α₁-Proteinase Inhibitor, Elastase Activity, and Lung Disease Severity in Cystic Fibrosis

Abstract

The potential role of neutrophil elastase in exacerbating pulmonary infection and tissue damage in cystic fibrosis (CF) has led to proposals for treatment of lung disease in CF with the elastase inhibitor, alpha 1-proteinase inhibitor (alpha 1PI). Reports that alpha 1PI is inactivated in the CF lung suggest that the effectiveness of alpha 1PI therapy depends on the quantity of elastase present and the extent of alpha 1PI inactivation, both of which are expected to vary with disease severity. In this study we assessed the elastase-alpha 1PI profile in sputum and plasma from CF patients with various degrees of pulmonary involvement. Levels of active elastase in sputum samples increased with severity of pulmonary disease (F ratio = 5.63, p < 0.01), as did sputum levels of alpha 1PI (F ratio = 4.88, p < 0.01). A positive correlation was observed between sputum levels of active elastase and alpha 1PI (r = 0.68, p < 0.005). Plasma alpha 1PI levels were also elevated in CF patients compared with control subjects (p < 0.005), indicating a compensatory increase in plasma and sputum levels of alpha 1PI in response to increased elastase load. Molar levels of total immunogenic neutrophil elastase were, on average, 12 times higher than alpha 1PI in CF sputum. These results suggest that the major contributor to the elevated levels of active elastase observed in the CF lung is an increase in elastase release rather than inactivation of alpha 1PI.

Mice Lacking Neutrophil Elastase Are Resistant to Bleomycin-Induced Pulmonary Fibrosis

“…Neutrophil elastase has been proposed to play a destructive role in lung diseases such as emphysema 49 and cystic fibrosis. 50 Our data introduce the concept that neutrophil elastase can support matrix production and tissue repair via TGF-␤-mediated pathways. Further studies of the mechanism by which neutrophil elastase activates TGF-␤ are needed; however, a re-evaluation of strategies for the use of neutrophil elastase inhibitors in the treatment of lung disease may be warranted.…”

Novel Neutrophil-Derived Proteins in Bronchoalveolar Lavage Fluid Indicate an Exaggerated Inflammatory Response in Pediatric Cystic Fibrosis Patients

“…Increased DEFAs may also contribute to tissue damage directly via their observed cytotoxic effects on cells (28 ), and indirectly by competing with neutrophil elastase (NE) for binding of the NE inhibitor, ␣-1-antitrypsin (29 ). Indeed, increased free NE activity is associated with CF inflammation and lung damage (30,31 ). S100A8/A9 heterodimer is chemotactic for neutrophils in vitro and in vivo (32 ).…”

Sputum Biomarkers of Inflammation and Lung Function Decline in Children with Cystic Fibrosis

“…Proteolytic activity is believed to be responsible for causing most of the bronchiectasis in CF (5,6). There is limited yet compelling evidence from small, single-center studies supporting an association between proteases and lung function measurements (7,8), chest radiograph scores (9)(10)(11), and illness severity scores (e.g., Shwachman-Kulczycki score) (9,10) in children and adults with CF. Furthermore, there are data that show the correlations between sputum protease levels and lung function are statistically significant across a larger diverse CF population (12).…”