Cystic fibrosis (CF) is the most common autosomal recessive genetic disease in Caucasians, affecting more than 100,000 individuals worldwide. It is caused by pathogenic variants in the gene encoding CFTR, an anion channel at the plasma membrane of epithelial and other cells. Many CF pathogenic variants disrupt the biosynthesis and trafficking of CFTR or reduce its ion channel function. The most frequent mutation, loss of a phenylalanine at position 508 (F508del), leads to misfolding, retention in the endoplasmic reticulum, and premature degradation of the protein. The therapeutics available for treating CF lung disease include antibiotics, mucolytics, bronchodilators, physiotherapy, and most recently CFTR modulators. To date, no cure for this life shortening disease has been found. Treatment with the Triple combination drug therapy, TRIKAFTA®, is composed of three drugs: Elexacaftor (VX-445), Tezacaftor (VX-661) and Ivacaftor (VX-770). This therapy, benefits persons with CF, improving their weight, lung function, energy levels (as defined by reduced fatigue), and overall quality of life. We examined the effect of combining LAU-7b oral treatment and Triple therapy combination on lung function in a F508deltm1EUR mouse model that displays lung abnormalities relevant to human CF. We assessed lung function, lung histopathology, protein oxidation, lipid oxidation, and fatty acid and lipid profiles in F508deltm1EUR mice.
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The original research article was published in the journal Frontiers in Pharmacology | Inflammation Pharmacology (https://doi.org/10.3389/fphar.2022.876842).
In the picture: FIGURE 3. Airway hyperplasia and cellular infiltration in the lungs of Wild-type (WT) and F508del/F508del (DD) mice; Hematoxylin and eosin (H&E) staining. (A) WT control mice (non-treated, NT and vehicle, VEH) (B–F) DD NT, VEH, LAU-7b, Triple and Triple + LAU-7b, respectively. (G) LAU-7b and Triple therapy treated DD mice have significantly lower lung cell infiltration compared to placebo treated DD mice. For each mouse, measurements were done with at least four different airways per lung. Quantification was done by counting the number of infiltrating cells around each of the four airways per lung and normalized by dividing the square of the perimeter “in millimeter” of the airway basement membrane. n equal 3–11 mice for each group, Two-way ANOVA with Bonferroni correction where *p < 0.05, **p < 0.01.