Elevated ferritin, mediated by IL-18 is associated with systemic inflammation and mortality in acute respiratory distress syndrome (ARDS).

BACKGROUND: Inflammatory subphenotypes have been identified in acute respiratory distress syndrome (ARDS). Hyperferritinaemia in sepsis is associated with hyperinflammation, worse clinical outcomes, and may predict benefit with immunomodulation. Our aim was to determine if raised ferritin identified a subphenotype in patients with ARDS. METHODS: Baseline plasma ferritin concentrations were measured in patients with ARDS from two randomised controlled trials of simvastatin (Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction-2 (HARP-2); discovery cohort, UK) and neuromuscular blockade (ROSE; validation cohort, USA). Results were analysed using a logistic regression model with restricted cubic splines, to determine the ferritin threshold associated with 28-day mortality. RESULTS: Ferritin was measured in 511 patients from HARP-2 (95% of patients enrolled) and 847 patients (84% of patients enrolled) from ROSE. Ferritin was consistently associated with 28-day mortality in both studies and following a meta-analysis, a log-fold increase in ferritin was associated with an OR 1.71 (95% CI 1.01 to 2.90) for 28-day mortality. Patients with ferritin >1380 ng/mL (HARP-2 28%, ROSE 24%) had a significantly higher 28-day mortality and fewer ventilator-free days in both studies. Mediation analysis, including confounders (acute physiology and chronic health evaluation-II score and ARDS aetiology) demonstrated a statistically significant contribution of interleukin (IL)-18 as an intermediate pathway between ferritin and mortality. CONCLUSIONS: Ferritin is a clinically useful biomarker in ARDS and is associated with worse patient outcomes. These results provide support for prospective interventional trials of immunomodulatory agents targeting IL-18 in this hyperferritinaemic subgroup of patients with ARDS.

Environmental pollutants exposure-derived extracellular vesicles: crucial players in respiratory disorders.

BACKGROUND: Individual exposure to environmental pollutants, as one of the most influential drivers of respiratory disorders, has received considerable attention due to its preventability and controllability. Considering that the extracellular vesicle (EV) was an emerging intercellular communication medium, recent studies have highlighted the crucial role of environmental pollutants derived EVs (EPE-EVs) in respiratory disorders. METHODS: PubMed and Web of Science were searched from January 2018 to December 2023 for publications with key words of environmental pollutants, respiratory disorders and EVs. RESULTS: Environmental pollutants could disrupt airway intercellular communication by indirectly stimulating airway barrier cells to secrete endogenous EVs, or directly transmitting exogenous EVs, mainly by biological pollutants. Mechanistically, EPE-EVs transferred specific contents to modulate biological functions of recipient cells, to induce respiratory inflammation and impair tissue and immune function, which consequently contributed to the development of respiratory diseases, such as asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pulmonary hypertension, lung cancer and infectious lung diseases. Clinically, EVs could emerged as promising biomarkers and biological agents for respiratory diseases attributed by their specificity, convenience, sensibility and stability. CONCLUSIONS: Further studies of EPE-EVs are helpful to understand the aetiology and pathology of respiratory diseases, and facilitate the precision respiratory medicine in risk screening, early diagnosis, clinical management and biotherapy.

Synthetic trimeric interleukin-6 receptor complexes with a STAT3 phosphorylation dominated activation profile.

