Revisiting α1-antitrypsin therapy in cystic fibrosis: can it still offer promise?

Abstract

The contribution of the neutrophil-derived serine protease neutrophil elastase (NE) to lung disease in cystic fibrosis (CF) is unquestioned and yet, despite promising preliminary studies in the last 20 yrs to investigate an effective therapy to negate the damaging effect of NE 1, this treatment has failed to take off for patients with CF. This is largely due to the scarcity of clinical trial data relating to this therapy. However, two recent publications 2, 3 signal a renewed interest in the application of treatment with inhaled α1-antitrypsin (AAT) as a panacea for the proteolytic damage occurring in CF lung disease. NE is released by neutrophils either on the cell membrane during cell migration or into the extracellular space upon stimulation by immune complexes, or by necrotic or apoptotic cells 4. AAT is one of the most important protease inhibitors involved in confining tissue proteolysis during an inflammatory response 5. Secreted by the liver, increased AAT concentrations are stimulated by interleukin (IL)-6 and it acts rapidly in the peripheral tissue to inhibit serine proteases, such as NE, cathepsin G and proteinase 3. While it is believed that AAT secretion is not impaired in CF 6, there are an overwhelming number of activated neutrophils in the lungs, the product of which is an excessive release of NE and other proteases, which cannot be contained by physiological AAT levels. In the current issue of the European Respiratory Journal Griese et al. 2 present findings on a prospective randomised study of AAT in CF. Griese et al. 2 set out to compare two different deposition patterns of inhaled AAT over a 4-week period to see which of the two provided the best clinical outcome. To achieve this they employed the new technology of …