Proteases and antiproteases in chronic neutrophilic lung disease - relevance to drug discovery

Abstract

Chronic inflammatory lung diseases such as cystic fibrosis and emphysema are characterized by higher-than-normal levels of pulmonary proteases. While these enzymes play important roles such as bacterial killing, their dysregulated expression or activity can adversely impact on the inflammatory process. The existence of efficient endogenous control mechanisms that can dampen or halt this overexuberant protease activity in vivo is essential for the effective resolution of inflammatory lung disease. The function of pulmonary antiproteases is to fulfil this role. Interestingly, in addition to their antiprotease activity, protease inhibitors in the lung also often possess other intrinsic properties that contribute to microbial killing or termination of the inflammatory process. This review will outline important features of chronic inflammation that are regulated by pulmonary proteases and will describe the various mechanisms by which antiproteases attempt to counterbalance exaggerated protease-mediated inflammatory events. These proteases, antiproteases and their modifiers represent interesting targets for therapeutic intervention.

Figure 1

Mechanism of neutrophil elastase (NE) induction of IL-8 in airway epithelial cells. Following its release from the azurophilic granules in response to a microbial insult, NE activates meprin-α or TNFα converting enzyme (TACE), which in turn cleave proTGFα to generate soluble TGFα as a ligand for the epidermal growth factor receptor (EGFR). EGFR co-localizes with TLR4 and a signal transduction cascade is initiated via MyD88 or Mal, IRAKs, TRAF6, transforming growth factor-beta-activated kinase 1 (TAK1) and the IκB kinases (IKKs), leading to a degradation of inhibitor of NFκB (IκB) proteins, activation of nuclear factor-κB (NFκB) and increased IL-8 gene transcription.