In Interleukin (IL)-6 signalling, IL-6 site I binds to the IL-6 receptor (IL-6R) first, following by IL-6 site II interaction to domain 2/3 of gp130 to form premature trimeric IL-6:IL-6R:gp130 receptor complexes. Formation of the mature hexameric receptor complex is then facilitated by the inter-trimeric interaction of IL-6 site III with domain 1 of the opposing gp130. The two gp130-associated Janus kinases (JAKs) trans-phosphorylate when their spatiotemporal pairing is correct, which causes the activation of STAT, ERK, and AKT pathways in a balanced manner. Since the intracellular domain (ICD) of IL-6R is not needed for STAT/ERK/AKT phosphorylation, we investigated the conditions under which a chimeric IL-6RECD-gp130TMD/ICD receptor protein confers biological activity. For IL-6RECD-gp130TMD/ICD, the extracellular domain (ECD) of IL-6R was fused to the transmembrane domain (TMD) and ICD of gp130. Co-expression of IL-6RECD-gp130TMD/ICD with signalling-deficient gp130 variants did not induce IL-6 signalling, suggesting that the assembly of hexameric complexes failed to dimerize the IL-6R-associated JAKs correctly. By mimicking the premature trimeric receptor complex, IL-6-mediated dimerization of IL-6RECD-gp130TMD/ICD with the single-cytokine-binding variant gp130ΔD1 induced signalling. Of note, IL-6 signalling via these synthetic gp130ΔD1:IL-6RECD-gp130TMD/ICD complexes resulted predominantly in STAT3 phosphorylation. A STAT3-dominated profile was also observed after IL-6-induced signalling mediated by a JAK-deficient IL-6RECD-gp130TMD/ICDΔJAK variant in complex with the JAK-proficient but STAT/ERK/AKT-deficient gp130JAKΔICD variant. Our data showed that effective ERK/AKT signalling could not be executed after intracellular domain swapping from gp130 to the IL-6R. Taken together, the chimeric IL-6R/gp130 receptor may be helpful in the creation of customized synthetic IL-6 signalling.

Macrophage migration inhibitory factor promotes glucocorticoid resistance of neutrophilic inflammation in a murine model of severe asthma.

BACKGROUND: Severe neutrophilic asthma is resistant to treatment with glucocorticoids. The immunomodulatory protein macrophage migration inhibitory factor (MIF) promotes neutrophil recruitment to the lung and antagonises responses to glucocorticoids. We hypothesised that MIF promotes glucocorticoid resistance of neutrophilic inflammation in severe asthma. METHODS: We examined whether sputum MIF protein correlated with clinical and molecular characteristics of severe neutrophilic asthma in the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort. We also investigated whether MIF regulates neutrophilic inflammation and glucocorticoid responsiveness in a murine model of severe asthma in vivo. RESULTS: MIF protein levels positively correlated with the number of exacerbations in the previous year, sputum neutrophils and oral corticosteroid use across all U-BIOPRED subjects. Further analysis of MIF protein expression according to U-BIOPRED-defined transcriptomic-associated clusters (TACs) revealed increased MIF protein and a corresponding decrease in annexin-A1 protein in TAC2, which is most closely associated with airway neutrophilia and NLRP3 inflammasome activation. In a murine model of severe asthma, treatment with the MIF antagonist ISO-1 significantly inhibited neutrophilic inflammation and increased glucocorticoid responsiveness. Coimmunoprecipitation studies using lung tissue lysates demonstrated that MIF directly interacts with and cleaves annexin-A1, potentially reducing its biological activity. CONCLUSION: Our data suggest that MIF promotes glucocorticoid-resistance of neutrophilic inflammation by reducing the biological activity of annexin-A1, a potent glucocorticoid-regulated protein that inhibits neutrophil accumulation at sites of inflammation. This represents a previously unrecognised role for MIF in the regulation of inflammation and points to MIF as a potential therapeutic target for the management of severe neutrophilic asthma.

Plasma thymic stromal lymphopoietin (TSLP) in adults with non-severe asthma: the EGEA study.

Thymic stromal lymphopoietin (TSLP), a cytokine involved in severe asthma treatment, was never studied in non-severe asthma.Among 969 adults from a large epidemiological study, cross-sectional analyses showed that plasma TSLP levels were associated with increased age and BMI, male sex, smoking and high TSLP levels (one IQR increase) with current asthma and poor lung function. High TSLP levels were also associated with persistence of asthma attacks (aOR=2.14 (95% CI 1.23 to 3.72)) and dyspnoea (aOR=2.71 (95% CI 1.39 to 5.28)) 10 years later.Our results suggest that TSLP could be a cytokine of interest in non-severe asthma, and its determinants of circulating levels could be considered in asthma management.

C reactive protein utilisation, a biomarker for early COVID-19 treatment, improves lenzilumab efficacy: results from the randomised phase 3 'LIVE-AIR' trial.

