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. 1987 Oct;129(1):44–53.

Activation of C5 by cobra venom factor is required in neutrophil-mediated lung injury in the rat.

G O Till 1, M L Morganroth 1, R Kunkel 1, P A Ward 1
PMCID: PMC1899690  PMID: 3661679

Abstract

Cobra venom factor (CVF)-induced systemic activation of the complement system in the rat has been shown to result in the development of acute lung microvascular injury and appearance in lungs and plasma of lipid peroxidation products. The pathogenesis of these events is dependent on complement and neutrophils and is sensitive to pretreatment of experimental animals with iron chelators or scavengers of hydroxyl radical. In order to further analyze the role of complement in the pathogenesis of acute lung injury in rats after systemic complement activation, two different CVFs have been employed in the present study. One was the previously used CVFn isolated from Naja n. naja venom, whereas the other factor, CVFh, was isolated from Naja h. haje venom. Both factors have been shown to activate the alternative complement pathway by forming a potent C3 convertase but differ with respect to their ability to bind and activate C5. CVFn but not CVFh activates C5 and distant complement components. When equal doses of C3-activating activity of CVFn or CVFh were injected intravenously into rats, CVFh-treated rats failed to develop acute lung injury, whereas CVFn-treated animals showed pronounced increases in lung vascular permeability. Similarly, in isolated blood perfused rat lungs neither the lung injury nor pulmonary hypertension caused by CVFn were found after injection of CVFh. In addition, CVFh-treated animals failed to show transient neutropenia or appearance in plasma of C5-derived chemotactic activity, although the extent of C3 conversion in vivo was identical to that seen in CVFn-treated rats. Morphologic examination of the lungs of the experimental animals revealed no signs of injury in CVFh-treated rats, whereas the lungs from CVFn-treated animals revealed interstitial and alveolar edema, as well as plugging of pulmonary capillaries with neutrophils, blebbing and/or destruction of vascular endothelial cells, fibrin deposition, and hemorrhage. These studies provide evidence that activation of the complement system involving C3 but not extending further in the complement sequence is not sufficient to bring about acute injury of the lung microvasculature and that the activation sequence must at least also involve C5.

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Selected References

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