Oxidative stress in cystic fibrosis lung disease: an early event, but worth targeting?

Hector, Andreas; Griese, Matthias; Hartl, Dominik

doi:10.1183/09031936.00038114

Cited by 34 publications

(24 citation statements)

References 34 publications

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“…A possible link between LTH and pulmonary function may rely on the role of systemic oxidative stress in the action of free radicals and NO bioavailability (2,37,46). In fact, excessive oxidative stress status has been observed in patients with obstructed airways and impaired lung function, including CF (5,16). Although the present study cannot determine a cause-effect relationship, future studies are needed to elucidate the causal mechanisms.…”

Section: Microvascular Function and Disease Severity: Clinical Relevancementioning

confidence: 64%

Evidence of microvascular dysfunction in patients with cystic fibrosis

Rodriguez‐Miguelez

Thomas

Seigler

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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Rodriguez-Miguelez P, Thomas J, Seigler N, Crandall R, McKie KT, Forseen C, Harris RA. Evidence of microvascular dysfunction in patients with cystic fibrosis. Am J Physiol Heart Circ Physiol 310: H1479 -H1485, 2016. First published April 15, 2016 doi:10.1152/ajpheart.00136.2016.-Cystic fibrosis (CF) is a genetic, multisystemic disorder with broad clinical manifestations apart from the well-characterized pulmonary dysfunction. Recent findings have described impairment in conduit vessel function in patients with CF; however, whether microvascular function is affected in this population has yet to be elucidated. Using laser-Doppler imaging, we evaluated microvascular function through postocclusive reactive hyperemia (PORH), local thermal hyperemia (LTH), and iontophoresis with acetylcholine (ACh). PORH [518 Ϯ 174% (CF) and 801 Ϯ 125% (control), P ϭ 0.039], LTH [1,338 Ϯ 436% (CF) and 1,574 Ϯ 620% (control), P ϭ 0.045], and iontophoresis with ACh [416 Ϯ 140% (CF) and 617 Ϯ 143% (control), P ϭ 0.032] were significantly lower in patients with CF than control subjects. In addition, the ratio of PORH to LTH was significantly (P ϭ 0.043) lower in patients with CF (55.3 Ϯ 5.1%) than control subjects (68.8 Ϯ 3.1%). Significant positive correlations between LTH and forced expiratory volume in 1 s (%predicted) (r ϭ 0.441, P ϭ 0.013) and between the PORH-to-LTH ratio and exercise capacity (r ϭ 0.350, P ϭ 0.049) were observed. These data provide evidence of microvascular dysfunction in patients with CF compared with control subjects. In addition, our data demonstrate a complex relationship between microvascular function and classical markers of disease severity (i.e., pulmonary function and exercise capacity) in CF. CYSTIC FIBROSIS (CF) is an inherited disorder that is predominantly characterized by pulmonary dysfunction; however, broader clinical manifestations, such as gastrointestinal, immune, endocrine, and musculoskeletal dysfunctions, are also present (36). Recently, our group reported conduit vascular endothelial dysfunction in young patients with CF (39). Importantly, this vascular impairment was observed in a population that exhibited preserved spirometric function and exercise capacity, which suggests a systemic consequence prior to the decrease in pulmonary function. Despite these recent observations, there appears to be a lack of understanding of the general functionality of the endothelium in CF.Impairments in endothelial function are highly related to a reduction in the bioavailability of nitric oxide (NO), a key vasodilator involved in the regulation of vessel tone and endothelium integrity (24). Decreases in NO balance have also been shown to contribute to impaired endothelial microvascular vasodilation (44). With use of laser-Doppler imaging technology, cutaneous blood flux can be quantified (45) to represent an accessible model of microvascular function (17). Postocclusive reactive hyperemia (PORH), local thermal hyperemia (LTH), and iontophoresis with acetylcholine (ACh), in combination with laser technology...

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Section: Microvascular Function and Disease Severity: Clinical Relevancementioning

confidence: 64%

Evidence of microvascular dysfunction in patients with cystic fibrosis

Rodriguez‐Miguelez

Thomas

Seigler

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…The data on statistically significantly increased and decreased pathways showed the involvement of inflammation-related pathways (Chemokine signaling pathway, Cytokines and inflammatory response, TGFβ signaling pathway), proteases-activated pathways (Osteoclast, Complement and coagulation cascade, Blood clotting cascade, matrix metalloproteinases) and oxidative stress-associated pathways (Oxidative stress, Keap-1-Nrf2, Oxidation by cytochrome P450) (Fig. 3c), which are also known to be associated in CF and COPD pathogenesis1234. Taken together, these pulmonary biochemical, histological and functional analysis, and comprehensive microarray analysis support the idea that C57/BL6J-βENaC-Tg mice are a good animal model that mimics the molecular pathogenesis of COPD and/or CF.…”

