Non-allergic eosinophilic inflammation and airway hyperresponsiveness induced by diesel engine exhaust through activating ILCs.

RATIONALE: Diesel engine exhaust (DEE) is associated with the development and exacerbation of asthma. Studies have shown that DEE can aggravate allergen-induced eosinophilic inflammation in lung. However, it remains not clear that whether DEE alone could initiate non-allergic eosinophilic inflammation and airway hyperresponsiveness (AHR) through innate lymphoid cells (ILCs) pathway. OBJECTIVE: This study aims to investigate the airway inflammation and hyperresponsiveness and its relationship with ILC after DEE exposure. METHOD: Non-sensitized BALB/c mice were exposed in the chamber of diesel exhaust or filtered air for 2, 4, and 6 weeks (4 h/day, 6 days/week). Anti-CD4 mAb or anti-Thy1.2 mAb was administered by intraperitoneal injection to inhibit CD4+T or ILCs respectively. AHR、airway inflammation and ILCs were assessed. RESULT: DEE exposure induced significantly elevated level of neutrophils, eosinophils, collagen content at 4, 6 weeks. Importantly, the airway AHR was only significant in the 4weeks-DEE exposure group. No difference of the functional proportions of Th2 cells was found between exposure group and control group. The proportions of IL-5+ILC2, IL-17+ILC significantly increased in 2, 4weeks-DEE exposure group. After depletion of CD4+T cells, both the proportion of IL-5+ILC2 and IL-17A ILCs was higher in the 4weeks-DEE exposure group which induced AHR, neutrophilic and eosinophilic inflammation accompanied by the IL-5, IL-17A levels. CONCLUSION: Diesel engine exhaust alone can imitate asthmatic characteristics in mice model. Lung-resident ILCs are one of the major effectors cells responsible for a mixed Th2/Th17 response and AHR.

An mTOR and DNA-PK dual inhibitor CC-115 hinders non-small cell lung cancer cell growth.

Molecularly-targeted agents are still urgently needed for better non-small cell lung cancer (NSCLC) therapy. CC-115 is a potent DNA-dependent protein kinase (DNA-PK) and mammalian target of rapamycin (mTOR) dual blocker. We evaluated its activity in different human NSCLC cells. In various primary human NSCLC cells and A549 cells, CC-115 potently inhibited viability, cell proliferation, cell cycle progression, and hindered cell migration/invasion. Apoptosis was provoked in CC-115-stimulated NSCLC cells. The dual inhibitor, however, was unable to induce significant cytotoxic and pro-apoptotic activity in the lung epithelial cells. In primary NSCLC cells, CC-115 blocked activation of mTORC1/2 and DNA-PK. Yet, CC-115-induced primary NSCLC cell death was more potent than combined inhibition of DNA-PK plus mTOR. Further studies found that CC-115 provoked robust oxidative injury in primary NSCLC cells, which appeared independent of mTOR-DNA-PK dual blockage. In vivo studies showed that CC-115 oral administration in nude mice remarkably suppressed primary NSCLC cell xenograft growth. In CC-115-treated NSCLC xenograft tissues, mTOR-DNA-PK dual inhibition and oxidative injury were detected. Together, CC-115 potently inhibits NSCLC cell growth.

Inhibition of TRPA1 reduces airway inflammation and hyperresponsiveness in mice with allergic rhinitis.

This study was conducted to investigate whether a transient receptor potential ankyrin 1 (TRPA1) antagonist (HC-030031) can reduce airway inflammation and hyperresponsiveness in a murine allergic rhinitis (AR) model. BALB/c mice were sensitized and challenged by ovalbumin (OVA) to induce AR. HC-030031 or vehicle was administrated to mice via intraperitoneal injection prior to OVA challenges. Nose-scratching events, histopathologic alterations of the airways, and bronchial hyperresponsiveness (BHR) were assessed. Differential cells and proinflammatory cytokines in the nasal lavage (NAL) and bronchoalveolar lavage (BAL) fluid were measured. Expressions of TRPA1 in nasal mucosa were examined by immunohistochemistry. TRPA1-expressing vagal neurons were labeled by immunofluorescent staining. HC-030031-treated AR mice had markedly reduced type-2 inflammation in nasal mucosa and ameliorated-nose-scratching events than AR mice received vehicle. HC-030031 treatment also dramatically reduced leucocyte numbers and IL-8 level in the BAL fluid, inhibited lower airway remodeling and fibrosis, and nearly abolished BHR. HC-0300031 treatment significantly inhibited the upregulated number of TRPA1 expressing nasal epithelial cells and TRPA1 expressing sensory neurons, leading to downregulation of SP in both upper and lower airways. Targeting TRPA1 may represent a promising strategy for treating AR and AR-related asthma.

Glial activation and inflammation in the NTS in a rat model after exposure to diesel exhaust particles.

