Novel Anti-Inflammatory Approaches for Cystic Fibrosis Lung Disease: Identification of Molecular Targets and Design of Innovative Therapies

Abstract

Cystic fibrosis (CF) is the most common genetic disorder among Caucasians, estimated to affect more than 70,000 people in the world. Severe and persistent bronchial inflammation and chronic bacterial infection, along with airway mucus obstruction, are hallmarks of CF lung disease and participate in its progression. Anti-inflammatory therapies are, therefore, of particular interest for CF lung disease. Furthermore, a better understanding of the molecular mechanisms involved in airway infection and inflammation in CF has led to the development of new therapeutic approaches that are currently under evaluation by clinical trials. These new strategies dedicated to CF inflammation are designed to treat different dysregulated aspects such as oxidative stress, cytokine secretion, and the targeting of dysregulated pathways. In this review, we summarize the current understanding of the cellular and molecular mechanisms that contribute to abnormal lung inflammation in CF, as well as the new anti-inflammatory strategies proposed to CF patients by exploring novel molecular targets and novel drug approaches.

Repurposing of CNS drugs to treat COVID-19 infection: targeting the sigma-1 receptor

“…It has been suggested that ER stress due to the replication of SARS-CoV-2 may contribute to inflammatory events (i.e., cytokine storm), which results in severe symptoms of acute respiratory distress syndrome accompanied by high mortality (Fig. 2 ) [ 1 , 18 – 21 ]. A case control study showed higher levels of ER stress markers [i.e., glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), phospho-extracellular signal regulated kinase (PERK)] in SARS-CoV-2 positive subjects [ 22 ].…”

Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Lung Diseases: Current Status and Perspectives

“…Additionally, high concentrations of IL-8 and other neutrophil chemokines are usually observed in CF airways, as is intense neutrophil recruitment ( Downey et al, 2009 ). This chronic inflammatory process leads to increased levels of oxidative burst, elastase, and pro-inflammatory mediators in the airways ( Tabary et al, 2006 ; Mitri et al, 2020 ).…”

Dysfunctional Inflammation in Cystic Fibrosis Airways: From Mechanisms to Novel Therapeutic Approaches

“…Some trials have also been performed with inhaled glucocorticoids in CF patients. Although they have a better safety profile than oral corticosteroids, current evidence is insufficient to prove their efficacy [ 18 , 19 ]. Thus, the use of inhaled corticosteroids may be appropriate in CF patients with signs and symptoms of asthma or allergic bronchopulmonary aspergillosis, while they are not recommended in patients without these comorbidities, and more studies are needed to better define their use in the CF population.…”

“…Several recent clinical studies of CF focused on modulation of MMP activity to improve disease outcome. A Phase II study with Andecaliximab/GS-5745 is in progress in adult patients with CF, and this could represent a novel approach to control tissue damage [ 19 ].…”

“…At present, there is evidence from preclinical data that antibodies directed against intracellular adhesion molecules and IL-8 might be promising tools [ 19 ]. SB-656933, an oral CXCR2 antagonist, has been tested in CF patients, and has demonstrated a good safety profile as well as the capability of modulating airway inflammation with an improvement of sputum inflammatory biomarkers [ 76 ].…”