Blockade of neutrophil extracellular traps ameliorates toluene diisocyanate-induced steroid-resistant asthma.

BACKGROUND AND PURPOSE: Toluene diisocyanate (TDI)-induced asthma is characterized by mixed inflammation dominated by neutrophils, and is refractory to steroid treatment. Neutrophil extracellular traps (NETs) play an important role in severe asthma, but their role in TDI-induced asthma models is unclear. This study focused on the role and mechanism of NETs in steroid-resistant TDI-induced asthma. METHODS: Induced sputum was collected from 85 asthmatic patients and 25 healthy controls to detect eDNA. A murine TDI-induced asthma model was prepared, and asthmatic mice were given dexamethasone or DNase I. In vitro, the human bronchial epithelial cell line HBE was stimulated with NETs or TDI-human serum albumin (TDI-HSA). RESULTS: Asthma patients had higher sputum eDNA compared to healthy subjects. In asthma patients, eDNA was positively correlated with sputum neutrophils, and negatively correlated with FEV1%predicted. Airway inflammation, airway reactivity, Th2 cytokine levels in lymph supernatant, and levels of NETs were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by DNase I, but not by dexamethasone. Inhibition of NETs improved interleukin (IL)-8 and MKP1 mRNA expression, and reduced phosphorylation of GR-S226 induced by TDI. Inhibition of NETs improved airway epithelial barrier disruption, as well as p38 and ERK signaling pathways in TDI-induced asthmatic mice. In vitro, NETs promoted the expression of IL-8 mRNA in HBE cells, and reduced the expression of MKP1. IL-8 elevation induced by NETs was suppressed by a p38 inhibitor or ERK inhibitor, but not by dexamethasone. Pretreatment with RAGE inhibitor reduced NETs induced p38/ERK phosphorylation and IL-8 levels in HBE cells. CONCLUSION: Our data suggest that targeting NETs might effectively improved TDI-induced airway inflammation and airway epithelial barrier function. This may potentially be a treatment for patients with steroid-resistance asthma.

[Lung sounds can be used as an indicator for assessing severity of chronic obstructive pulmonary disease at the initial diagnosis].

OBJECTIVE: To assess the value of pulmonary auscultation for evaluating the severity of chronic obstructive pulmonary disease (COPD) at the initial diagnosis. METHODS: The patients with newly diagnosed COPD in our hospital between May, 2016 and May, 2019 were enrolled in this study. According to the findings of pulmonary auscultation, the lung sounds were classified into 5 groups: normal breathing sounds, weakened breathing sounds, weakened breathing sounds with wheezing, obviously weakened breathing sounds, and obviously weakened breathing sounds with wheezing. The pulmonary function of the patients was graded according to GOLD guidelines, and the differential diagnosis of COPD from asthmatic asthma COPD overlap (ACO) was made based on the GOLD guidelines and the European Respiratory Criteria. RESULTS: A total of 1046 newly diagnosed COPD patients were enrolled, including 949 male and 97 female patients with a mean age of 62.6± 8.71. According to the GOLD criteria, 88.1% of the patients were identified to have moderate or above COPD, 50.0% to have severe or above COPD; a further diagnosis of ACO was made in 347 (33.2%) of the patients. ANOVA analysis showed significant differences in disease course, FEV1, FEV1%, FEV1/FVC, FVC, FVC% and mMRC among the 5 auscultation groups (P < 0.001), but FENO did not differ significantly among them (P=0.097). The percentage of patients with wheezing in auscultation was significantly greater in ACO group than in COPD group (P < 0.001). Spearman correlation analysis showed that lung sounds was significantly correlated with disease severity, FEV1, FEV1%, FVC and FVC% of the patients (P < 0.001); Multiple linear regression analysis showed that a longer disease course, a history of smoking and lung sounds were all associated with poorer lung functions and a greater disease severity. CONCLUSIONS: Lung sounds can be used as an indicator for assessing the severity of COPD at the initial diagnosis.