CD4<sup>+</sup>T cell-dependent airway mucus production occurs in response to IL-5 expression in lung

Justice, J. Paul; Crosby, Jeff; Borchers, Michael T.; Tomkinson, Adrian; Lee, J. J.; Lee, N. A.

doi:10.1152/ajplung.00195.2001

Cited by 41 publications

(29 citation statements)

References 40 publications

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“…Th2 cytokines, VEGF, T cells, and eosinophils are required to produce airway mucus accumulation and goblet cell degranulation (Zhu et al, 1999;Justice et al, 2002;Lee et al, 2004a, b). Although a direct role of ROS in these cells can not be ruled out, the observed decrease in mucus production in AD4-treated lung tissue may be attributed to an indirect effect on goblet cells resulting from the combination of a substantial drop in Th2 cytokine and VEGF levels as well as reduction in eosinophilia in OVA-sensitized and -challenged mice.…”

Section: Discussionmentioning

confidence: 99%

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Lee

Kim²,

Park³

et al. 2007

Exp Mol Med

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Reactive oxygen species (ROS) play an important role in the pathogenesis of airway inflammation and hyperresponsiveness. Recent studies have demonstrated that antioxidants are able to reduce airway inflammation and hyperreactivity in animal models of allergic airway disease. A newly developed antioxidant, small molecular weight thiol compound, N-acetylcysteine amide (AD4) has been shown to increase cellular levels of glutathione and to attenuate oxidative stress related disorders such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis. However, the effects of AD4 on allergic airway disease such as asthma are unknown. We used ovalbumin (OVA)-inhaled mice to evaluate the role of AD4 in allergic airway disease. In this study with OVA-inhaled mice, the increased ROS generation, the increased levels of Th2 cytokines and VEGF, the increased vascular permeability, the increased mucus production, and the increased airway resistance in the lungs were significantly reduced by the administration of AD4. We also found that the administration of AD4 decreased the increases of the NF-κB and hypoxia-inducible factor-1α (HIF-1α ) levels in nuclear protein extracts of lung tissues after OVA inhalation. These results suggest that AD4 attenuates airway inflammation and hyperresponsiveness by regulating activation of NF-κB and HIF-1α as well as reducing ROS generation in allergic airway disease.

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Section: Discussionmentioning

confidence: 99%

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Lee

Kim²,

Park³

et al. 2007

Exp Mol Med

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“…The mucus content of all of the airways per section (20 to 30, proximal to distal) was measured from groups of four to five animals as published previously. 34 An imaging program (Image ProPlus; Media Cybernetics) was used to quantify the area and intensity of PAS staining per airway. The airway MI was calculated by summing the ratio of the PAS-positive epithelial area to the total epithelial area per section and dividing by the number of airways per section.…”

Section: Assessment Of Goblet Cell Hyperplasia and Mucus Overproductionmentioning

confidence: 99%

Pseudomonas aeruginosa Exotoxin Pyocyanin Causes Cystic Fibrosis Airway Pathogenesis

Caldwell

Chen

Goetzmann

et al. 2009

The American Journal of Pathology

146

177

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The cystic fibrosis (CF) airway bacterial pathogen Pseudomonas aeruginosa secretes multiple virulence factors. Among these, the redox active exotoxin pyocyanin (PCN) is produced in concentrations up to 100 mol/L during infection of CF and other bronchiectatic airways. However, the contributions of PCN during infection of bronchiectatic airways are not appreciated. In this study, we demonstrate that PCN is critical for chronic infection in mouse airways and orchestrates adaptive immune responses that mediate lung damage. Wild-type FVBN mice chronically exposed to PCN developed goblet cell hyperplasia and metaplasia, airway fibrosis, and alveolar airspace destruction. Furthermore, after 12 weeks of exposure to PCN, mouse lungs down-regulated the expression of T helper (Th) type 1 cytokines and polarized toward a Th2 response. Cellular analyses indicated that chronic exposure to PCN profoundly increased the lung population of recruited macrophages , CD4 ؉ T cells , and neutrophils responsible for the secretion of these cytokines. PCN-mediated goblet cell hyperplasia and metaplasia required Th2 cytokine signaling through the Stat6 pathway. In summary , this study establishes that PCN is an important P. aeruginosa virulence factor capable of directly inducing pulmonary pathophysiology in mice , consistent with changes observed in CF and other bronchiectasis lungs.

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“…In the absence of IL-13, Th2 cells that produced IL-4 and IL-5 could no longer stimulate mucus production (40,41). Furthermore, mucus hypersecretion in transgenic mice with lung-specific overexpression of IL-4, IL-5, or IL-9 was found to be IL-13 dependent (41)(42)(43). For example, mucous metaplasia was abolished in transgenic mice overexpressing IL-9 when IL-13 signaling was inhibited through STAT6 deletion.…”

Section: Mechanisms Of Mucus Metaplasia Th2 Cytokinesmentioning

confidence: 99%

Advances in Mucous Cell Metaplasia

Curran

Cohn

2010

Am J Respir Cell Mol Biol

156

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Mucous cell metaplasia is induced in response to harmful insults and provides front-line protection to clear the airway of toxic substances and cellular debris. In chronic airway diseases mucous metaplasia persists and results in airway obstruction and contributes significantly to morbidity and mortality. Mucus hypersecretion involves increased expression of mucin genes, and increased mucin production and release. The past decade has seen significant advances in our understanding of the molecular mechanisms by which these events occur. Inflammation stimulates epidermal growth factor receptor activation and IL-13 to induce both Clara and ciliated cells to transition into goblet cells through the coordinated actions of FoxA2, TTF-1, SPDEF, and GABA A R. Ultimately, these steps lead to up-regulation of MUC5AC expression, and increased mucin in goblet cell granules that fuse to the plasma membrane through actions of MARCKS, SNAREs, and Munc proteins. Blockade of mucus in exacerbations of asthma and chronic obstructive pulmonary disease may affect morbidity. Development of new therapies to target mucus production and secretion are now possible given the advances in our understanding of molecular mechanisms of mucous metaplasia. We now have a greater incentive to focus on inhibition of mucus as a therapy for chronic airway diseases.

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CD4⁺T cell-dependent airway mucus production occurs in response to IL-5 expression in lung

Cited by 41 publications

References 40 publications

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Pseudomonas aeruginosa Exotoxin Pyocyanin Causes Cystic Fibrosis Airway Pathogenesis

Advances in Mucous Cell Metaplasia

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CD4+T cell-dependent airway mucus production occurs in response to IL-5 expression in lung

Cited by 41 publications

References 40 publications

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

A novel thiol compound, N-acetylcysteine amide, attenuates allergic airway disease by regulating activation of NF-κB and hypoxia-inducible factor-1α

Pseudomonas aeruginosa Exotoxin Pyocyanin Causes Cystic Fibrosis Airway Pathogenesis

Advances in Mucous Cell Metaplasia

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Product

Resources

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CD4⁺T cell-dependent airway mucus production occurs in response to IL-5 expression in lung