Long-term exposure to particulate matter 2.5 mu m (PM2.5) air pollution is associated with an increased risk of lung cancer. However, the evidence is limited in low-income and middle-income countries. We estimated the association between the incidence of lung cancer and PM2.5 air pollution exposure in the Urban Employee Basic Medical Insurance (UEBMI) beneficiaries in China. A total of 16 483 new lung cancer cases diagnosed from 12 966 137 UEBMI beneficiaries from 36 cities between 2013 and 2016. The relative risk for lung cancer associated with a 10 mu g/m(3) increase in 3-year PM2.5 exposure was 1.12 (95% CI 1.00 to 1.26). The population attributable risk estimated for a reduction in PM2.5 concentration to 35 mu g/m(3) corresponded to a decrease of 14% in cases of lung cancer. Reducing PM2.5 air pollution has a significant public health benefit.
Introduction Eosinophils are critical in allergic disorders, and promoting eosinophil death effectively attenuates allergic airway inflammation. Ferroptosis is a recently described novel form of cell death; however, little is known about ferroptosis in eosinophils and related diseases. This study aimed to investigate the effects of ferroptosis-inducing agents (FINs) on eosinophil death and allergic airway inflammation, and to explore their potential synergistic effect with glucocorticoids (GCs). Methods Eosinophils isolated from the peripheral blood of humans or mice were incubated with FINs, and eosinophil ferroptosis was assessed. The in vivo effects of FINs alone or in combination with dexamethasone (DXMS) were examined in a mouse model of allergic airway inflammation. Bronchoalveolar lavage fluid and lung tissue were collected to examine airway inflammation. Results Treatment with FINs time and dose dependency induced cell death in human and mouse eosinophils. Interestingly, FINs induced non-canonical ferroptosis in eosinophils, which generated morphological characteristics unique to ferroptosis and was iron dependent but was independent of lipid peroxidation. The antioxidants glutathione and N-acetylcysteine significantly attenuated FIN-induced cell death. Treatment with FINs triggered eosinophil death in vivo and eventually relieved eosinophilic airway inflammation in mice. Furthermore, FINs exerted a synergistic effect with DXMS to induce eosinophil death in vitro and to alleviate allergic airway inflammation in vivo. Conclusions FINs induced ferroptosis-like cell death of eosinophils, suggesting their use as a promising therapeutic strategy for eosinophilic airway inflammation, especially due to the advantage of their synergy with GCs in the treatment of allergic disorders.
Background Type 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated. Objective To investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model. Methods Circulating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well. Results The number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS. Conclusions These results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.
Background Current literature supports cross-sectional association between childhood obstructive sleep apnoea (OSA) and elevated blood pressure (BP). However, long-term cardiovascular outcomes in children with OSA remain unexplored. Objective To evaluate the associations of childhood OSA with BP parameters in a prospective 10 year follow-up study. Methods Participants were recruited from a cohort established for our previous OSA epidemiological study. They were invited to undergo clinical examination, overnight polysomnography and 24-hour ambulatory BP monitoring. Multivariate linear regression was used to assess the associations of baseline childhood OSA with BP outcomes at follow-up. Multivariable log-binomial regression was used with inverse probability weighting to assess the adjusted associations of childhood OSA with hypertension and non-dipping of nocturnal BP in adulthood. Results 243 participants (59% male) attended the follow-up visit. The mean age was 9.8 (SD +/- 1.8) and 20.2 (SD +/- 1.9) years at baseline and follow-up respectively, with a mean follow-up duration of 10.4 (SD +/- 1.1) years. Childhood moderate-to-severe OSA was associated with higher nocturnal systolic blood pressure (SBP) (difference from normal controls: 6.5 mm Hg, 95% CI 2.9 to 10.1) and reduced nocturnal dipping of SBP (-4.1%, 95% CI -6.3% to 1.8%) at follow-up, adjusted for age, sex, Body Mass Index and height at baseline, regardless of the presence of OSA at follow-up. Childhood moderate-to-severe OSA was also associated with higher risk of hypertension (relative risk (RR) 2.5, 95% CI 1.2 to 5.3) and non-dipping of nocturnal SBP (RR 1.3, 95% CI 1.0 to 1.7) at follow-up. Conclusion Childhood OSA was found to be an independent risk factor for adverse BP outcomes in adulthood.
