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Bronchiectasis is a chronic airway disease characterized by dysbiosis, persistent inflammation, and permanent structural airway damage. Neutrophilic inflammation is a key pathogenic feature, as indicated by enhanced neutrophil-derived proteases and formation of neutrophil extracellular traps (NETs), associated with poor prognosis. However, recent studies have identified an eosinophilic endotype in up to 30% of patients, characterized by higher levels of type 2 (T2) cytokines and fractional exhaled nitric oxide (FeNO). The role of T helper (Th) cells in the dysregulated inflammatory environment of bronchiectasis remains unclear. Evidence suggests that persistent bacterial infection can skew adaptive immunity from Th1 toward Th2 response, while the airway microbiome-IL-17 axis is also a critical regulator of chronic inflammation. T regulatory (Treg) cells have been shown to play a protective role against excessive chronic inflammation by modulating the function of several types of effector cells, including the Th17 subset. However, the capacity of this subset to delay or prevent disease progression remains to be determined Microbial dysbiosis, with loss of diversity and increased quantity of bacterial pathogens, may also be important for disease progression, and emerging evidence indicates that distinct inflammatory endotypes associate with specific microbiota alterations, especially in severe disease. In this review, we provide an overview of the immune cells and cytokine signaling that are involved in the pathogenesis of bronchiectasis. Additionally, we present the main endotypes of bronchiectasis and explore the relationships between the type of inflammation and alterations in microbiota, as well as the potential benefits of targeting specific pathophysiological mechanisms for the management of bronchiectasis. This review also examines how bacterial infection can shift adaptive immunity from Th1 toward Th2 responses, the role of the airway microbiome-IL-17 axis in chronic inflammation and the potential protective role of Treg cells against excessive inflammation. Novel therapeutic strategies are highlighted, with focus on targeting specific cytokine signaling pathways and restoring Th17/Treg balance These developments underscore a shift toward precision medicine in bronchiectasis, emphasizing the importance of identifying specific inflammatory endotypes to tailor treatment strategies effectively.

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory lung disease with high morbidity and mortality. The IL-36 family are proinflammatory cytokines that are known to shape innate immune responses, including those critical to bacterial pneumonia. The objective of this study was to determine whether IL-36 cytokines promote a proinflammatory milieu in the lungs of long-term smokers with and without COPD. Concentrations of IL-36 cytokines were measured in plasma and BAL fluid from subjects in a pilot study (  = 23) of long-term smokers with and without COPD and from a variety of lung cells (from 3-5 donors) stimulated with bacteria or cigarette smoke components . Pulmonary macrophages were stimulated with IL-36 cytokines , and chemokine and cytokine production was assessed. IL-36α and IL-36γ are produced to varying degrees in murine and human lung cells in response to bacterial stimuli and cigarette smoke components . Moreover, whereas IL-36γ production is upregulated early after cigarette smoke stimulation and wanes over time, IL-36α production requires a longer duration of exposure. IL-36α and IL-36γ are enhanced systemically and locally in long-term smokers with and without COPD, and local IL-36α concentrations display a positive correlation with declining ventilatory lung function and increasing proinflammatory cytokine concentrations. , IL-36α and IL-36γ induce proinflammatory chemokines and cytokines in a concentration-dependent fashion that requires IL-36R and MyD88. IL-36 cytokine production is altered in long-term smokers with and without COPD and contributes to shaping a proinflammatory milieu in the lungs.

