Protease–Antiprotease Imbalance in Bronchiectasis

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.

Sputum from patients with primary ciliary dyskinesia contains high numbers of dysfunctional neutrophils and inhibits efferocytosis

“…In the group of PCD patients with positive sputum culture, higher NE activity also correlated with reduced FEV 1 . Of note, we found no correlation between NE activity and NE protein levels, supporting the notion that the balance between NE and native NE inhibitors may vary strongly between the patients, as described by Oriano et al [ 42 ].…”

Bacterial Proteases as Potentially Exploitable Modulators of SARS-CoV-2 Infection: Logic from the Literature, Informatics, and Inspiration from the Dog

“…PAB entails interplay within a superset of proteases, plus an adaptive array of stimulatory and inhibitory proteins and peptides [100][101][102][103]. PAB plays a major role in immunoregulatory function and helps to determine relative resistance or susceptibility to both influenza and COVID-19 infections [104,105], whereas imbalances are implicated in respiratory and gastrointestinal autoimmune conditions [106][107][108][109].…”

“…Protease/antiprotease imbalance is a hot topic in respiratory pathology research. While COPD and bronchiectasis are more extensively studied as examples of respiratory proteolytic disorders [106,107,129,130], allergic asthma pathology is generally also considered in this category [131,132]. To relate PAB knowledge to COVID-19 pathology, we may begin by considering antiproteases, whose effects on respiratory disorders have been widely studied [104].…”

Multiplex quantification of C-terminal alpha-1-antitrypsin peptides provides a novel approach for characterizing systemic inflammation

“…Complex formation of A1AT with serine proteases does not only cause inactivation of both substrates but also cleavage of the SERPIN at the reactive site centered at Met 382 -Ser. However, several non-target enzymes are also able to cleave A1AT in the RCL (reactive center loop) region causing functional loss of the primary regulator towards human serine proteinases and thus increase the risk for the development of lung emphysema and other acute or chronic inflammatory conditions which are known pathophysiological consequences among A1AT deficient individuals 4 .…”