Background Pulmonary cysts and spontaneous pneumothorax are presented in most patients with Birt-Hogg-Dube (BHD) syndrome, which is caused by loss of function mutations in the folliculin (FLCN) gene. The pathogenic mechanisms underlying the cystic lung disease in BHD are poorly understood. Methods Mesenchymal Flcn was specifically deleted in mice or in cultured lung mesenchymal progenitor cells using a Cre/loxP approach. Dynamic changes in lung structure, cellular and molecular phenotypes and signalling were measured by histology, immunofluorescence staining and immunoblotting. Results Deletion of Flcn in mesoderm-derived mesenchymal cells results in significant reduction of postnatal alveolar growth and subsequent alveolar destruction, leading to cystic lesions. Cell proliferation and alveolar myofibroblast differentiation are inhibited in the Flcn knockout lungs, and expression of the extracellular matrix proteins Col3a1 and elastin are downregulated. Signalling pathways including mTORC1, AMP-activated protein kinase, ERK1/2 and Wnt-beta-catenin are differentially affected at different developmental stages. All the above changes have statistical significance (p<0.05). Conclusions Mesenchymal Flcn is an essential regulator during alveolar development and maintenance, through multiple cellular and molecular mechanisms. The mesenchymal Flcn knockout mouse model provides the first in vivo disease model that may recapitulate the stages of cyst development in human BHD. These findings elucidate the developmental origins and mechanisms of lung disease in BHD.
Background Birt-Hogg-Dube Syndrome (BHDS) characterised by skin fibrofolliculomas, kidney tumour and pulmonary cysts/pneumothorax is caused by folliculin (FLCN) germline mutations. The pathology of both neoplasia and focused tissue loss of BHDS strongly features tissue-specific behaviour of the gene. Isolated cysts/pneumothorax is the most frequent atypical presentation of BHDS and often misdiagnosed as primary spontaneous pneumothorax (PSP). Deferential diagnosis of BHDS with isolated pulmonary presentation (PSP-BHD) from PSP is essential in lifelong surveillance for developing renal cell carcinoma. Methods The expression profiles of microRNAs (miRNAs) in cystic lesions of PSP-BHD and PSP were determined via microarray. The selected upregulated miRNAs were further confirmed in the plasma of an expanded cohort of PSP-BHD patients by reverse transcription quantitative PCR (RT-qPCR). Their diagnostic accuracy was evaluated. Moreover, the cellular functions and targeted signalling pathways of FLCN-regulated miRNAs were assessed in various cell lines and in the lesion tissue contexts. Results Cystic lesions of PSP-BHD and PSP showed different miRNAs profiles with a significant upregulation of miR-424-5p and let-7d-5p in PSP-BHD. The combination of the two effectively predicted BHDS patients. In vitro studies revealed a suppressive effect of FLCN on miR-424-5p and let-7d-5p expressions specifically in lung epithelial cells. The ectopic miRNAs triggered epithelial apoptosis and epithelial transition of mesenchymal cells and suppressed the reparative responses in cells and tissues with FLCN deficiency. Conclusion The upregulation of miR-424-5p and let-7d-5p by FLCN deficiency occurred in epithelial cells and marked the PSP-BHD condition, which contributed to a focused degenerative pathology in the lung of PSP-BHD patients.
Background Biomarker-based tests for diagnosing TB currently rely on detectingMycobacterium tuberculosis(Mtb) antigen-specific cellular responses. While this approach can detect Mtb infection, it is not efficient in diagnosing TB, especially for patients who lack aetiological evidence of the disease. Methods We prospectively enrolled three cohorts for our study for a total of 630 subjects, including 160 individuals to screen protein biomarkers of TB, 368 individuals to establish and test the predictive model and 102 individuals for biomarker validation. Whole blood cultures were stimulated with pooled Mtb-peptides or mitogen, and 640 proteins within the culture supernatant were analysed simultaneously using an antibody-based array. Sixteen candidate biomarkers of TB identified during screening were then developed into a custom multiplexed antibody array for biomarker validation. Results A two-round screening strategy identified eight-protein biomarkers of TB: I-TAC, I-309, MIG, Granulysin, FAP, MEP1B, Furin and LYVE-1. The sensitivity and specificity of the eight-protein biosignature in diagnosing TB were determined for the training (n=276), test (n=92) and prediction (n=102) cohorts. The training cohort had a 100% specificity (95% CI 98% to 100%) and 100% sensitivity (95% CI 96% to 100%) using a random forest algorithm approach by cross-validation. In the test cohort, the specificity and sensitivity were 83% (95% CI 71% to 91%) and 76% (95% CI 56% to 90%), respectively. In the prediction cohort, the specificity was 84% (95% CI 74% to 92%) and the sensitivity was 75% (95% CI 57% to 89%). Conclusions An eight-protein biosignature to diagnose TB in a high-burden TB clinical setting was identified.