Background Bronchopulmonary Dysplasia (BPD) in infants born prematurely is a risk factor for chronic airway obstruction later in life. The distribution of T cell subtypes in the large airways is largely unknown. Objective To characterize cellular and T cell profiles in the large airways of young adults with a history of BPD. Methods Forty-three young adults born prematurely (preterm ( n  = 20), BPD ( n  = 23)) and 45 full-term-born (asthma ( n  = 23), healthy ( n  = 22)) underwent lung function measurements, and bronchoscopy with large airway bronchial wash (BW). T-cells subsets in BW were analyzed by immunocytochemistry. Results The proportions of both lymphocytes and CD8 + T cells in BW were significantly higher in BPD (median, 6.6%, and 78.0%) when compared with asthma (3.4% and 67.8%, p  = 0.002 and p  = 0.040) and healthy (3.8% and 40%, p  < 0.001 and p  < 0.001). In all adults born prematurely (preterm and BPD), lymphocyte proportion correlated negatively with forced vital capacity ( r = -0.324, p  = 0.036) and CD8 + T cells correlated with forced expiratory volume in one second, FEV 1 ( r =-0.448, p  = 0.048). Correlation-based network analysis revealed that lung function cluster and BPD-birth cluster were associated with lymphocytes and/or CD4 + and CD8 + T cells. Multivariate regression analysis showed that lymphocyte proportions and BPD severity qualified as independent factors associated with FEV 1 . Conclusions The increased cytotoxic T cells in the large airways in young adults with former BPD, suggest a similar T-cell subset pattern as in the small airways, resembling features of COPD. Our findings strengthen the hypothesis that mechanisms involving adaptive and innate immune responses are involved in the development of airway disease due to preterm birth. What is already known on this topic Bronchopulmonary Dysplasia (BPD) in infants born prematurely is a risk factor for chronic airway obstruction in adulthood. Cytotoxic T cells are increased in bronchoalveolar lavage in adults with former BPD. What this study adds We are able to demonstrate that inflammatory cell profiles in the bronchial wash from the large airway of preterm adults differ from healthy subjects born at term. Subjects with a history of BPD display an increased proportion of lymphocytes, mainly CD8 + T cells, and a lower proportion of CD4 + T cells. Furthermore, the number of cytotoxic T cells is associated with lung function. How this study might affect research practice and/or policy This study provides evidence of an immunological profile characterized by increased cytotoxic T cells in adults born prematurely, which suggests the involvement of both adaptive and innate immune mechanisms in the development of airway disease associated with preterm birth.

Artificial nanoparticles accumulate a protein corona layer in biological fluids, which significantly influences their bioactivity. As nanosized obligate intracellular parasites, viruses share many biophysical properties with artificial nanoparticles in extracellular environments and here we show that respiratory syncytial virus (RSV) and herpes simplex virus type 1 (HSV-1) accumulate a rich and distinctive protein corona in different biological fluids. Moreover, we show that corona pre-coating differentially affects viral infectivity and immune cell activation. In addition, we demonstrate that viruses bind amyloidogenic peptides in their corona and catalyze amyloid formation via surface-assisted heterogeneous nucleation. Importantly, we show that HSV-1 catalyzes the aggregation of the amyloid β-peptide (Aβ 42 ), a major constituent of amyloid plaques in Alzheimer’s disease, in vitro and in animal models. Our results highlight the viral protein corona as an acquired structural layer that is critical for viral–host interactions and illustrate a mechanistic convergence between viral and amyloid pathologies. The protein corona around artificial nanoparticles is known to influence activity and biological fate, the formation around viruses is less well understood. Here, the authors observe the formation of protein corona on viruses and study the effects this corona has on viral infectivity and on amyloid protein assembly.

Background Interleukin (IL)-26 is produced by T helper type 17 (Type 17) cells and exerts immunomodulatory plus antimicrobial effects. Previous studies show that local IL-26 concentrations in the airways are higher in patients with uncontrolled than in those with controlled asthma, and that this intriguing cytokine bears biomarker potential. Here, we determined how systemic IL-26 relates to allergen sensitization, asthma severity, and to IL-17 A in children. Methods Serum samples were obtained from children with ( n  = 60) and without ( n  = 17) sensitization to dog allergen, and IL-26 and IL-17 A protein concentrations were measured using ELISA. Self-reported history, including medication use and validated symptom-based questionnaire scores, was recorded. Results The serum concentrations of IL-26 were enhanced in allergen-sensitized subjects and correlated with those of IL-17 A in a positive manner. However, the IL-26 concentrations did not markedly differ between allergen-sensitized subjects with and without asthma, eczema, allergic rhinitis, or a history of food allergy. Notably, IL-26 concentrations correlated with increasing Asthma Control Test (ACT) scores in a positive manner and with inhaled corticosteroid in a negative manner, amongst sensitized subjects with asthma. Moreover, subjects with asthma requiring ≥ 1 course of oral corticosteroids in the preceding 12 months had decreased IL-26 concentrations. Conclusion This study forwards evidence that systemic IL-26, just like IL-17 A, is involved in allergen sensitization among children. The association of systemic IL-26 with improved asthma control is compatible with the cellular sources being recruited into the airways in severe asthma, which supports that this kinocidin bears potential as a biomarker and therapeutic target.