Airway pollution can affect the central nervous system, but whether this causes glial activation and inflammation in the nucleus of solitary tract (NTS) remains unclear. We used a rat model with exposure to diesel exhaust particulate matter (DEP) at 200 µg/m3 (low exposure) and 1000 µg/m3 (high exposure) for 14 days. Activation of microglia and astrocytes in the NTS was assessed using Iba-1 and glial fibrillary acidic protein (GFAP) staining. The expression of neurotrophic factors including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) in the NTS were evaluated by immunofluorescence. Changes in the intracellular structure of NTS neurons were observed via electron microscopy. Inflammatory cytokines and oxidant stress levels in the medulla were also measured. Exposure to DEP can cause NTS inflammation as well as airway inflammation, especially in the H-exposure group. We showed that the numbers of microglia and astrocytes in the NTS, as well as NGF expression in the NTS, were significantly higher in both exposure groups than in controls, but BDNF or GDNF expression was not detected. Exposure to DEP induced ultrastructural changes in NTS neurons as reflected by endoplasmic reticulum dilation, ribosomal loss, mitochondrial vacuolization, and a sparse myelin sheath. Medulla inflammation and an imbalance of oxidants and antioxidants also resulted from exposure to DEP. The H-exposure group showed an imbalance of oxidants and antioxidants with decreased levels of SOD and GSH and increased levels of MDA and ROS compared to the control group (both p < 0.01) in the medulla. Inflammatory cytokines (IL-1ß, IL-6, and TNF-α) were also significantly increased in the H-exposure group. Fourteen days of exposure to DEP can affect the NTS neurons in rat. Glial activation and inflammation may play important roles in the response of the NTS to DEP.

Prevalence and risk factors of mental distress in China during the outbreak of COVID-19: A national cross-sectional survey.

OBJECTIVE: As a result of the pandemic of COVID-19, the public have been experiencing psychological distress. However, the prevalence of psychological distress during the COVID-19 pandemic remains unknown. Our objective was to evaluate the prevalence of psychological distress during COVID-19 outbreak and their risk factors, especially their internal paths and causality. METHODS: A nationwide cross-sectional survey of the prevalence of mental disorders was conducted. We used Hospital Anxiety and Depression Scale (HADS) to estimate the prevalence of anxiety and depression. The internal paths and the causality of the psychological health were analyzed using a structural equation modeling (SEM) approach. RESULTS: A total of 24,789 respondents completed the survey. We found that the overall prevalence of anxiety, depression, combination of anxiety, and depression were 51.6% (95% CI: 51.0-52.2), 47.5% (95% CI: 46.9-48.1), and 24.5% (95% CI: 24.0-25.0), respectively. The risk of psychological disorders in men was higher than that in women. The status of psychological health was different across different age groups, education levels, occupations, and income levels. The SEM analysis revealed that inadequate material supplies, low income, low education, lack of knowledge or confidence of the epidemic, and lack of exercise are major risk factors for psychological distress. CONCLUSIONS: The evidence from this survey poses serious challenges related to the high prevalence of psychological distress, but also offers strategies to deal with the mental health problems caused by the COVID-19 pandemic.

Age and Sex Distribution of Chinese Chronic Cough Patients and Their Relationship With Capsaicin Cough Sensitivity.

PURPOSE: An older female predominance has been reported among chronic cough patients in Western countries, which is considered to be associated with a higher cough sensitivity in females. However, the characteristics of Chinese chronic cough patients remain unclear. This study aimed to explore the age and sex distribution as well as their relationship with cough reflex sensitivity to capsaicin in Chinese chronic cough patients. METHODS: We analyzed the demographic features of 1,882 consecutive chronic cough patients who attended our cough clinic in Guangzhou, China. Cough sensitivity to capsaicin, which was defined as the lowest concentration of capsaicin causing 5 coughs or more (C5), was measured in 539 of the 1,882 patients and 68 healthy volunteers. RESULTS: The mean age of the patients was 43.0 ± 13.7 years and patients aged <50 years accounted for more than two-thirds of the study population. Around 87% of the patients were never-smokers. The proportion of females (51.5%) was almost equal to that of males (48.5%). The pattern of the age and sex distribution was consistently reflected within most common causes of chronic cough, while a female predominance was shown in patients with cough-variant asthma and patients aged ≥50 years. Female patients had higher cough sensitivity to capsaicin than male patients (log C5: 1.58 ± 0.84 vs. 2.04 ± 0.84 µmol/L, P = 0.001), and patients aged ≥50 years had higher cough sensitivity to capsaicin than patients aged <50 years. CONCLUSIONS: In China, patients with chronic cough have a roughly equal sex distribution and a middle-aged predominance, irrespective of a higher cough sensitivity to capsaicin in females and older patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02591550.

Vagotomy decreases the neuronal activities of medulla oblongata and alleviates neurogenic inflammation of airways induced by repeated intra-esophageal instillation of HCl in guinea pigs.

Neuronal activity in the medulla oblongata and neurogenic inflammation of airways were investigated in a guinea pig model induced by repeated intra-esophageal instillation of hydrochloric acid (HCl) after vagotomy. Unilateral vagotomy was performed in the vagotomy group, while a sham-operation was performed in the sham group. Operation was not conducted in sham control group. Airway inflammation was observed with hematoxylin and eosin (HE) staining. C-fos protein was measured by immunohistochemistry (IHC) and Western blot (WB). Substance P was examined by IHC and enzyme-linked immuno sorbent assay (ELISA). Airway microvascular permeability was detected by evans blue dye (EBD) fluorescence. Inflammation of airway was observed in the trachea and bronchi after chronic HCl perfusion into the lower esophagus, and was alleviated after unilateral vagotomy. C-fos expression in the medulla oblongata was lower in the vagotomy group compared to the sham control and sham groups. Substance P-like immunoreactivity (SP-li), concentration and microvascular leakage in airway were lower in the vagotomy group than that in the other groups. Our results suggest that vagotomy improved neurogenic inflammation of airways and decreased neuronal activities, the afferent nerves and neurons in medulla oblongata may be involved in neurogenic inflammation of airways mediated by esophageal-bronchial reflex.