Complement mediators: key regulators of airway tissue remodeling in asthma

Abstract

The complement mediators are the major effectors of the immune balance, which operates at the interface between the innate and adaptive immunity, and is vital for many immunoregulatory functions. Activation of the complement cascade through the classical, alternative or lectin pathways thus generating opsonins like C3b and C5b, anaphylatoxins C3a and C5a, chemotaxin, and inflammatory mediators, which leads to cellular death. Complement mediators that accelerate the airway remodeling are not well defined; however, an uncontrolled Th2-driven adaptive immune response has been linked to the major pathophysiologic features of asthma, including bronchoconstriction, airway hyperresponsiveness, and airway inflammation. The mechanisms leading to complement mediated airway tissue remodeling, and the effect of therapy on preventing and/or reversing it are not clearly understood. This review highlights complement-mediated inflammation, and the mechanism through it triggers the airway tissue injury and remodeling in the airway epithelium that could serve as potential targets for developing a new drug to rescue the asthma patients.

Fig. 1

Model shows active mediators of the complement cascade during inflammation in airway asthma. Further, it highlights activation of inflammatory cells (Basophils, PMNs and Macrophages) through complement receptor binding and downstream release of inflammatory mediators. As shown, all these mediators contribute in tissue damage and remodeling. APL-1 and APL-2, are derivatives of Compstatin, bind to and inhibit complement activation at the C3 level, thus blocking all major effector pathways of complement activation. (Both APL-1 and APL-2 are under clinical trials).

Fig. 2

Model shows IL-13 and TGF-β mediated sub-epithelial fibrosis. Both of these cytokines are released post complement activation in airway lumen. Further, TGF- β1 promotes the differentiation of fibroblast into myofibroblast, and IL-13 stimulates collagen type-1 production by the airway fibroblast in a matrix metalloproteinase (MMP)-2 and TGF-β1-dependent manner.

Fig. 3

Simple illustration of complement inhibition approach to prevent fibrosis. This figure shows how blocking C3a and C5a prevent downstream activation of inflammatory mediators and subdue fibrotic process.