Administration of vitamin E attenuates airway inflammation through restoration of Nrf2 in a mouse model of asthma.

Accumulating evidence reveals that ROS is one of the key mediators that contribute to the development of asthma. Studies on antioxidants have shown to have beneficial effects on asthma management. However, we still do not know the precise mechanism, and the effects depend on age. This study was conducted to assess the levels of ROS and the effect of antioxidants in younger and older mice using an eosinophilic asthma model. We analyzed airway hyperresponsiveness (AHR), cytokines in bronchoalveolar lavage fluid (BALF), inflammatory cell counts, and the expression levels of NFκB, Nrf2, EPx, and EDN in the lung tissue, as well as the level of ROS in the lung tissue and BALF. The degree of eosinophilia and the levels of IL-5, ROS, and NFκB were significantly increased, whereas the endogenous levels of vitamin E and Nrf2 were decreased in the lung and BALF in the older mice compared to younger mice. The administration of vitamin E attenuated AHR, airway inflammation, and the level of IL-13 and ROS and enhanced the Nrf2 level in the older mice compared to the younger mice. Taken together, vitamin E treatment may have the therapeutic potential through restoration of the Nrf2 level, especially in elderly asthma.

Extracellular Traps: A Novel Therapeutic Target for Severe Asthma.

Asthma is a complicated disease defined by a combination of clinical symptoms and physiological characteristics. Typically, asthma is diagnosed by the presence of episodic cough, wheezing, or dyspnea triggered by variable environmental factors (allergens and respiratory infections), and reversible airflow obstruction. To date, the majority of asthmatic patients have been adequately controlled by anti-inflammatory/bronchodilating agents, but those with severe asthma (SA) have not been sufficiently controlled by high-dose inhaled corticosteroids-long-acting beta-agonists plus additional controllers including leukotriene modifiers. Accordingly, these uncontrolled patients provoke a special issue, because they consume high healthcare resources, requiring innovative precision medicine solutions. Recently, phenotyping based on biomarkers of airway inflammation has led to elucidating the pathophysiological mechanism of SA, where emerging evidence has highlighted the significance of eosinophil or neutrophil extracellular traps contributing to the development of SA. Here, we aimed to provide current findings about extracellular traps as a novel therapeutic target for asthma to address medical unmet needs.

Role of Thymus and Activation-Regulated Chemokine in Allergic Asthma.

BACKGROUND: Asthma is a chronic inflammatory airway disease characterized by the predominant infiltration of inflammatory cells in the airways. Thymus and activation-regulated chemokine/C-C motif chemokine 17 (TARC/CCL17) is a chemokine responsible for trafficking T helper 2 cells into sites of allergic inflammation. OBJECTIVE: To validate the role of TARC in association with clinical and inflammatory parameters in adult asthmatics. METHODS: We enrolled 128 asthmatic patients and 70 healthy controls (HCs). Asthma-related clinical and laboratory parameters, including lung function and eosinophil counts, were measured. Serum levels of TARC, free immunoglobulin E (IgE), and eosinophil-derived neurotoxin (EDN) were determined by using enzyme-linked immunosorbent assay; serum total IgE level was measured using ImmunoCAP. The levels of inflammatory lipid mediators, such as leukotriene E4 (LTE4), 15-hydroxyeicosatetraenoic acid (15-HETE), thromboxane B2 (TXB2), and prostaglandin F2α (PGF2α), were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Serum TARC levels are significantly higher in asthmatics than in HCs and in allergic asthmatics than in HCs (P < 0.010 for all), with significantly negative correlations between serum TARC levels and FEV1%/MMEF% values (r = -0.314, r = -0.268, P < 0.050 for both). The patients with higher serum TARC levels had higher levels of serum total and free IgE levels (P < 0.050 for both) with positive correlations to serum levels of EDN, TXB2, and 15-HETE (r = 0.233, r = 0.264, and r = 0.223, respectively, P < 0.050 for all). CONCLUSION: We suggest the role of TARC in allergic asthma via contributing to mast cell and eosinophilic inflammation.

NSAID-Exacerbated Respiratory Disease (NERD): From Pathogenesis to Improved Care.

Nonsteroidal antiinflammatory drug (NSAID)-exacerbated respiratory disease (NERD) is characterized by moderate-to-severe asthma and a higher prevalence of chronic rhinosinusitis/nasal polyps, but is a highly heterogeneous disorder with various clinical manifestations. Two major pathogenic mechanisms are: (1) overproduction of cysteinyl leukotrienes with dysregulation of arachidonic acid metabolism and (2) increased type 2 eosinophilic inflammation affected by genetic mechanisms. Aspirin challenge is the gold standard to diagnose NERD, whereas reliable in vitro biomarkers have yet not been identified. Therapeutic approaches have been done on the basis of disease severity with the avoidance of culprit and cross-reacting NSAIDs, and when indicated, aspirin desensitization is an effective treatment option. Biologic approaches targeting Type 2 cytokines are emerging as potential therapeutic options. Here, we summarize the up-to-date evidence of pathophysiologic mechanisms and diagnosis/management approaches to the patients with NERD with its phenotypic classification.

Osteopontin contributes to late-onset asthma phenotypes in adult asthma patients.

Patients with late-onset asthma (LOA) have poor clinical outcomes. Osteopontin (OPN) is associated with airway inflammation and remodeling. To investigate the role of OPN in LOA compared to early-onset asthma (EOA), serum OPN levels were compared between 131 adult asthma patients (48 LOA and 83 EOA patients) and 226 healthy controls (HCs). BALB/c mice were sensitized with ovalbumin with/without polyinosinic-polycytidylic acid (poly(I:C)) from week 6 (A6 mice) or week 12 (A12 mice) after birth. Airway hyperresponsiveness (AHR), bronchoalveolar lavage fluid (BALF), cell counts, histology, and Spp1 expression were assessed. The levels of OPN, transforming growth factor ß1 (TGF-ß1), chitinase 3-like 1 (CH3L1), and interleukin (IL) 5 were measured by ELISA. The expression of Smad3 phosphorylation and tissue transglutaminase 2 (TGM2) was evaluated by Western blot. The serum OPN levels were significantly higher in asthma patients than in HCs and in LOA patients than in those with EOA (P < 0.05) and were positively correlated with serum TGF-ß1 and CH3L1 (r = 0.174, r = 0.264; P < 0.05). A12 mice showed elevated AHR with increased levels of OPN/TGF-ß1/IL-5 in BALF and Spp1 compared to A6 mice. Poly(I:C) induced remarkable TGF-ß1, CH3L1, Th2 cytokine, and OPN levels in BALF and the expression of phosphorylated Smad3, TGM2, and Spp1 in the lungs. OPN triggered TGF-ß1/Smad3 signaling in the lungs, which was suppressed by dexamethasone and anti-IL5 antibody. In conclusion, aging and exposure to viral infections may induce OPN release and consequently modulate inflammation and TGF-ß1/Smad3-related remodeling, contributing to the development of LOA.