Abstract
Airway inflammation plays a central role in bronchiectasis. Protease–antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases’ over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease–antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.
Highlights
Bronchiectasis is a chronic respiratory disease characterized by an irreversible pathological dilation of the bronchi associated with a chronic syndrome of cough, sputum production and recurrent respiratory infections [1]
Several enzymes are associated with neutrophilic inflammation in bronchiectasis, and a high number of proteins coordinate neutrophil recruitment into the lung [27]
We previously reported the role of these molecules in decreasing exacerbation risk in patients with high levels of active NE (aNE); future studies should focus on the use of these compounds in inhibiting aNE in patients with low baseline levels of aNE, which usually increases during exacerbations
Summary
Bronchiectasis is a chronic respiratory disease characterized by an irreversible pathological dilation of the bronchi associated with a chronic syndrome of cough, sputum production and recurrent respiratory infections [1]. One of the current paradigms for bronchiectasis onset and progression is represented by a vicious vortex in which bacterial infection, airway inflammation, lung tissue disruption, and impaired mucous clearance are regarded as the major components [6,7]. Ciliary dysfunction and failure of the muco-ciliary clearance, as demonstrated in patients with primary ciliary dyskinesia (PCD) and cystic fibrosis (CF), increases the risk of pulmonary infections and airway inflammation leading to the chronicity of the vortex [11,12,13] Systemic immune diseases, such as immunodeficiency or extra-pulmonary autoimmune diseases, may cause a delayed resolution of respiratory infections followed by inflammation and structural lung damage, determining the entry in the pathophysiological vicious cycle [14,15]. Bacteria may produce proteases that may be involved in the protease–antiproteases balance in bronchiectasis, we decided to focus only on proteases produced by the host [23,24]
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