John Wiley & Sons, Ltd. KEY WORDS Ð macrophage; metabolism; cholesterol; necrosis ABBREVIATIONS Ð ZAS, zymosan activated serum; MAC, membrane attack complex; Glc, glucose; Gln, glutamine; Pyr, pyruvate INTRODUCTION The ®rst studies concerning the promotion of cell death by the complement system (CS) indicated that the eect was due to an increase in membrane permeability on the target cell. In anucleated cells, the membrane attack complex (MAC) is able to induce cell death through the promotion of ionic instability leading to disruption of cell function and consequent death. Later studies showed that in nucleated cells, swelling is not enough to promote cell death and that the cell response to injury is related to its metabolic condition. 1 The injury promoted by CS can be divided into three distinct phases. The ®rst phase is an immediate increase in intracellular calcium through the opening of a channel sensitive to nifedipine, 2 in the second phase the leak of ATP and its precursors through transmembrane channels occurs, leading to the third phase in which the cellular membrane no longer acts as an osmotic barrier, therefore losing its selectivity. According to results obtained in studies with dierent types of injury, the mechanism of CS- induced cell death emphasizes the importance of cellular metabolism in the response to injury. Therefore, the capacity for macromolecule syn- thesis (e.g., lipids and proteins), and the incorpora- tion of such molecules in plasma membranes is a pivotal feature in the resistance of nucleated cells to injury promoted by the CS. Other factors such as the maintenance of adequate cAMP levels, 3 calcium and zinc, 4 inositol phosphate and kinase concentration, 5,6 as well as the capacity to synthe- sise high molecular weight proteins 7 seem also to be very important in avoiding cell death in the presence of activated MAC. However, the under- standing of the mechanisms of MAC-induced cell CCC 0263±6484/99/030175±08$17 . 50 Received 20 August 1998 Copyright # 1999 John Wiley & Sons, Ltd. Accepted 25 January 1999 CELL BIOCHEMISTRY AND FUNCTION Cell Biochem. Funct. 17, 175±182 (1999) *Correspondence to: Luis F. B. P. Costa Rosa, Departamento de Histologia e Embriologia, Instituto de CieÃncias BiomeÂdicas I, Universidade de SaÁo Paulo, Av. Lineu Prestes, 1524, 05508- 900, ButanaÁ, SaÁo Paulo, SP, Brasil. Contract grant sponsor: FAPESP. Contract grant no: 95/3117-6.