Asthma-like Features Research Articles

Blood eosinophil count variability in chronic obstructive pulmonary disease and severe asthma

BackgroundBlood eosinophils are essential biomarkers that vary substantially over time in patients with COPD and asthma. However, no study has identified the changes and effects in the changes of the blood eosinophil counts over time in both diseases. This study aimed to demonstrate blood eosinophil variability in patients with COPD and severe asthma based on these backgrounds. MethodsA total of 172 patients with COPD from the Hokkaido COPD cohort study and 96 patients with severe asthma from the Hokkaido Severe Asthma Cohort Study, whose blood eosinophil counts were measured annually over a 3-year period, were analyzed. The factors contributing to consistently high or low blood eosinophil counts were examined in each cohort. The stability of the eosinophil classification (<150, 150–299, ≥300 cells/μL) was compared based on the number of asthma-like features in patients with COPD and the smoking status in patients with severe asthma. ResultsAmong all the patients, the most stable range of baseline blood eosinophil counts differed between the two diseases, with <150 cells/μL in COPD and ≥300 cells/μL in severe asthma. In COPD, the number of asthma-like features (bronchodilator reversibility, blood eosinophilia, and atopy) affects the blood eosinophil count variation patterns. In severe asthma, smoking status did not affect the blood eosinophil count variation patterns. ConclusionsWe identified variations in the blood eosinophil counts and their contributing factors in patients with COPD and severe asthma.

Monensin inhibits mast cell mediated airway contractions in human and guinea pig asthma models

Asthma is a common respiratory disease associated with airway hyperresponsiveness (AHR), airway inflammation and mast cell (MC) accumulation in the lung. Monensin, an ionophoric antibiotic, has been shown to induce apoptosis of human MCs. The aim of this study was to define the effect of monensin on MC responses, e.g., antigen induced bronchoconstriction, and on asthmatic features in models of allergic asthma. Tracheal segments from house dust mite (HDM) extract sensitized guinea pigs were isolated and exposed to monensin, followed by histological staining to quantify MCs. Both guinea pig tracheal and human bronchi were used for pharmacological studies in tissue bath systems to investigate the monensin effect on tissue viability and antigen induced bronchoconstriction. Further, an HDM-induced guinea pig asthma model was utilized to investigate the effect of monensin on AHR and airway inflammation. Monensin decreased MC number, caused MC death, and blocked the HDM or anti-IgE induced bronchoconstriction in guinea pig and human airways. In the guinea pig asthma model, HDM-induced AHR, airway inflammation and MC hyperplasia could be inhibited by repeated administration of monensin. This study indicates that monensin is an effective tool to reduce MC number and MCs are crucial for the development of asthma-like features.

Enhanced efficacy of formoterol-montelukast salt in relieving asthma features and in preserving β2-agonists rescue therapy

Adrenergic β2-agonists represent a mainstay in asthma management. Their chronic use has been associated with decreased bronchoprotection and rebound hyperresponsiveness. Here we investigate on the possible therapeutic advantage of a pharmacological association of β2-agonists with montelukast, a highly selective leukotriene receptor antagonist, in modulating bronchial reactivity and controlling asthma features. The study has been conducted in vitro and in vivo and also takes advantage of the synthesis of a salt that gave us the possibility to simultaneously administer in vivo formoterol and montelukast (MFS). In vitro studies demonstrate that montelukast (1) preserves β2-agonist response in isolated bronchi by preventing homologous β2-adrenoceptor desensitization; (2) reduces desensitization by modulating β2-receptor translocation in bronchial epithelial cells. In vivo studies demonstrate that sensitized mice receiving formoterol or montelukast display a significant reduction in airway hyperresponsiveness, but the β2-agonist relaxing response is still impaired. Allergen challenge causes β2 heterologous desensitization that is further increased by treatment in vivo with formoterol. Conversely MFS not only inhibits airway hyperresponsiveness but it rescues the β2-agonist response. Histological analysis confirms the functional data, demonstrating an enhanced therapeutic efficiency of MSF in controlling also pulmonary metaplasia and lung inflammation. MFS is efficacious also when sensitized mice received the drug by local administration. In conclusion, the data obtained evidenced a therapeutic advantage in the association of β2-agonists with montelukast in the control of asthma-like features and a better rescue bronchodilation response to β2-agonists.

