The Role of MMPs in the Era of CFTR Modulators: An Additional Target for Cystic Fibrosis Patients?

Abstract

Cystic fibrosis (CF) is a high-prevalence disease characterized by significant lung remodeling, responsible for high morbidity and mortality worldwide. The lung structural changes are partly due to proteolytic activity associated with inflammatory cells such as neutrophils and macrophages. Matrix metalloproteases (MMPs) are the major proteases involved in CF, and recent literature data focused on their potential role in the pathogenesis of the disease. In fact, an imbalance of proteases and antiproteases was observed in CF patients, resulting in dysfunction of protease activity and loss of lung homeostasis. Currently, many steps forward have been moved in the field of pharmacological treatment with the recent introduction of triple-combination therapy targeting the CFTR channel. Despite CFTR modulator therapy potentially being effective in up to 90% of patients with CF, there are still patients who are not eligible for the available therapies. Here, we introduce experimental drugs to provide updates on therapy evolution regarding a proportion of CF non-responder patients to current treatment, and we summarize the role of MMPs in pathogenesis and as future therapeutic targets of CF.

Toward a Systematic Assessment of Sex Differences in Cystic Fibrosis

“…Vermeer et al [ 38 ] reported that higher expression of MMP9 in asthma patients was shown to decrease the functionality of cell barriers (specifically the tight junction pathway), which can limit the protection against bacteria entering the cells. However, MMP9 was shown to correlate adversely with lung function in CF patients [ 39 ] and has been discussed as a potential future therapeutic target in CF [ 40 ]. Female-biased expression of the chemokine CXCL5, also part of the IL-17 signaling pathway, could partly account for more intense inflammation reactions in females.…”

Modulation of Plasmatic Matrix Metalloprotease 9: A Promising New Tool for Understanding the Variable Clinical Responses of Patients with Cystic Fibrosis to Cystic Fibrosis Transmembrane Conductance Regulator Modulators

“…MMP9, which is expressed by several immune cells, such as monocytes/macrophages and neutrophils [41,42], has been detected in association with CF progression [18,20,28]. In addition, MMP9 levels are higher during CF progression, which is characterized by an acute pulmonary exacerbation associated with increased inflammation due to the recruitment of many monocytes to the site of the inflammation and damage [28,43].…”

Neutrophil-Derived Proteases in Lung Inflammation: Old Players and New Prospects

“…During homeostasis, metzincin expression tends to be low, and is upregulated during pathologies, such as COPD, ARDS, and CF [243][244][245][246]. MMP-8 (neutrophil collagenase) is perhaps the best-known neutrophil-derived metzincin, though neutrophils are also a major source of MMP-9 (gelatinase B) [247].…”