An airway epithelial iNOS–DUOX2–thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma

Voraphani, Nipasiri; Gladwin, Mark T.; Contreras, Adriana; Kaminski, Naftali; Tedrow, John; Milošević, Jadranka; Bleecker, Eugene R.; Meyers, Deborah A.; Ray, Anuradha; Ray, Prabir; Erzurum, Serpil C.; Busse, William W.; Zhao, Jiang; Trudeau, John B.; Wenzel, Sally E.

doi:10.1038/mi.2014.6

Cited by 104 publications

(115 citation statements)

References 52 publications

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“…This focuses our attention on other effector functions of the T cell cytokines in asthma pathophysiology. We have recently shown synergistic interactions between IFN-γ and low levels of IL-13 in induction of nitro-oxidative stress in primary airway epithelial cells (33). Despite the use of high doses of oral CS, IL-13 was still detectable at low levels in the BAL cell culture supernatants of SA subjects in our study ( Figure 1C).…”

Section: Discussionmentioning

confidence: 56%

High IFN-γ and low SLPI mark severe asthma in mice and humans

Raundhal¹,

Morse²,

Khare³

et al. 2015

J. Clin. Invest.

335

304

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Results SA subjects harbor more IFN-γ + CD4+ T cells in their airways compared with MMA subjects. A total of 66 subjects, 33 classified with MMA and 33 classified with SA, were included in this study; details of patient characteristics are included in Table 1. Of note, biological samples, such as cells in BAL fluid used for differential cell counts and cytokine expression, were analyzed from a subset of these subjects based on availability, as described in each figure legend. Since the recovery of BAL Severe asthma (SA) is a challenge to control, as patients are not responsive to high doses of systemic corticosteroids (CS). In contrast, mild-moderate asthma (MMA) is responsive to low doses of inhaled CS, indicating that Th2 cells, which are dominant in MMA, do not solely orchestrate SA development. Here, we analyzed broncholalveolar lavage cells isolated from MMA and SA patients and determined that IFN-γ (Th1) immune responses are exacerbated in the airways of individuals with SA, with reduced Th2 and IL-17 responses. We developed a protocol that recapitulates the complex immune response of human SA, including the poor response to CS, in a murine model. Compared with WT animals, Ifng -/-mice subjected to this SA model failed to mount airway hyperresponsiveness (AHR) without appreciable effect on airway inflammation. Conversely, AHR was not reduced in Il17ra -/-mice, although airway inflammation was lower. Computer-assisted pathway analysis tools linked IFN-γ to secretory leukocyte protease inhibitor (SLPI), which is expressed by airway epithelial cells, and IFN-γ inversely correlated with SLPI expression in SA patients and the mouse model. In mice subjected to our SA model, forced SLPI expression decreased AHR in the absence of CS, and it was further reduced when SLPI was combined with CS. Our study identifies a distinct immune response in SA characterized by a dysregulated IFN-γ/SLPI axis that affects lung function.

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Section: Discussionmentioning

confidence: 56%

High IFN-γ and low SLPI mark severe asthma in mice and humans

Raundhal¹,

Morse²,

Khare³

et al. 2015

J. Clin. Invest.

335

304

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“…IL-13 and IFN-γ synergistically enhanced iNOS activation and production of nitrite and 3 nitro-tyrosine (3NT) in epithelial cells, which correlated with increased H 2 O 2 production (114). This in vitro effect on oxidative stress in the epithelial cells closely corresponded to high levels of 3NT and IFNG mRNA in the lungs of severe asthma subjects (114). Figure 2 illustrates our current understanding of altered immune responses in the nasal tissue and airways that underlie severe asthma.…”

Section: Downstream Effects Of Ifn-γ Influencing the Severe Asthma Phmentioning

confidence: 99%

“…Thus, it is possible that SLPI plays a fundamental role in inhibiting both allergen-and cell-associated proteases such that SLPI downregulation promotes a severe asthma phenotype via effects on AHR, FeNO levels, and airway remodeling. IFN-γ also synergizes with type 2 cytokines such as IL-13 to promote nitro-oxidative stress in airway epithelial cells (114). IL-13 and IFN-γ synergistically enhanced iNOS activation and production of nitrite and 3 nitro-tyrosine (3NT) in epithelial cells, which correlated with increased H 2 O 2 production (114).…”

Section: Downstream Effects Of Ifn-γ Influencing the Severe Asthma Phmentioning

confidence: 99%

“…Ancillary studies of type 2-targeted therapies to define better biomarkers are clearly needed to further guide the use of these therapies. While a Th1 response has been associated with severe asthma in different studies (48,(89)(90)(91)114), more investigations are necessary using larger patient cohorts for a better understanding of the prevalence of this response and to also determine whether this response is related to specific patient demographics. The influence of comorbidities on severe asthma pathogenesis also needs to be better understood for therapeutic guidance.…”

Section: Downstream Effects Of Ifn-γ Influencing the Severe Asthma Phmentioning

confidence: 99%

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Current concepts of severe asthma

Ray¹,

Raundhal²,

Oriss³

et al. 2016

Journal of Clinical Investigation

197

175

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“…These ROS can react with the 'constitutively' produced NO, leading to the observed unchanged 3-nitrotyrosine (3-NT) levels in patients with asthma [30]. Indeed, an in vitro study using human alveolar epithelial cells of patients with severe asthma, has shown that not only nitrite, produced by iNOS, but also H 2 O 2 , produced by dual oxidases, are important in the formation of 3-NT [51].…”

Section: Inducible No Synthase Inhibitorsmentioning

confidence: 99%

Role of the nitric oxide–soluble guanylyl cyclase pathway in obstructive airway diseases

Dupont

Glynos²,

Bracke

et al. 2014

Pulmonary Pharmacology & Therapeutics

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a b s t r a c tNitric oxide (NO) is a gaseotransmitter, which is involved in many signaling processes in health and disease. Three enzymes generate NO from L-arginine, with citrulline formed as a by-product: neuronal NO synthase (nNOS or NOS1), endothelial NOS (eNOS or NOS3) and inducible NOS (iNOS or NOS2). NO is a ligand of soluble guanylyl cyclase (sGC), an intracellular heterodimer enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP). cGMP further activates protein kinase G that eventually reduces the smooth muscle tone in bronchi or vessels. Phosphodiesterase 5 (PDE 5 ) degrades cGMP to GMP. However, NO reacts with superoxide anion (O À 2 ), leading to formation of the proinflammatory molecule peroxynitrite.Under physiological conditions, NO plays a homeostatic bronchoprotective role in healthy subjects. In obstructive airway diseases, NO can be beneficial by its bronchodilating effect, but could also be detrimental by the formation of peroxynitrite. Since asthma and COPD are associated with increased levels of exhaled NO, chronic inflammation and increased airway smooth muscle tone, the NO/sGC/cGMP pathway could be involved in these highly prevalent obstructive airway diseases. Here we review the involvement of NO, NO synthases, guanylyl cyclases, cGMP and phophodiesterase-5 in asthma and COPD and potential therapeutic approaches to modulate this pathway.

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An airway epithelial iNOS–DUOX2–thyroid peroxidase metabolome drives Th1/Th2 nitrative stress in human severe asthma

Cited by 104 publications

References 52 publications

High IFN-γ and low SLPI mark severe asthma in mice and humans

High IFN-γ and low SLPI mark severe asthma in mice and humans

Current concepts of severe asthma

Role of the nitric oxide–soluble guanylyl cyclase pathway in obstructive airway diseases

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