Chronic Obstructive Pulmonary Disease With Asthma-Like Features in the General Population in China.

BackgroundPatients with features of both asthma and chronic obstructive pulmonary disease (COPD) are seen commonly in the clinic but less is known in the general population. We investigated the prevalence and the heterogeneity of COPD with concomitant features of asthma in Chinese adult population.MethodsCOPD was defined as post-bronchodilator ratio of forced expiratory volume in 1s (FEV1) to forced vital capacity of less than the lower limits of normal. COPD with concomitant features of asthma was defined as either COPD with asthma diagnosed by self-reported physician-diagnosis or by presence of current wheeze, or as COPD with high bronchodilator response (HBR) defined as an increase in FEV1 >15% and >400 ml after bronchodilator.ResultsCOPD with concomitant features of asthma was found in 1.62% (95% CI 1.31–2.00) of adults (≥20 years) or in 15.2% (95% CI 13.0–17.7) of COPD patients. Compared with COPD with HBR, COPD with asthma diagnosis or wheeze were older (61.8 ± 1.1 years vs. 47.4 ± 2.8 years, P < 0.001), and with a lower post-bronchodilator FEV1%pred (68.2 ± 2.3 vs. 96.6 ± 3.4, P < 0.001). Age, smoking status, biomass use and allergic rhinitis were associated with increasing prevalence of COPD with asthma diagnosis or wheeze, and had greater impaired health status, more comorbidities and more acute exacerbations in the preceding 12 months.ConclusionsCOPD with concomitant features of asthma is common in people with COPD and those with COPD with asthma diagnosis or wheeze experience worse clinical severity than COPD with HBR. These findings will help toward the definition of the asthma-COPD overlap condition.

Respiratory and cardiovascular effects of ambient particulate matter from dust storm and non-dust storm periods in Kuwait

Epidemiological studies demonstrate a positive association between daily changes in concentrations of ambient airborne particulate matter (PM) and adverse respiratory and cardiovascular health effects. However, physicochemical properties of PM can vary greatly across geographical, atmospheric, and temporal conditions and influence the relative toxicity of airborne PM. The purpose of this study was to investigate the adverse pulmonary and cardiovascular health effects of ambient PM collected from discrete sampling sites in Kuwait during dust storm (DS) and non-dust storm (NDS) conditions. Collected dust samples were characterized for their chemical composition using atomic absorption, GC–MS, and HPLC–MS analyses. Male BALB/cJ mice were exposed to 100 µg of either NDS or dust storm (DS) PM in 50 µl of PBS by oropharyngeal aspiration. Lung function was measured and bronchoalveolar lavage was conducted at 1, 7, and 14 days post-exposure. Ischemia–reperfusion injury was performed 24 h after exposures by obstructing the left main coronary artery approximately 4 mm distal to its origin for 20 min, followed by 2 h. of reperfusion. Exposure to either NDS or DS PM resulted in airway hyperresponsiveness to acetylcholine compared to PBS controls. Total protein and cells in BAL fluid were elevated in both dust groups one day after exposure; however, DS PM induced a greater increase in cell numbers than did NDS PM, particularly in neutrophils, eosinophils, and lymphocytes. Representative lung sections exhibited positive staining for mucus in large airways at 7 days which resolved by 14 days in dust storm-exposed mice but persisted in NDS-exposed animals. Our findings suggest that NDS PM may be more effective in producing an adaptive immune response, while the early inflammation induced by DS PM may better resolve. We also observed a prolonged airway mucus response after exposure to NDS PM, suggesting it may produce more asthma-like features than dust storm PM. PM-induced changes to cardiac ischemia–reperfusion injury were not observed in this study. The lack of cardiovascular response may have been due to the limited exposure and single time point used in this study.