Section: Resultsmentioning

confidence: 95%

“…2j,k; Supplementary Fig. 1), and these parameters were altered by pharmacological and genetic approaches targeting proteases- and oxidative stress-pathways that are typically activated in COPD/CF lung1234, C57/BL6J-βENaC-Tg mice could be a clinically promising animal model to discover the novel targets of COPD/CF lung diseases.…”

Section: Discussionmentioning

confidence: 99%

“…In these disorders, defective mucus clearance, excessive inflammation, protease-antiprotease imbalance and oxidative stress have been considered to influence the seriousness1234. Because COPD is a worldwide leading cause of morbidity and mortality1 and CF is the most common lethal inherited disorder in Caucasians3, identification of the key molecules and pathways underlying disease pathogenesis has been the subject of extensive research for many years.…”

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confidence: 99%

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Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases

Shuto¹,

Kamei²,

Fujikawa³

et al. 2016

Sci Rep

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Protease-antiprotease imbalance and oxidative stress are considered to be major pathophysiological hallmarks of severe obstructive lung diseases including chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF), but limited information is available on their direct roles in the regulation of pulmonary phenotypes. Here, we utilized βENaC-transgenic (Tg) mice, the previously established mouse model of severe obstructive lung diseases, to produce lower-mortality but pathophysiologically highly useful mouse model by backcrossing the original line with C57/BL6J mice. C57/BL6J-βENaC-Tg mice showed higher survival rates and key pulmonary abnormalities of COPD/CF, including mucous hypersecretion, inflammatory and emphysematous phenotypes and pulmonary dysfunction. DNA microarray analysis confirmed that protease- and oxidative stress-dependent pathways are activated in the lung tissue of C57/BL6J-βENaC-Tg mice. Treatments of C57/BL6J-βENaC-Tg mice with a serine protease inhibitor ONO-3403, a derivative of camostat methylate (CM), but not CM, and with an anti-oxidant N-acetylcystein significantly improved pulmonary emphysema and dysfunction. Moreover, depletion of a murine endogenous antioxidant vitamin C (VC), by genetic disruption of VC-synthesizing enzyme SMP30 in C57/BL6J-βENaC-Tg mice, exaggerated pulmonary phenotypes. Thus, these assessments clarified that protease-antiprotease imbalance and oxidative stress are critical pathways that exacerbate the pulmonary phenotypes of C57/BL6J-βENaC-Tg mice, consistent with the characteristics of human COPD/CF.

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“…Oxidative stress markers are often raised despite routine supplementation with liposoluble antioxidant vitamins, such as vitamin E or carotenoids [12]. Oxidative stress has been shown to produce lung damage in CF patients at an early age [13,14].…”

Section: Introductionmentioning

confidence: 99%

Inflammation and Oxidation Biomarkers in Patients with Cystic Fibrosis: The Influence of Azithromycin

Olveira¹,

Padilla²,

Dorado³

et al. 2017

Eurasian J Med

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Objective: In addition to their antibiotic effect, macrolides appear to modulate the inflammatory response in cystic fibrosis (CF) and could influence oxidative stress. The objective of this study was to assess oxidation biomarkers and levels of inflammation and to determine whether there is an association between these parameters and the intake of macrolides. Materials and Methods:The subjects included in this cross-sectional study were, on the one hand, clinically stable patients with CF and, on the other, healthy controls. The following serum and plasma inflammatory and oxidative stress biomarkers were measured: interleukin-6 (IL-6), reactive C protein (RCP), tumor necrosis alpha (TNF-α), glutathione peroxidase (GPx), total antioxidant capacity (TAC), catalase (CAT), and superoxide dismutase (SOD), together with markers of lipid peroxidation (8-isoprostanes and thiobarbituric acid reactive substances [TBARS]). Clinical, anthropometric, lung function, radiological, and analytical variables (albumin, prealbumin, vitamins, and zinc) were also recorded. Results:We studied 36 adults with CF and 41 controls. No differences were observed in age, gender, or anthropometric variables. The patients had significantly higher levels of IL-6, TNF-α, RCP, TBARS, and isoprostanes, and lower levels of SOD than the controls. Twenty-three of the patients were treated with azithromycin, and they had more severe clinical and radiological parameters than those who were not but nevertheless presented significantly lower levels of TNF-α. No differences were observed in the markers of oxidation.Conclusion: Inflammation and oxidation biomarkers were increased in patients with CF compared with controls. The use of azithromycin was associated with reduced TNF-α levels and did not influence oxidation parameters.

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Oxidative stress in cystic fibrosis lung disease: an early event, but worth targeting?

Cited by 34 publications

References 34 publications

Evidence of microvascular dysfunction in patients with cystic fibrosis

Evidence of microvascular dysfunction in patients with cystic fibrosis

Pharmacological and genetic reappraisals of protease and oxidative stress pathways in a mouse model of obstructive lung diseases

Inflammation and Oxidation Biomarkers in Patients with Cystic Fibrosis: The Influence of Azithromycin

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