Oxidation increases mucin polymer cross-links to stiffen airway mucus gels

Yuan, Shaopeng; Hollinger, Martin; Lachowicz-Scroggins, Marrah E.; Kerr, Sheena C.; Dunican, Eleanor M.; Daniel, Brian; Ghosh, Sudakshina; Erzurum, Serpil C.; Willard, Belinda; Hazen, Stanley A; Huang, Xiaozhu; Carrington, Stephen D.; Oscarson, Stefan; Fahy, John V.

doi:10.1126/scitranslmed.3010525

Cited by 217 publications

(210 citation statements)

References 41 publications

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“…They also had marked increases in sputum cell gene expression for type 2 cytokines, such as IL-5 and IL-13, and a relative increase in MUC5AC gene expression over MUC5B. This latter finding is relevant because cysteine domains are more prevalent in MUC5AC than in MUC5B (24), and we have previously shown that neutrophil-driven oxidation in the airways in cystic fibrosis can crosslink cysteine-rich mucin polymers to stiffen the mucus gel (11). In our studies, we found strong evidence that eosinophil-driven oxidation mediates mucus plug formation in asthma.…”

Section: Epo Generates Oxidants That Crosslink Cysteines and Stiffen mentioning

confidence: 75%

“…Notably, the product of the reaction between thiocyanate and H 2 O 2 , catalyzed by EPO, is hypothiocyanous acid (HOSCN), which is known to target thiol groups as a cytotoxic mechanism (10). Recently, we have reported that oxidation of cysteine thiol groups -abundant in mucin polymers -is a mechanism of mucus gel stiffening in the lung (11), but the possibility that EPO promotes mucus plug formation by generating oxidants that modify mucins is not considered in reviews of the pathologic effects of eosinophils in the asthmatic airway (12).…”

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confidence: 99%

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Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction

Dunican

Elicker²,

Gierada

et al. 2018

Journal of Clinical Investigation

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BACKGROUND.The link between mucus plugs and airflow obstruction has not been established in chronic severe asthma, and the role of eosinophils and their products in mucus plug formation is unknown. METHODS.In clinical studies, we developed and applied a bronchopulmonary segment-based scoring system to quantify mucus plugs on multidetector computed tomography (MDCT) lung scans from 146 subjects with asthma and 22 controls, and analyzed relationships among mucus plug scores, forced expiratory volume in 1 second (FEV1), and airway eosinophils. Additionally, we used airway mucus gel models to explore whether oxidants generated by eosinophil peroxidase (EPO) oxidize cysteine thiol groups to promote mucus plug formation. RESULTS.Mucus plugs occurred in at least 1 of 20 lung segments in 58% of subjects with asthma and in only 4.5% of controls, and the plugs in subjects with asthma persisted in the same segment for years. A high mucus score (plugs in ≥ 4 segments) occurred in 67% of subjects with asthma with FEV1 of less than 60% of predicted volume, 19% with FEV1 of 60%-80%, and 6% with FEV1 greater than 80% (P < 0.001) and was associated with marked increases in sputum eosinophils and EPO. EPO catalyzed oxidation of thiocyanate and bromide by H 2 O 2 to generate oxidants that crosslink cysteine thiol groups and stiffen thiolated hydrogels. CONCLUSION.Mucus plugs are a plausible mechanism of chronic airflow obstruction in severe asthma, and EPO-generated oxidants may mediate mucus plug formation. We propose an approach for quantifying airway mucus plugging using MDCT lung scans and suggest that treating mucus plugs may improve airflow in chronic severe asthma. TRIAL REGISTRATION. Clinicaltrials.gov NCT01718197, NCT01606826, NCT01750411, NCT01761058, NCT01761630, NCT01759186, NCT01716494, and NCT01760915.FUNDING. NIH grants P01 HL107201, R01 HL080414, U10 HL109146, U10 HL109164, U10 HL109172, U10 HL109086, U10 HL109250, U10 HL109168, U10 HL109257, U10 HL109152, and P01 HL107202 and National Center for Advancing Translational Sciences grants UL1TR0000427, UL1TR000448, and KL2TR000428.

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Section: Epo Generates Oxidants That Crosslink Cysteines and Stiffen mentioning

confidence: 75%

mentioning

confidence: 99%

Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction

Dunican

Elicker²,

Gierada

et al. 2018

Journal of Clinical Investigation

Self Cite

413

324

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“…Third, we do not know if the marked increases in oxidized tyrosine that we detect in plasma occur in other inflammatory and/ or fibrotic lung disorders, such as cystic fibrosis or chronic obstructive pulmonary disease. Levels of o,o9-dityrosine and 3-nitrotyrosine have been shown to be elevated in sputum samples from adult patients with cystic fibrosis (37,38). Increased levels of 3-nitrotyrosine have been observed in exhaled breath condensate of patients with chronic obstructive pulmonary disease, and in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome (39,40).…”

Section: Discussionmentioning

confidence: 95%

Oxidative Modifications of Protein Tyrosyl Residues Are Increased in Plasma of Human Subjects with Interstitial Lung Disease

