Complement activation and inhibition in wound healing

Abstract

Complement activation is needed to restore tissue injury; however, inappropriate activation of complement, as seen in chronic wounds can cause cell death and enhance inflammation, thus contributing to further injury and impaired wound healing. Therefore, attenuation of complement activation by specific inhibitors is considered as an innovative wound care strategy. Currently, the effects of several complement inhibitors, for example, the C3 inhibitor compstatin and several C1 and C5 inhibitors, are under investigation in patients with complement-mediated diseases. Although (pre)clinical research into the effects of these complement inhibitors on wound healing is limited, available data indicate that reduction of complement activation can improve wound healing. Moreover, medicine may take advantage of safe and effective agents that are produced by various microorganisms, symbionts, for example, medicinal maggots, and plants to attenuate complement activation. To conclude, for the development of new wound care strategies, (pre)clinical studies into the roles of complement and the effects of application of complement inhibitors in wound healing are required.

Figure 1

A simplified overview of the complement activation cascade after injury leading to wound healing. Three major pathways of complement activation, that is, the classical pathway (CP), the alternative pathway (LP), and the lectin pathway (LP), and two minor pathways initiated by properdin and thrombin are known. C is a complement component, MASP is mannan-binding serine peptidase, fB and D are factors B and D, SCIN is staphylococcal complement inhibitor, sCR1 is soluble complement receptor 1, fH is factor H, CR2 is complement receptor 2 and MAC is membrane attack complex. For simplicity, not all of the natural regulators of complement activation are shown in this diagram. The (pre)clinical complement inhibitors are denoted in bold and the complement factors that have been investigated in burn wound models in italic. C1 inhibitor affects C1r, C1s from the CP, and MASP 1 and MASP 2 from the LP. C4 knockout also affects both CP and LP.

Figure 2

Dose-dependent effect of fresh collected maggot ES on activation of the classical pathway (white bars), the alternative pathway (grey bars), and the lectin pathway (black bars) in normal human sera. The complement activation in four different sera was determined with the enzyme immunoassays from Wieslab (EuroDiagnostica BV, Arnhem, The Netherlands) according to manufacturer's instructions. The percentages inhibition was calculated using the values in the sera without maggot ES as 0%. The results are means and SD of four independent experiments.