Neutrophil extracellular trap production and CCL4L2 expression influence corticosteroid response in asthma.

The association between neutrophil extracellular traps (NETs) and response to inhaled corticosteroids (ICS) in asthma is unclear. To better understand this relationship, we analyzed the blood transcriptomes from children with controlled and uncontrolled asthma in the Taiwanese Consortium of Childhood Asthma Study using weighted gene coexpression network analysis and pathway enrichment methods. We identified 298 uncontrolled asthma-specific differentially expressed genes and one gene module associated with neutrophil-mediated immunity, highlighting a potential role for neutrophils in uncontrolled asthma. We also found that NET abundance was associated with nonresponse to ICS in patients. In a neutrophilic airway inflammation murine model, steroid treatment could not suppress neutrophilic inflammation and airway hyperreactivity. However, NET disruption with deoxyribonuclease I (DNase I) efficiently inhibited airway hyperreactivity and inflammation. Using neutrophil-specific transcriptomic profiles, we found that CCL4L2 was associated with ICS nonresponse in asthma, which was validated in human and murine lung tissue. CCL4L2 expression was also negatively correlated with pulmonary function change after ICS treatment. In summary, steroids fail to suppress neutrophilic airway inflammation, highlighting the potential need to use alternative therapies such as leukotriene receptor antagonists or DNase I that target the neutrophil-associated phenotype. Furthermore, these results highlight CCL4L2 as a potential therapeutic target for individuals with asthma refractory to ICS.

Analysis of Volatile Organic Compounds in Exhaled Breath Following a COMEX-30 Treatment Table.

The COMEX-30 hyperbaric treatment table is used to manage decompression sickness in divers but may result in pulmonary oxygen toxicity (POT). Volatile organic compounds (VOCs) in exhaled breath are early markers of hyperoxic stress that may be linked to POT. The present study assessed whether VOCs following COMEX-30 treatment are early markers of hyperoxic stress and/or POT in ten healthy, nonsmoking volunteers. Because more oxygen is inhaled during COMEX-30 treatment than with other treatment tables, this study hypothesized that VOCs exhaled following COMEX-30 treatment are indicators of POT. Breath samples were collected before and 0.5, 2, and 4 h after COMEX-30 treatment. All subjects were followed-up for signs of POT or other symptoms. Nine compounds were identified, with four (nonanal, decanal, ethyl acetate, and tridecane) increasing 33-500% in intensity from before to after COMEX-30 treatment. Seven subjects reported pulmonary symptoms, five reported out-of-proportion tiredness and transient ear fullness, and four had signs of mild dehydration. All VOCs identified following COMEX-30 treatment have been associated with inflammatory responses or pulmonary diseases, such as asthma or lung cancer. Because most subjects reported transient pulmonary symptoms reflecting early-stage POT, the identified VOCs are likely markers of POT, not just hyperbaric hyperoxic exposure.

Biomarkers and asthma management: analysis and potential applications.

PURPOSE OF REVIEW: Asthma features a high degree of heterogeneity in both pathophysiology and therapeutic response, resulting in many asthma patients being treated inadequately. Biomarkers indicative of underlying pathological processes could be used to identify disease subtypes, determine prognosis and to predict or monitor treatment response. However, the newly identified as well as more established biomarkers have different applications and limitations. RECENT FINDINGS: Conventional markers for type 2-high asthma, such as blood eosinophils, fraction of exhaled nitric oxide, serum IgE and periostin, feature limited sensitivity and specificity despite their significant correlations. More distinctive models have been developed by combining biomarkers and/or using omics techniques. Recently, a model with a positive predictive value of 100% for identification of type 2-high asthma based on a combination of minimally invasive biomarkers was developed. SUMMARY: Individualisation of asthma treatment regimens on the basis of biomarkers is necessary to improve asthma control. However, the suboptimal properties of currently available conventional biomarkers limit its clinical utility. Newly identified biomarkers and models based on combinations and/or omics analysis must be validated and standardised before they can be routinely applied in clinical practice. The development of robust biomarkers will allow development of more efficacious precision medicine-based treatment approaches for asthma.