OBJECTIVE: COVID-19 severity is correlated with granulocyte macrophage colony-stimulating factor (GM-CSF) and C reactive protein (CRP) levels. In the phase three LIVE-AIR trial, lenzilumab an anti-GM-CSF monoclonal antibody, improved the likelihood of survival without ventilation (SWOV) in COVID-19, with the greatest effect in participants having baseline CRP below a median of 79 mg/L. Herein, the utility of baseline CRP to guide lenzilumab treatment was assessed. DESIGN: A subanalysis of the randomised, blinded, controlled, LIVE-AIR trial in which lenzilumab or placebo was administered on day 0 and participants were followed through Day 28. PARTICIPANTS: Hospitalised COVID-19 participants (N=520) with SpO2 ≤94% on room air or requiring supplemental oxygen but not invasive mechanical ventilation. INTERVENTIONS: Lenzilumab (1800 mg; three divided doses, q8h, within 24 hours) or placebo infusion alongside corticosteroid and remdesivir treatments. MAIN OUTCOME MEASURES: The primary endpoint was the time-to-event analysis difference in SWOV through day 28 between lenzilumab and placebo treatments, stratified by baseline CRP. RESULTS: SWOV was achieved in 152 (90%; 95% CI 85 to 94) lenzilumab and 144 (79%; 72 to 84) placebo-treated participants with baseline CRP <150 mg/L (HR: 2.54; 95% CI 1.46 to 4.41; p=0.0009) but not with CRP ≥150 mg/L (HR: 1.04; 95% CI 0.51 to 2.14; p=0.9058). A statistically significant interaction between CRP and lenzilumab treatment was observed (p=0.044). Grade ≥3 adverse events with lenzilumab were comparable to placebo in both CRP strata. No treatment-emergent serious adverse events were attributed to lenzilumab. CONCLUSION: Hospitalised hypoxemic patients with COVID-19 with baseline CRP <150 mg/L derived the greatest clinical benefit from treatment with lenzilumab. TRIAL REGISTRATION NUMBER: NCT04351152; ClinicalTrials.gov.

Latent class analysis-derived subphenotypes are generalisable to observational cohorts of acute respiratory distress syndrome: a prospective study.

RATIONALE: Using latent class analysis (LCA), two subphenotypes of acute respiratory distress syndrome (ARDS) have consistently been identified in five randomised controlled trials (RCTs), with distinct biological characteristics, divergent outcomes and differential treatment responses to randomised interventions. Their existence in unselected populations of ARDS remains unknown. We sought to identify subphenotypes in observational cohorts of ARDS using LCA. METHODS: LCA was independently applied to patients with ARDS from two prospective observational cohorts of patients admitted to the intensive care unit, derived from the Validating Acute Lung Injury markers for Diagnosis (VALID) (n=624) and Early Assessment of Renal and Lung Injury (EARLI) (n=335) studies. Clinical and biological data were used as class-defining variables. To test for concordance with prior ARDS subphenotypes, the performance metrics of parsimonious classifier models (interleukin 8, bicarbonate, protein C and vasopressor-use), previously developed in RCTs, were evaluated in EARLI and VALID with LCA-derived subphenotypes as the gold-standard. RESULTS: A 2-class model best fit the population in VALID (p=0.0010) and in EARLI (p<0.0001). Class 2 comprised 27% and 37% of the populations in VALID and EARLI, respectively. Consistent with the previously described 'hyperinflammatory' subphenotype, Class 2 was characterised by higher proinflammatory biomarkers, acidosis and increased shock and worse clinical outcomes. The similarities between these and prior RCT-derived subphenotypes were further substantiated by the performance of the parsimonious classifier models in both cohorts (area under the curves 0.92-0.94). The hyperinflammatory subphenotype was associated with increased prevalence of chronic liver disease and neutropenia and reduced incidence of chronic obstructive pulmonary disease. Measurement of novel biomarkers showed significantly higher levels of matrix metalloproteinase-8 and markers of endothelial injury in the hyperinflammatory subphenotype, whereas, matrix metalloproteinase-9 was significantly lower. CONCLUSION: Previously described subphenotypes are generalisable to unselected populations of non-trauma ARDS.

Altered distribution, activation and increased IL-17 production of mucosal-associated invariant T cells in patients with acute respiratory distress syndrome.

