Cigarette smoke can activate the alternative pathway of complement in vitro by modifying the third component of complement.

Abstract

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 < 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 ['4Cjmethylamine 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.

Regulated complement deposition on the surface of human endothelial cells: Effect of tobacco smoke and shear stress

“…The present study did not investigate if the observed complement activation was due to tobacco smoke-induced oxidant damage to EC. In addition, given the short half life of the reactive thioester bond in C4b [41], it has not been possible to determine whether the observed increase in EC surface C4d reflects TS induced fluid phase complement activation [14,15] with subsequent binding of C4b to EC surfaces, or enhanced classical pathway complement activation by EC affected by TS. In either case, complement activation on or near EC will contribute to vascular inflammation.…”

“…Cigarette smoke has been described to induce plasma chemotaxins and anaphylatoxins, C3a and C5a [14]. Moreover, Kew et al [15] reported that tobacco smoke extract modifies C3 in vitro, leading to activation of the alternative complement pathway. We postulate that complement activation on altered vascular endothelial cells serves both protective and pathologic functions.…”

A common haplotype in the complement regulatory gene factor H ( HF1/CFH ) predisposes individuals to age-related macular degeneration

“…Cigarette smoke has been shown to activate the alternative complement pathway through the modification of C3 in vitro (56). Similar processes acting in vivo could promote inflammatory events at the RPE-choroid interface in the eye that hasten drusen formation and exacerbate the genetic susceptibility to AMD that is conferred by the at-risk HF1 haplotype.…”

Complement in age-related macular degeneration: a focus on function

“…42 Cigarette smoke has been shown to activate C3 in vitro and makes it less susceptible to inactivation by CFH and CFI. 43 In vivo, tobacco activates the classical pathway. 44 AREDS reported that high dietary intake of omega-3 long chain polyunsaturated fatty acids was associated with lower risk of neovascular AMD.…”