Airway hyperresponsiveness and inflammation in Japanese patients with human immunodeficiency virus 1 infection

IntroductionDespite the growing population of long-term survivors with human immunodeficiency virus 1 (HIV) exhibiting asthma-like features worldwide, the pathogenesis underlying airway hyperresponsiveness (AHR) and airway inflammation remains unclear. We aimed to investigate AHR and airway inflammation in an HIV-infected Japanese population. MethodsOf 94 Japanese participants, 10 HIV-infected participants with asthma were excluded from the study. We compared the characteristics of HIV-infected (n = 34) and non-HIV-infected participants (n = 50). Eosinophilic, neutrophilic, mixed (eosinophilic and neutrophilic), and paucigranulocytic airway inflammatory phenotypes were classified based on induced sputum characteristics. ResultsThe prevalence of AHR in HIV-infected participants (32.4%) was significantly higher than that in their non-HIV-infected counterparts (10.0%) (P = 0.0213). The multivariate nominal logistic regression analysis revealed HIV as an independent risk factor for AHR. HIV-infected participants were significantly more likely to have a neutrophilic airway inflammatory phenotype than non-HIV-infected participants (P = 0.0358). Furthermore, HIV-infected participants with AHR demonstrated a significant correlation between AHR levels and the percentage of sputum neutrophils (r = −0.65, P = 0.0316). The percentage of sputum neutrophils was negatively associated with the blood CD4 cell count (r = −0.66, P = 0.0266). ConclusionsWe observed the high prevalence of AHR and neutrophilic airway inflammatory phenotype in Japanese participants with stable HIV infection. Our findings provide insight into the mechanisms of AHR and may facilitate the development of novel treatment for individuals with AHR and HIV infection.

Novel acute hypersensitivity pneumonitis model induced by airway mycosis and high dose lipopolysaccharide

BackgroundInhalation of fungal spores is a strong risk factor for severe asthma and experimentally leads to development of airway mycosis and asthma-like disease in mice. However, in addition to fungal spores, humans are simultaneously exposed to other inflammatory agents such as lipopolysaccharide (LPS), with uncertain relevance to disease expression. To determine how high dose inhalation of LPS influences the expression of allergic airway disease induced by the allergenic mold Aspergillus niger (A. niger).MethodsC57BL/6J mice were intranasally challenged with the viable spores of A. niger with and without 1 μg of LPS over two weeks. Changes in airway hyperreactivity, airway and lung inflammatory cell recruitment, antigen-specific immunoglobulins, and histopathology were determined.ResultsIn comparison to mice challenged only with A. niger, addition of LPS (1 μg) to A. niger abrogated airway hyperresponsiveness and strongly attenuated airway eosinophilia, PAS+ goblet cells and TH2 responses while enhancing TH1 and TH17 cell recruitment to lung. Addition of LPS resulted in more severe, diffuse lung inflammation with scattered, loosely-formed parenchymal granulomas, but failed to alter fungus-induced IgE and IgG antibodies.ConclusionsIn contrast to the strongly allergic lung phenotype induced by fungal spores alone, addition of a relatively high dose of LPS abrogates asthma-like features, replacing them with a phenotype more consistent with acute hypersensitivity pneumonitis (HP). These findings extend the already established link between airway mycosis and asthma to HP and describe a robust model for further dissecting the pathophysiology of HP.

Tracheal Stenosis Presenting as Asthma Following Short-term Intubation

Among different causes of acquired tracheal stenosis, endotracheal intubation is the commonest one. Though usually occurs after prolonged intubation or tracheostomy, tracheal stenosis may even develop following short duration of intubation. Patients commonly present with cough, wheeze, breathlessness and stridor which often mimics bronchial asthma, hence leads to a delay in diagnosis, as features may appear months to year after the procedure or even patients may remain undiagnosed especially when history is misleading. In this report we present a 28-year-old lady having an untold history of endotracheal intubation with asthma-like features who was getting treatment accordingly. With a gradually deteriorating clinical condition, she underwent our consultation. Repeated history, review of previous medical records, and necessary investigations made us establishing the confirmatory diagnosis. Prompt intervention relieved her symptoms.&#x0D; J Bangladesh Coll Phys Surg 2021; 39(3): 205-208

Asthma in Cystic Fibrosis: Definitions and Implications of This Overlap Syndrome.

