Cigarette smoke can activate the alternative pathway of complement in vitro by modifying the third component of complement.
Cigarette smoking is associated with significant increases in the number of pulmonary mononuclear phagocytes and neutrophils. A potent chemoattractant for these cells is C5a, a peptide generated during complement (C) activation. We, therefore, investigated the possibility that cigarette smoke could activate the complement system in vitro. Our results show that factor(s) (mol wt less than 1,000) present in an aqueous solution of whole, unfiltered cigarette smoke can deplete the hemolytic capacity of whole human serum in a dose-dependent manner. The particle-free, filtered gas phase of cigarette smoke is inactive. The smoke factor(s) do not activate serum C1, but do deplete serum C4 activity. Treatment of purified human C3 with whole smoke solution modifies the molecule such that its subsequent addition to serum (containing Mg/EGTA to block the classical pathway) results in consumption of hemolytic complement by activation of the alternative pathway. Smoke-modified C3 shows increased anodal migration in agarose electrophoresis, but this is not due to proteolytic cleavage of the molecule as evidenced by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In contrast to methylamine-treated C3, C3 treated with smoke is only partially susceptible to the action of the complement regulatory proteins Factors H and I. In addition, smoke-modified C3 has diminished binding to Factor H as compared with methylamine-treated C3. Finally, smoke-modified C3 incorporates [14C]methylamine which suggests that the thiolester bond may be intact. These data indicate that aqueous whole cigarette smoke solution can modify C3 and activate the alternative pathway of complement, perhaps by a previously unrecognized mechanism. Should this occur in vivo, complement activation might partly account for the extensive pulmonary leukocyte recruitment observed in smokers.
Kew
R R
RR
Ghebrehiwet
B
B
Janoff
A
A
D003167:Complement Activation; D003172:Complement C1 / Q000378:metabolism; D003176:Complement C3 / Q000276:immunology / Q000378:metabolism*; D003180:Complement C3b Inactivator Proteins / Q000378:metabolism / Q000494:pharmacology; D003181:Complement C4 / Q000378:metabolism; D017242:Complement Factor H; D017244:Complement Factor I; D003170:Complement Pathway, Alternative; D010450:Endopeptidases / Q000494:pharmacology; D006461:Hemolysis; D006801:Humans; D066298:In Vitro Techniques; D007460:Iodoacetamide / Q000378:metabolism; D008744:Methylamines / Q000378:metabolism; D011485:Protein Binding; D012907:Smoking; D012996:Solutions
C493495:CFH protein, human; D003172:Complement C1; D003176:Complement C3; D003180:Complement C3b Inactivator Proteins; D003181:Complement C4; D008744:Methylamines; D012996:Solutions; D017242:Complement Factor H; C027451:methylamine; D010450:Endopeptidases; D017244:Complement Factor I; D007460:Iodoacetamide