Introduction Airway epithelial cells are recognised as an essential controller for the initiation and perpetuation of asthmatic inflammation, yet the detailed mechanisms remain largely unknown. This study aims to investigate the roles and mechanisms of the mechanistic target of rapamycin (MTOR)-autophagy axis in airway epithelial injury in asthma. Methods We examined the MTOR-autophagy signalling in airway epithelium from asthmatic patients or allergic mice induced by ovalbumin or house dust mites, or in human bronchial epithelial (HBE) cells. Furthermore, mice with specific MTOR knockdown in airway epithelium and autophagy-related lc3b (-/-) mice were used for allergic models. Results MTOR activity was decreased, while autophagy was elevated, in airway epithelium from asthmatic patients or allergic mice, or in HBE cells treated with IL33 or IL13. These changes were associated with upstream tuberous sclerosis protein 2 signalling. Specific MTOR knockdown in mouse bronchial epithelium augmented, while LC3B deletion diminished allergen-induced airway inflammation and mucus hyperproduction. The worsened inflammation caused by MTOR deficiency was also ameliorated in lc3b (-/-) mice. Mechanistically, autophagy was induced later than the emergence of allergen-initiated inflammation, particularly IL33 expression. MTOR deficiency increased, while knocking out of LC3B abolished the production of IL25 and the eventual airway inflammation on allergen challenge. Blocking IL25 markedly attenuated the exacerbated airway inflammation in MTOR-deficiency mice. Conclusion Collectively, these results demonstrate that allergen-initiated inflammation suppresses MTOR and induces autophagy in airway epithelial cells, which results in the production of certain proallergic cytokines such as IL25, further promoting the type 2 response and eventually perpetuating airway inflammation in asthma.
Background Exposure to zinc was suggested to be associated with pulmonary damage, but whether zinc exposure affects lung function remains unclear. Objectives To quantify the association between urinary zinc and lung function and explore the potential mechanisms. Methods Urinary zinc and lung function were measured in 3917 adults from the Wuhan-Zhuhai cohort and were repeated after 3 years of follow-up. Indicators of systemic inflammation (C reactive protein), lung epithelium integrity (club cell secretory protein-16) and oxidative damage (8-hydroxy-2 '-deoxyguanosine and 8-isoprostane) were measured at baseline. Linear mixed models were used to estimate the exposure-response relationship between urinary zinc and lung function. Mediation analyses were conducted to assess mediating roles of inflammation and oxidative damage in above relationships. Results Each 1-unit increase in log-transformed urinary zinc values was associated with a 35.72 mL decrease in forced vital capacity (FVC) and a 24.89 mL decrease in forced expiratory volume in 1 s (FEV1) in the baseline analyses. In the follow-up analyses, there was a negative association between urinary zinc and FVC among participants with persistent high urinary zinc levels, with an estimated change of -93.31 mL (95% CI -178.47 to -8.14). Furthermore, urinary zinc was positively associated with restrictive ventilatory impairment. The mediation analyses suggested that C reactive protein mediated 8.62% and 8.71% of the associations of urinary zinc with FVC and FEV1, respectively. Conclusion Urinary zinc was negatively associated with lung function, and the systemic inflammation may be one of the underlying mechanisms.
Global incidence and temporal trends of asbestosis are rarely explored. Using the detailed information on asbestosis from the Global Burden of Disease (GBD) 2017, we described the age-standardised incidence rate (ASIR) and its average annual percentage change. A Joinpoint Regression model was applied to identify varying temporal trends over time. Although the use of asbestos has been completely banned in many countries, the ASIR of asbestosis increased globally from 1990 to 2017. Furthermore, the most pronounced increases in ASIR of asbestosis were detected in high-income North America and Australasia. These findings indicate that efforts to change the asbestos regulation policy are urgently needed.
Background Perturbed iron homeostasis is a risk factor for tuberculosis (TB) progression and an indicator of TB treatment failure and mortality. Few studies have evaluated iron homeostasis as a TB diagnostic biomarker. Methods We recruited participants with TB, latent TB infection (LTBI), cured TB (RxTB), pneumonia (PN) and healthy controls (HCs). We measured serum levels of three iron biomarkers including serum iron, ferritin and transferrin, then established and validated our prediction model. Results We observed and verified that the three iron biomarker levels correlated with patient status (TB, HC, LTBI, RxTB or PN) and with the degree of lung damage and bacillary load in patients with TB. We then built a TB prediction model, neural network (NNET), incorporating the data of the three iron biomarkers. The model showed good performance for diagnosis of TB, with 83% (95% CI 77 to 87) sensitivity and 86% (95% CI 83 to 89) specificity in the training data set (n=663) and 70% (95% CI 58 to 79) sensitivity and 92% (95% CI 86 to 96) specificity in the test data set (n=220). The area under the curves (AUCs) of the NNET model to discriminate TB from HC, LTBI, RxTB and PN were all >0.83. Independent validation of the NNET model in a separate cohort (n=967) produced an AUC of 0.88 (95% CI 0.85 to 0.91) with 74% (95% CI 71 to 77) sensitivity and 92% (95% CI 87 to 96) specificity. Conclusions The established NNET TB prediction model discriminated TB from HC, LTBI, RxTB and PN in a large cohort of patients. This diagnostic assay may augment current TB diagnostics.