OBJECTIVE: Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T cells that are engaged in a number of diseases, but their roles in acute respiratory distress syndrome (ARDS) are not fully examined yet. This study aimed to examine levels and functions of MAIT cells in patients with ARDS. METHODS: Peripheral blood samples from patients with ARDS (n=50) and healthy controls (HCs, n=50) were collected. Levels of MAIT cells, cytokines, CD69, programmed cell death-1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) were measured by flow cytometry. RESULTS: Circulating MAIT cell levels were significantly reduced in patients with ARDS than in HCs. MAIT cell levels were inversely correlated with disease severity and mortality. Cytokine production profiles in MAIT cells showed that percentages of interleukin (IL)-17 producing MAIT cell were significantly higher in patients with ARDS than in HCs. Patients with ARDS exhibited higher expression levels of CD69, PD-1 and LAG-3 in circulating MAIT cells. Moreover, levels of MAIT cells and expression levels of CD69, PD-1 and IL-17 in MAIT cells were higher in bronchoalveolar lavage fluid samples than in peripheral blood samples. Our in vitro experiments showed that MAIT cells triggered macrophages to produce proinflammatory cytokines such as tumour necrosis factor-α, IL-1ß and IL-8. CONCLUSIONS: This study demonstrates that circulating MAIT cells are numerically deficient in patients with ARDS. In addition, MAIT cells were found to be activated, migrate into lung, secrete IL-17 and then stimulate macrophages. These findings suggest that MAIT cells contribute to the worsening of inflammation in the lung of patients with ARDS.

Biologic therapy practices in severe asthma; outcomes from the UK Severe Asthma Registry and survey of specialist opinion.

BACKGROUND: several biological treatments have become available for management of severe asthma. There is a significant overlap in the indication of these treatments with lack of consensus on the first-line biologic choice and switching practice in event of treatment failure. AIMS: to evaluate outcomes of biologic treatments through analysis of the UK Severe Asthma Registry (UKSAR), and survey of the UK severe asthma specialists' opinion. METHODS: patients registered in the UKSAR database and treated with biologics for severe asthma in the period between January 2014 and August 2021, were studied to explore biologic treatments practice. This was complemented by survey of opinion of severe asthma specialists. RESULTS: a total of 2,490 patients from 10 severe asthma centres were included in the study (mean age 51.3 years, 61.1% female, mean BMI 30.9kg/m2 ). Biologics use included mepolizumab 1,115 (44.8%), benralizumab 925 (37.1%), omalizumab 432 (17.3%), dupilumab 13 (0.5%), and reslizumab 5 (0.2%). Patients on omalizumab were younger and had earlier age of onset asthma than those prescribed mepolizumab or benralizumab. Patients prescribed mepolizumab and benralizumab had similar clinical characteristics. Those on benralizumab were more likely to continue treatment at approximately one year follow up (93.9%), than those on mepolizumab (80%), or omalizumab (69.6%). The first choice biologic differed between centres and changed over the study time period. Experts' opinion also diverged in terms of biologic initiation choice and switching practice. CONCLUSION: We observed significant variation and divergence in the prescribing practices of biologics in severe asthma that necessitates further research and standardisation.

Multifaceted roles of IL-38 in inflammation and cancer.

Interleukin (IL)-38 is the least well-understood cytokine of the IL-1 family. Since its discovery twenty years ago, numerous studies have linked IL-38 to diverse pathologies, especially in the context of autoimmune and inflammatory processes, while its role in cancer has been less explored. Broad anti-inflammatory effects have been reported for IL-38 in both in vitro and in vivo models, and, together with its homology to the IL-1 and IL-36 receptor antagonists, have raised expectations about its potential therapeutic utility. Data in human and mouse experimental systems support a negative regulatory role of IL-38 on the Th17 axis through effects on T cells and myeloid cells. Additional studies point to tolerogenic functions of IL-38, acting on dendritic cells and regulatory T cells, as well as to inhibition of pro-inflammatory macrophage activity. IL-38 further exhibits anti-inflammatory and tissue protective properties in epithelial and mesenchymal cells. However, published data also reveal variability and inconsistent dose-dependencies of these anti-inflammatory effects, as well as context-dependent pro-inflammatory properties of IL-38, and are difficult to interpret due to the high heterogeneity in the materials and experimental designs used across studies. In addition, it is still not clear which receptor(s) is/are fundamental for IL-38 signalling, and the biological impact of N-terminal processing of the protein remains to be clarified. In this review, we provide an overview of our current knowledge of IL-38 biology, discuss persistent controversies surrounding this cytokine, and highlight some questions to be addressed to facilitate progress towards a better understanding of its mechanisms of action.