Background Bronchopulmonary dysplasia (BPD) is a risk factor for respiratory disease in adulthood. Despite the differences in underlying pathology, patients with a history of BPD are often treated as asthmatics. We hypothesized that pulmonary outcomes and health-related quality of life (HRQoL) were different in adults born preterm with and without a history of BPD compared to asthmatics and healthy individuals. Methods We evaluated 96 young adults from the LUNAPRE cohort ( clinicaltrials.gov/ct2/show/NCT02923648 ), including 26 individuals born preterm with a history of BPD (BPD), 23 born preterm without BPD (preterm), 23 asthmatics and 24 healthy controls. Extensive lung function testing and HRQoL were assessed. Results The BPD group had more severe airway obstruction compared to the preterm-, (FEV 1−  0.94 vs. 0.28 z-scores; p  ≤ 0.001); asthmatic- (0.14 z-scores, p  ≤ 0.01) and healthy groups (0.78 z-scores, p  ≤ 0.001). Further, they had increased ventilation inhomogeneity compared to the preterm- (LCI 6.97 vs. 6.73, p  ≤ 0.05), asthmatic- (6.75, p  = 0.05) and healthy groups (6.50 p ≤ 0.001). Both preterm groups had lower D LCO compared to healthy controls ( p  ≤ 0.001 for both). HRQoL showed less physical but more psychological symptoms in the BPD group compared to asthmatics. Conclusions Lung function impairment and HRQoL in adults with a history of BPD differed from that in asthmatics highlighting the need for objective assessment of lung health.

Objectives Ventilator-associated pneumonia (VAP) is difficult to diagnose using clinical criteria and no biomarkers have yet been proved to be sufficiently accurate. The use of the neutrophil-derived Heparin-binding protein (HBP) as a biomarker for pneumonia was investigated in this exploratory case–control study in two intensive care units at a tertiary referral hospital. Methods Patients with clinical signs of pneumonia were recruited and bronchoalveolar lavage fluid (BALF) or bronchial wash (BW) samples were collected. Mechanically ventilated and lung healthy subjects were recruited as controls. HBP was measured with enzyme-linked immunosorbent assay. Results BALF was collected from 14 patients with pneumonia and 14 healthy controls. Median HBP in BALF pneumonia samples was 14,690 ng/ml and controls 16.2 ng/ml ( p  < 0.0001). BW was collected from 10 pneumonia patients and 10 mechanically ventilated controls. Median HBP in BW pneumonia was 9002 ng/ml and controls 7.6 ng/ml ( p  < 0.0001). Conclusions These data indicate that HBP concentrations is significantly higher in lower airway samples from patients with pneumonia than control subjects and is a potentially useful biomarker for diagnosis of VAP.

Abstract Chronic obstructive pulmonary disease (COPD) is associated with colonization by bacterial pathogens and repeated airway infections, leading to exacerbations and impaired lung function. The highly glycosylated mucins in the mucus lining the airways are an important part of the host defense against pathogens. However, mucus accumulation can contribute to COPD pathology. Here, we examined whether inflammation is associated with glycosylation changes that affect interactions between airway mucins and pathogens. We isolated mucins from lower airway samples (n = 4–9) from long-term smokers with and without COPD and from never-smokers. The most abundant terminal glycan moiety was N-acetylneuraminic acid (Neu5Ac) among smokers with and without COPD and N-acetyl-hexoseamine among never-smokers. Moraxella catarrhalis bound to MUC5 mucins from smokers with and without COPD. M. catarrhalis binding correlated with inflammatory parameters and Neu5Ac content. M. catarrhalis binding was abolished by enzymatic removal of Neu5Ac. Furthermore, M. catarrhalis bound to α2,6 sialyl-lactose, suggesting that α2,6 sialic acid contributes to M. catarrhalis binding to mucins. Furthermore, we detected more M. catarrhalis binding to mucins from patients with pneumonia than to those from control subjects (n = 8–13), and this binding correlated with C-reactive protein and Neu5Ac levels. These results suggest a key role of inflammation-induced Neu5Ac in the adhesion of M. catarrhalis to airway mucins. The inflammation-induced ability of MUC5 mucins to bind M. catarrhalis is likely a host defense mechanism in the healthy lung, although it cannot be excluded that impaired mucociliary clearance limits the effectiveness of this defense in patients with COPD.

