Oxidative stress and abnormal bioactive lipids in early cystic fibrosis lung disease

Scholte, Bob J.; Horati, Hamed; Veltman, Mieke; Vreeken, Rob J.; Garratt, Luke W.; Tiddens, Harm A.W.M.; Janssens, Hettie M.; Stick, Stephen M.

doi:10.1016/j.jcf.2019.04.011

Cited by 34 publications

(31 citation statements)

References 45 publications

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“…The present data compare functional aspects of airway and intestinal epithelial cells from newborn WT and CFTR-knockout piglets [ 28 ]. Pulmonary oxidative stress response and abnormal bioactive lipids have been demonstrated in CF lung disease [ 20 , 45 ], suggesting early pulmonary inflammation [ 42 , 52 ]. Lipid peroxidation was also detected in the present study in the airways of newborn CFTR−/− piglets, providing evidence for an early pulmonary inflammation in the absence of bacterial colonization (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Transport properties in CFTR−/− knockout piglets suggest normal airway surface liquid pH and enhanced amiloride-sensitive Na+ absorption

Benedetto

Centeio

Ousingsawat

et al. 2020

Pflugers Arch - Eur J Physiol

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Previous analysis of CFTR-knockout (CFTR−/−) in piglets has provided important insights into the pathology of cystic fibrosis. However, controversies exist as to the true contribution of CFTR to the pH balance in airways and intestine. We therefore compared ion transport properties in newborn wild-type (CFTR+/+) and CFTR-knockout (CFTR−/− piglets). Tracheas of CFTR−/− piglets demonstrated typical cartilage malformations and muscle cell bundles. CFTR−/− airway epithelial cells showed enhanced lipid peroxidation, suggesting inflammation early in life. CFTR was mainly expressed in airway submucosal glands and was absent in lungs of CFTR−/− piglets, while expression of TMEM16A was uncompromised. mRNA levels for TMEM16A, TMEM16F, and αβγENaC were unchanged in CFTR−/− airways, while mRNA for SLC26A9 appeared reduced. CFTR was undetectable in epithelial cells of CFTR−/− airways and intestine. Small intestinal epithelium of CFTR−/− piglets showed mucus accumulation. Secretion of both electrolytes and mucus was activated by stimulation with prostaglandin E2 and ATP in the intestine of CFTR+/+, but not of CFTR−/− animals. pH was measured inside small bronchi using a pH microelectrode and revealed no difference between CFTR+/+ and CFTR−/− piglets. Intracellular pH in porcine airway epithelial cells revealed only a small contribution of CFTR to bicarbonate secretion, which was absent in cells from CFTR−/− piglets. In contrast to earlier reports, our data suggest a minor impact of CFTR on ASL pH. In contrast, enhanced amiloride-sensitive Na+ absorption may contribute to lung pathology in CFTR−/− piglets, along with a compromised CFTR- and TMEM16A-dependent Cl− transport.

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Section: Discussionmentioning

confidence: 99%

“…Finally, some CFTR-knockout mouse models did show signs of lung/airway inflammation even in the absence of mucus obstruction [ 53 ]. Thus, early intrinsic inflammation without mucus plugging or bacterial infection may initiate CF lung disease [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Transport properties in CFTR−/− knockout piglets suggest normal airway surface liquid pH and enhanced amiloride-sensitive Na+ absorption

Benedetto

Centeio

Ousingsawat

et al. 2020

Pflugers Arch - Eur J Physiol

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“…Ceramide is central to sphingolipid pathways involved in several human diseases and accumulation of ceramide has been shown in pathologies such as COPD, cystic fibrosis, PF, ischemia/reperfusion injury and acute inflammation. Unlike cystic fibrosis [124] and COPD [125] definitive studies relating to ceramide levels in BAL fluid, plasma, or lung tissue to collagen deposition or fibrosis in IPF lungs have not been performed. In bleomycin-induced PF, changes in ceramide levels in BAL fluid and lung tissue were not significantly different from control mice, although S1P levels were elevated [126].…”

Section: Ceramide Metabolism and Signaling In Pulmonary Fibrosismentioning

confidence: 99%

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Suryadevara

Ramchandran

Kamp

et al. 2020

IJMS

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.

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“…An intrinsic defect associated with CFTR deficiency is the susceptibility of CF airway cells to accumulate ROS, particularly during pathogen infection. Evidence shows increased oxidative stress in CF (37,(110)(111)(112)(113)(114)(115)(116). Although several studies suggest that the oxidative stress in CF is a direct consequence of mitochondrial dysfunction due to perturbed CFTR signaling, others suggest that the accumulation of ROS in CF depends on there being a reduced antioxidant capacity (113).…”

Section: Cftr Protein Defects Cooperate To Pro-inflammatory Intracellmentioning

confidence: 99%

Role of Cystic Fibrosis Bronchial Epithelium in Neutrophil Chemotaxis

et al. 2020

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Oxidative stress and abnormal bioactive lipids in early cystic fibrosis lung disease

Cited by 34 publications

References 45 publications

Transport properties in CFTR−/− knockout piglets suggest normal airway surface liquid pH and enhanced amiloride-sensitive Na+ absorption

Transport properties in CFTR−/− knockout piglets suggest normal airway surface liquid pH and enhanced amiloride-sensitive Na+ absorption

Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

Role of Cystic Fibrosis Bronchial Epithelium in Neutrophil Chemotaxis

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