Treating inflammation and pulmonary exacerbations in cystic fibrosis patients
Targeting prophylactic agents in cystic fibrosis patients: the pathway to treating inflammation and pulmonary exacerbations?
Cystic fibrosis (CF) is a complex autosomal recessive channelopathy attributed to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, resulting in increased morbidity and decreased life expectancy.
This is primarily due to pulmonary disease in patients who have the condition. CF pulmonary disease is characterised by chronic infection with Pseudomonas Aeruginosa and sustained neutrophil dominant inflammation. A significant challenge when caring for patients with CF is the lack of effective anti-inflammatory therapies.
In the study available here, Prof. Gerry McElvaney and his respiratory medicine team at RCSI investigate the role of inflammasome inhibitors as both anti-inflammatory and anti-infective agents in patients with CF. They detail the potential use of these agents in the prophylactic setting, as well as for the management of pulmonary exacerbations.
The NLRP3 inflammasome, which is a composite of adaptor and effector proteins, is highly expressed in myeloid cells, the progenitor cells for granulocytes, monocytes, erythrocytes and platelets.
The inflammasome complex plays a role in the regulation of inflammation, the immune response and apoptosis, hence the reason why targeting it may represent a novel therapeutic strategy to modulate inflammation, a key component of the pathology underlying CF.
The paper also focuses on immunometabolism and IL-1β production in neutrophils, an area that has not been studied in any great detail to date. When measuring IL-1β in patients with cystic fibrosis, the authors found that bronchoalveolar lavage (BAL) and sputum samples contained significantly more IL-1β and neutrophils when compared to healthy controls. Importantly, they also observed that neutrophil percentage in these samples correlated strongly with IL-1β levels.
This reveals that IL-1β is a clinically relevant readout of neutrophil-predominant airway inflammation in CF.
A selective small molecular inhibitor of the NLRP3 inflammasome, MCC950, was shown to abrogate the IL-1β response in both CF and healthy control neutrophils in a dose-dependent manner, showing that NLRP3 is the predominant inflammasome involved in IL-1β production in CF neutrophils.
In their in-vivo model, the authors demonstrated that treatment with MCC950 during infection with Pseudomonas Aeruginosa resulted in a 92% reduction of IL-1β at lung level when compared to untreated controls. MCC950 also resulted in improved clearance of Pseudomonas Aeruginosa in untreated mice when compared to untreated controls.
This study supports the potential role for NLRP3 inhibitors as a prophylactic agent and also for the treatment of pulmonary exacerbations for patients with CF, potentially increasing survival rates for this cohort.
Journal Article Information:
Specific Inhibition of the NLRP3 Inflammasome as an Antiinflammatory Strategy in Cystic Fibrosis
Am J Respir Crit Care Med. 2019 Dec 1;200(11):1381–1391.
DOI: https://doi.org/10.1164/rccm.201905-1013OC
