Dysregulation of the Arachidonic Acid Pathway in Cystic Fibrosis: Implications for Chronic Inflammation and Disease Progression
Abstract
:1. Introduction
2. Alteration of the AA Pathway in CF, from Precursors to Metabolites
2.1. n-3 and n-6 PUFA
2.2. Arachidonic Acid
2.3. Metabolites
2.3.1. The COX Pathway
2.3.2. The LOX Pathway
2.3.3. The CYP450 Pathway and Oxidative Stress
2.4. Role of CFTR Dysfunction in CF Abnormal Fatty Acid Metabolism
2.5. Therapeutic Strategies to Modulate AA Metabolism in CF
3. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Strategy | Target | Clinical Outcome | Ref. |
---|---|---|---|
Ivacaftor | Patients with CF carrying at least one G551D CFTR mutation (n = 40). | AA and PGE2 levels decrease, but no effects on LA and DHA deficiency. | [117] |
CF pediatric patients (mean age = 11.7 years) (n = 11), for 12 months. | Reduced AA/EPA and AA/DHA ratios on red blood cell membranes. | [120] | |
DHA | Patients with CF (range 20–40 years) (n = 15), for 6 months. | Increased DHA and 17-OH DHA levels. Reduction in LTB4, 15-HETE and PGE2 levels, but no improvements of FEV1 and FVC. | [120] |
Five randomized controlled trials (n = 106). | Low DHA benefits and relatively low side effects. | [123] | |
CF pediatric patients (Mean age = 11.7 years) (n = 22) for 12 months. | Improved FVC and FEV1, but PMN elastase, resolvin D1, IL-8, and TNF-alpha remained unaffected. | [124] | |
Ibuprofen | Patients with CF with mild lung disease (range 5–39 years) (n = 85), for 4 years. | Slowed lung disease progression, risk of GI bleeding. | [125] |
Steroids (aerosol) | 13 trials with patients with CF (range 6–55 years) (n = 506). | Modest general benefits. | [130] |
BLT1 antagonist | CF pediatric patients (range 6–17 years) and adult patients (>18 years) with mild-to-moderate lung disease, for 24 weeks. | Serious pulmonary adverse effects. | [133] |
Acebilustat | Adult patients with CF (range 28–55 years) (n = 17) with mild-to-moderate lung disease for 15 days. | Reduced sputum PMN and elastase. Trend toward reduction in serum C-reactive protein and sputum DNA. | [135] |
Adult patients with CF (range 18–35 years) (n = 199) for 48 weeks. | Absence of improvement in pulmonary function (FEV1) and pulmonary exacerbations. Trend toward reduced exacerbations in people with early lung disease. | [136] | |
Montelukast | Patients with CF (range 5–18 years) (n = 16), for 21 days. | Reduced eosinophilic inflammation, improved exercise tolerance, cough, and wheezing, decreased IL-8 and myeloperoxidase levels. | [137,138,139,140] |
Zafirlukast | Patients with CF (range 20–32 years) (n = 25), for 4 months. | Benefits in chest radiograph appearance and physical examination without any improvement in respiratory functions. | [141] |
Inhaled GSH | Patients with CF (range 18–39 years) (n = 17), for 14 days. | Reduced PGE2 levels, increased CD4+ and CD8+ T-cells levels. 8-isoprostanes levels remained unchanged. | [142] |
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D’Orazio, S.; Mattoscio, D. Dysregulation of the Arachidonic Acid Pathway in Cystic Fibrosis: Implications for Chronic Inflammation and Disease Progression. Pharmaceuticals 2024, 17, 1185. https://doi.org/10.3390/ph17091185
D’Orazio S, Mattoscio D. Dysregulation of the Arachidonic Acid Pathway in Cystic Fibrosis: Implications for Chronic Inflammation and Disease Progression. Pharmaceuticals. 2024; 17(9):1185. https://doi.org/10.3390/ph17091185
Chicago/Turabian StyleD’Orazio, Simona, and Domenico Mattoscio. 2024. "Dysregulation of the Arachidonic Acid Pathway in Cystic Fibrosis: Implications for Chronic Inflammation and Disease Progression" Pharmaceuticals 17, no. 9: 1185. https://doi.org/10.3390/ph17091185