There is published evidence that a modest increase in blood eosinophils during stable COPD indicates future risk for exacerbations and a potential utility of inhaled corticosteroids. This has been perceived as an argument for targeting systemic eosinophil mobilization to prevent exacerbations in COPD, but there are no published data on systemic eosinophil mobilization during exacerbations in patients without allergy. We investigated long-term tobacco smokers (LTS: ≥10 pack-years) with COPD and chronic bronchitis (COPD-CB; GOLD stage 1-4; = 47) but no allergy; LTS without COPD and CB (LTS;  = 10), and healthy never-smokers (HNS;  = 10) during stable disease for cross-sectional comparisons. For longitudinal comparisons, we followed the COPD-CB group for 15 months during stable disease and exacerbations, excluding samples affected by systemic corticosteroids. We quantified blood concentrations of eosinophils, the activity marker eosinophilic cationic protein (ECP) and the chemokine interleukin (IL)-4. During stable disease, the concentrations of eosinophils were similar for the COPD-CB and the LTS group, although higher than in the HNS group. The concentrations of ECP and IL-4 were not markedly different in the COPD-CB and LTS groups either. During exacerbations, the concentrations of eosinophils, ECP and IL-4 were not further increased, and there was even a mathematical trend towards a decrease for these concentrations. The clinical evidence presented here suggests that, by average, there is no additional mobilization of eosinophils during exacerbations in patients with COPD and chronic bronchitis but no allergy. Thus, in this common phenotype, the immunological rationale for targeting systemic eosinophils during exacerbations remains unaccounted for, which motivates verification studies in large cohorts stratified for allergy and chronic bronchitis.

Background  The main long-term complication after lung transplantation is bronchiolitis obliterans syndrome (BOS), a deadly condition in which neutrophils may play a critical pathophysiological role. Recent studies show that the cytokine interleukin IL-26 can facilitate neutrophil recruitment in response to pro-inflammatory stimuli in the airways. In this pilot study, we characterized the local involvement of IL-26 during BOS and acute rejection (AR) in human patients. Method  From a biobank containing bronchoalveolar lavage (BAL) samples from 148 lung transplant recipients (LTR), clinically-matched patient pairs were identified to minimize the influence of clinical confounders. We identified ten pairs (BOS/non-BOS) with BAL samples harvested on three occasions for our longitudinal investigation and 12 pairs of patients with and without AR. The pairs were matched for age, gender, preoperative diagnosis, type of and time after surgery. Extracellular IL-26 protein was quantified in cell-free BAL samples using an enzyme-linked immunosorbent assay. Intracellular IL-26 protein in BAL cells was determined using immunocytochemistry (ICC) and flow cytometry. Results  The median extracellular concentration of IL-26 protein was markedly increased in BAL samples from patients with BOS (p < 0.0001) but not in samples from patients with AR. Intracellular IL-26 protein was confirmed in alveolar macrophages and lymphocytes (through ICC and flow cytometry) among BAL cells obtained from BOS patients. Conclusions  Local IL-26 seems to be involved in BOS but not AR, and macrophages as well as lymphocytes constitute cellular sources in this clinical setting. The enhancement of extracellular IL-26 protein in LTRs with BOS warrants further investigation of its potential as a target for diagnosing, monitoring, and treating BOS.