Pennathur

Vivekanandan-Giri²,

Locy

et al. 2016

Am J Respir Crit Care Med

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Rationale: Interstitial lung diseases (ILDs) are associated with oxidative stress. Plasma biomarkers that are directly linked to oxidative stress responses in this disease have not been identified. Stable oxidation products of tyrosine residues in proteins may reflect the oxidative microenvironment in the lung or a systemic inflammatory state.Objectives: To determine if levels of protein tyrosine oxidation are elevated in plasma of patients with ILD compared with an age-and sex-matched healthy control cohort.Methods: Three tyrosine oxidation products (3-chlorotyrosine, 3-nitrotyrosine, and o,o9-dityrosine) were quantified by tandem mass spectrometry in cellular models, a mouse model of injuryinduced fibrosis, and in plasma of healthy control subjects and patients with ILD (n = 42 in each group).Measurements and Main Results: Plasma levels of 3-chlorotyrosine, 3-nitrotyrosine, and o,o9-dityrosine were markedly elevated in patients with ILD compared with control subjects with receiver operating characteristic curves separating these groups of 0.872, 0.893, and 0.997, respectively. In a murine model of lung fibrosis, levels of all three oxidative tyrosine modifications were increased in plasma and lung tissue. Cellular models support a critical role for a heme peroxidase and enzymatic sources of reactive oxygen species in the generation of these oxidized products.Conclusions: We demonstrate an increase in oxidized tyrosine moieties within proteins in the circulating plasma of patients with ILD. These data support the potential for development of oxidative stress-related biomarkers in early diagnosis, prognostication, and/or in evaluating responsiveness to emerging therapies for ILD.

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“…The apparent discrepancy between these findings is likely attributable to the timing of evaluation of lung tissues after the final challenge with antigen, which differed. Of interest in this regard is the recent demonstration that airway mucins are targets for oxidation, manifested by disulfide-based cross-links that increase mucin elasticity in association with pathological mucus gel formation (28). It is not known at this time whether mucins are targets for PSSG, and whether this attenuates cross-linking.…”

Section: Discussionmentioning

confidence: 99%

Ablation of Glutaredoxin-1 Modulates House Dust Mite–Induced Allergic Airways Disease in Mice

Hoffman¹,

Qian²,

Nolin³

et al. 2016

Am J Respir Cell Mol Biol

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Protein S-glutathionylation (PSSG) is an oxidant-induced posttranslational modification of protein cysteines that impacts structure and function. The oxidoreductase glutaredoxin-1 (Glrx1) under physiological conditions catalyzes deglutathionylation and restores the protein thiol group. The involvement of Glrx1/PSSG in allergic inflammation induced by asthma-relevant allergens remains unknown. In the present study, we examined the impact of genetic ablation of Glrx1 in the pathogenesis of house dust mite (HDM)-induced allergic airways disease in mice. Wild-type (WT) or Glrx1 2/2 mice were instilled intranasally with HDM on 5 consecutive days for 3 weeks. As expected, overall PSSG was increased in Glrx1 2/2 HDM mice as compared with WT animals. Total cells in bronchoalveolar lavage fluid were similarly increased in HDMtreated WT and Glrx1 2/2 mice. However, in response to HDM, mice lacking Glrx1 demonstrated significantly more neutrophils and macrophages but fewer eosinophils as compared with HDM-exposed WT mice. mRNA expression of the Th2-associated cytokines IL-13 and IL-6, as well as mucin-5AC (Muc5ac), was significantly attenuated in Glrx1 2/2 HDM-treated mice. Conversely, mRNA expression of IFN-g and IL-17A was increased in Glrx1 2/2 HDM mice compared with WT littermates. Restimulation of singlecell suspensions isolated from lungs or spleens with HDM resulted in enhanced IL-17A and decreased IL-5 production in cells derived from inflamed Glrx1 2/2 mice compared with WT animals. Finally, HDM-induced tissue damping and elastance were significantly attenuated in Glrx1 2/2 mice compared with WT littermates. These results demonstrate that the Glrx1-PSSG axis plays a pivotal role in HDM-induced allergic airways disease in association with enhanced type 2 inflammation and restriction of IFN-g and IL-17A.Keywords: asthma; protein S-glutathionylation; IL-17A; IFN-g; neutrophils Clinical RelevanceThis study demonstrates that the protein S-glutathionylation (PSSG)-glutaredoxin redox axis controls the nature of adaptive immune and inflammatory responses in an experimental model of allergic airways disease in mice. This advances our understanding the role that oxidative processes play in allergic disease and provides a platform for targeting PSSG chemistry to combat allergic airways disease.

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Oxidation increases mucin polymer cross-links to stiffen airway mucus gels

Cited by 217 publications

References 41 publications

Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction

Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction

Oxidative Modifications of Protein Tyrosyl Residues Are Increased in Plasma of Human Subjects with Interstitial Lung Disease

Ablation of Glutaredoxin-1 Modulates House Dust Mite–Induced Allergic Airways Disease in Mice

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