Coordination of Mucosal Immunity by Innate Lymphoid Cells.

Mucosal barrier surfaces of the mammalian body are frequent sites of pathogen colonization or entry and are also densely colonized with trillions of normally beneficial microbes, termed the microbiota. Therefore, it is paramount that the host immune system recognizes these microbes and is capable of differentiating between them. To this end, a multitude of mechanisms have evolved to carefully balance the need for immune activation in the face of infections while maintaining an appropriate level of tolerance to protect both the host and the beneficial microbes from hyperactivation. These mechanisms include the deployment of an emerging class of tissue-resident innate immune cells, innate lymphoid cells (ILCs), that are enriched at mucosal barriers such as the lungs and intestines, and are critical mediators of tissue homeostasis, tolerance, repair, and innate immunity. Recent findings have provided insight into the regulation of these cells and their interactions, not only with microbes, both commensal and foreign, but also with other systems of the body to prevent disease and promote tissue health. Here, we discuss recent findings in the regulation and function of ILCs, including a focus on their interactions with bodily systems, such as the nervous system, and how these interactions affect their functionality in states of health, infection, and disease.

Add-on azithromycin reduces sputum cytokines in non-eosinophilic asthma: an AMAZES substudy.

Add-on azithromycin (AZM) significantly reduces exacerbations in poorly controlled asthma irrespective of disease phenotype. In a predefined substudy of the original AMAZES protocol (500 mg, three times a week for 48 weeks), we report that AZM treatment reduces key sputum inflammatory proteins (interleukin (IL)-6, IL-1ß and extracellular DNA), which is more evident in non-eosinophilic asthma (NEA). Moreover, AZM reduced Haemophilus influenzae load only in NEA. Our data support the anti-inflammatory effects of AZM in poorly controlled asthma. Prospective studies are required to identify patients that derive greatest benefit from AZM add-on therapy.

Role of the IL-33/ST2 axis in cigarette smoke-induced airways remodelling in chronic obstructive pulmonary disease.

BACKGROUND: Efficient therapy and potential prophylaxis are confounded by current ignorance of the pathogenesis of airway remodelling and blockade in COPD. OBJECTIVE: To explore the role of the IL-33/ST2 axis in cigarette smoke (CS) exposure-induced airways remodelling. METHODS: C57BL/6, BALB/c and IL-1RL1 -/- mice exposed to CS were used to establish an animal surrogate of COPD (air-exposed=5~8, CS-exposed=6~12). Hallmarks of remodelling were measured in mice. Cigarette smoke extract (CSE)-induced proliferation and protein production in vitro by fibroblasts in the presence of anti-interleukin-33 (anti-IL-33) or hST2 antibodies were measured. Expression of IL-33 and ST2 and other remodelling hallmarks were measured, respectively, in bronchoalveolar lavage fluid (BALF) (controls=20, COPD=20), serum (controls=59, COPD=90) and lung tissue sections (controls=11, COPD=7) from patients with COPD and controls. RESULTS: Wild-type mice exposed to CS elevated expression of hallmarks of tissue remodelling in the lungs and also in the heart, spleen and kidneys, which were significantly abrogated in the IL-1RL1 -/- mice. Fibroblasts exposed to CSE, compared with control, exhibited early cellular translocation of IL-33, accompanied by proliferation and elevated protein synthesis, all inhabitable by blockade of IL-33/ST2 signalling. Expression of IL-33 and ST2 and hallmarks of tissue remodelling were significantly and proportionally elevated in BALF, serum and tissue samples from patients with COPD. CONCLUSIONS: Exposure to CS induces remodelling changes in multiple organs. The data support the hypothesis that CS-induced lung collagen deposition is at least partly a result of CS-induced IL-33 translocation and release from local fibroblasts.

COVID-19, immunothrombosis and venous thromboembolism: biological mechanisms.

Thrombotic events that frequently occur in COVID-19 are predominantly venous thromboemboli (VTE) and are associated with increasing disease severity and worse clinical outcomes. Distinctive microvascular abnormalities in COVID-19 include endothelial inflammation, disruption of intercellular junctions and microthrombi formation. A distinct COVID-19-associated coagulopathy along with increased cytokines and activation of platelets, endothelium and complement occur in COVID-19, which is more frequent with worsening disease severity. This proinflammatory milieu may result in immunothrombosis, a host defence mechanism that can become dysregulated, leading to excess formation of immunologically mediated thrombi which predominantly affect the microvasculature. The haemostatic and immune systems are intricately linked, and multifactorial processes are likely to contribute to VTE and immunothrombosis in COVID-19. This state-of-the-art review will explore the pathobiological mechanisms of immunothrombosis and VTE in COVID-19 focusing on: COVID-19-associated coagulopathy, pathology, endothelial dysfunction and haemostasis, the immune system and thrombosis, genetic associations and additional thrombotic mechanisms. An understanding of the complex interplay between these processes is necessary for developing and assessing how new treatments affect VTE and immunothrombosis in COVID-19.

Eosinophilic inflammation in COPD: from an inflammatory marker to a treatable trait.

The heterogeneity of chronic obstructive pulmonary disease (COPD) creates many diagnostic, prognostic, treatment and management challenges, as the pathogenesis of COPD is highly complex and the underlying cellular and molecular mechanisms remain poorly understood. A reliable, easy-to-measure, clinically relevant biomarker would be invaluable for improving outcomes for patients. International and national guidance for COPD suggests using blood eosinophil counts as a biomarker to help estimate likely responsiveness to inhaled corticosteroids (ICS) and, potentially, to aid effective management strategies. However, with the mechanism underlying the association between higher eosinophil levels and ICS effect unknown, use of the blood eosinophil count in COPD continues to be widely debated by the respiratory community.Two international meetings involving respiratory medicine specialists, immunologists and primary and secondary care clinicians were held in November 2018 and March 2019, facilitated and funded by GlaxoSmithKline plc. The aims of these meetings were to explore the role of eosinophils in the disease processes of COPD and as prognostic and diagnostic markers, and to identify areas of deficient knowledge that warrant further research. The consensus views of the attendees on key topics, contextualised with current literature, are summarised in this review article, with the aim of aiding ongoing research into the disease processes of COPD and the development of biomarkers to aid clinical management.Under certain conditions, eosinophils can be recruited to the lung, and increasing evidence supports a role for eosinophilic inflammation in some patients with COPD. Infiltration of eosinophils across the bronchial vascular epithelium into the airways is promoted by the actions of immunoregulatory cells, cytokines and chemokines, where eosinophil-mediated inflammation is driven by the release of proinflammatory mediators.Multiple studies and two meta-analyses suggest peripheral blood eosinophils may correlate positively with an increased likelihood of exacerbation reduction benefits of ICS in COPD. The studies, however, vary in design and duration and by which eosinophil levels are viewed as predictive of an ICS response. Generally, the response was seen when eosinophil levels were 100-300 cells/µL (or higher), levels which are traditionally viewed within the normal range. Some success with interleukin-5-targeted therapy suggests that the eosinophilic phenotype may be a treatable trait.The use of biomarkers could help to stratify treatment for COPD-the goal of which is to improve patient outcomes. Some evidence supports eosinophils as a potential biomarker of a treatable trait in COPD, though it is still lacking and research is ongoing. A unified consensus and a practical, accessible and affordable method of utilising any biomarker for COPD was thought to be of most importance. Challenges around its utilisation may include presenting a clear and pragmatic rationale for biomarker-driven therapy, guidance on ICS withdrawal between primary and secondary care and a lack of financial incentives supporting broad application in clinical practice. Future treatments should, perhaps, be more targeted rather than assuming the primary disease label (COPD or asthma) will define treatment response.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and receptors in type 1, type 2 and type 17 inflammation in cross-sectional asthma study.

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) reportedly promotes, or conversely, resolves inflammation in asthma. In this study of TRAIL and cell receptors in sputum, bronchoalveolar lavage and biopsy from subjects in the Severe Asthma Research Program at Wake Forest, the high TRAIL group had significant increases in all leucocytes, and was associated with increased type 1, type 2 and type 17 cytokines, but not type 9 interleukin 9. Two variants at loci in the TRAIL gene were associated with higher sputum levels of TRAIL. Increased TRAIL decoy receptor R3/DcR1 was observed on sputum leucocytes compared with death receptor R1/DR4, suggesting reduced apoptosis and prolonged cellular inflammation.

Cross-sectional and longitudinal associations between urinary zinc and lung function among urban adults in China.

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.

Effects of Wnt signaling on epithelial to mesenchymal transition in chronic rhinosinusitis with nasal polyp.

BACKGROUND: Epithelial to mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP). Wnt signaling is causative for EMT, whereas the mechanism in CRSwNP is not fully understood. OBJECTIVE: We sought to evaluate the role of Wnt signaling in EMT of CRSwNP using a murine nasal polyp (NP) model and human tissues. METHODS: Inflammatory markers and EMT-related molecules were evaluated in NP models using adenomatosis polyposis coli (Apc)Min/+ mice with activated Wnt signaling and NP models treated with Wnt signaling inhibitor, indocyanine green-001 (ICG-001). EMT markers and Wnt signaling-associated mediators were analysed using human sinonasal tissues from control subjects and CRSwNP patients. RESULTS: ApcMin/+ mice-induced NPs exhibited more frequent polypoid lesions and upregulation of Wnt-related molecules, including nuclear ß-catenin, WNT3A and cyclin D1. Markers of EMT were significantly overexpressed in the ApcMin/+ NP mice (p<0.001 for E-cadherin and α-smooth muscle actin), and interleukin (IL)-17A+ cells and neutrophilic infiltration were increased in ApcMin/+ NP mice (p<0.001). Inhibition of Wnt signaling via ICG-001 resulted in significantly decreased nasal polypoid lesions (p<0.001), EMT-related markers (p=0.019 for E-cadherin and p=0.002 for vimentin) and the mRNA levels of IL-4 (p<0.001) and IL-17A (p=0.004) compared with the positive control group. Finally, nuclear ß-catenin (p=0.042) was significantly increased compared with the control, and the expression levels of Wnt ligands and receptors were upregulated in human NP tissues (p=0.045 for WNT3A and p=0.042 for FZD2), suggesting increased Wnt signaling and EMT in CRSwNP. CONCLUSION: Wnt signaling may contribute to the pathogenesis of NPs through EMT. Therefore, inhibition of Wnt signaling may be a potential therapeutic strategy for patients with CRSwNP.

RAGE-induced ILC2 expansion in acute lung injury due to haemorrhagic shock.

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.

Zinc supplementation ameliorates lung injury by reducing neutrophil recruitment and activity.

INTRODUCTION: Zinc is well known for its anti-inflammatory effects, including regulation of migration and activity of polymorphonuclear neutrophils (PMN). Zinc deficiency is associated with inflammatory diseases such as acute lung injury (ALI). As deregulated neutrophil recruitment and their hyper-activation are hallmarks of ALI, benefits of zinc supplementation on the development of lipopolysaccharides (LPS)-induced ALI were tested. METHODS: 64 C57Bl/6 mice, split into eight groups, were injected with 30 µg zinc 24 hours before exposure to aerosolised LPS for 4 hours. Zinc homoeostasis was characterised measuring serum and lung zinc concentrations as well as metallothionein-1 expression. Recruitment of neutrophils to alveolar, interstitial and intravascular space was assessed using flow cytometry. To determine the extent of lung damage, permeability and histological changes and the influx of protein into the bronchoalveolar lavage fluid were measured. Inflammatory status and PMN activity were evaluated via tumour necrosis factor α levels and formation of neutrophil extracellular traps. The effects of zinc supplementation prior to LPS stimulation on activation of primary human granulocytes and integrity of human lung cell monolayers were assessed as well. RESULTS: Injecting zinc 24 hours prior to LPS-induced ALI indeed significantly decreased the recruitment of neutrophils to the lungs and prevented their hyperactivity and thus lung damage was decreased. Results from in vitro investigations using human cells suggest the transferability of the finding to human disease, which remains to be tested in more detail. CONCLUSION: Zinc supplementation attenuated LPS-induced lung injury in a murine ALI model. Thus, the usage of zinc-based strategies should be considered to prevent detrimental consequences of respiratory infection and lung damage in risk groups.