Cystic fibrosis (CF) is a multisystem, autosomal recessive disease that leads to progressive loss of lung function. Respiratory symptoms for both CF and asthma include cough, wheezing, and dyspnea. There is debate within the CF community on how to best define and distinguish CF-asthma overlap syndrome (CFAOS) from asthma-like features, though CFAOS is well-recognized. We aim to review the epidemiology, diagnosis, and treatment of asthma in CF and explore areas where further research is needed. There has been considerable improvement in the understanding and treatment of asthma over the past two decades leading to novel therapies such as biologic agents that target the airway inflammation in asthmatics based on their asthma phenotype. These therapies are being studied in CFAOS and are promising treatments. This review provides a comprehensive overview of the definition, epidemiology, diagnosis, and current treatment of CFAOS.

Asthma-Like Features and Anti-Asthmatic Drug Prescription in Children with Non-CF Bronchiectasis.

Bronchiectasis and asthma may share some characteristics and some patients may have both conditions. The present study aimed to examine the rationale of prophylactic inhaled corticosteroids (ICS) prescription in children with bronchiectasis. Data of children with radiologically established bronchiectasis were retrospectively reviewed. Episodes of dyspnea and wheezing, spirometric indices, total serum IgE, blood eosinophil counts, sensitization to aeroallergens, and air-trapping on expiratory CT scans, were recorded. The study included 65 children 1.5–16 years old, with non-CF bronchiectasis. Episodes of dyspnea or wheezing were reported by 22 (33.8%) and 23 (35.4%), respectively. Skin prick tests to aeroallergens (SPTs) were positive in 15 (23.0%) patients. Mosaic pattern on CT scans was observed in 37 (56.9%) patients. Dyspnea, presence of mosaic pattern, positive reversibility test, and positive SPTs were significantly correlated with the prescription of ICS. The prescription of ICS in children with bronchiectasis is more likely when there are certain asthma-like characteristics. The difficulty to set the diagnosis of real asthma in cases of bronchiectasis may justify the decision of clinicians to start an empirical trial with ICS in certain cases.

Noncanonical role for Ku70/80 in the prevention of allergic airway inflammation via maintenance of airway epithelial cell organelle homeostasis.

Airway epithelial homeostasis is under constant threat due to continuous exposure to the external environment, and abnormally robust sensitivity to external stimuli is critical to the development of airway diseases, including asthma. Ku is a key nonhomologous end-joining DNA repair protein with diverse cellular functions such as VDJ recombination and telomere length maintenance. Here, we show a novel function of Ku in alleviating features of allergic airway inflammation via the regulation of mitochondrial and endoplasmic reticulum (ER) stress. We first determined that airway epithelial cells derived from both asthmatic lungs and murine asthma models demonstrate increased expression of 8-hydroxy-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Ku protein expression was dramatically reduced in the bronchial epithelium of patients with asthma as well as in human bronchial epithelial cells exposed to oxidative stress. Knockdown of Ku70 or Ku80 in naïve mice elicited mitochondrial collapse or ER stress, leading to bronchial epithelial cell apoptosis and spontaneous development of asthma-like features, including airway hyperresponsiveness, airway inflammation, and subepithelial fibrosis. These findings demonstrate an essential noncanonical role for Ku proteins in asthma pathogenesis, likely via maintenance of organelle homeostasis. This novel function of Ku proteins may also be important in other disease processes associated with organelle stress.

5α-dihydrotestosterone abrogates sex bias in asthma like features in the mouse

Androgen levels inversely correlate with the incidence, susceptibility and severity of asthma. However, whether male sex hormones such as 5α-dihydrotestosterone (DHT) have beneficial effects on asthma symptoms and/or could affect asthma susceptibility have not been investigated. DHT administration to female mice, during the sensitization phase, abrogates the sex bias in bronchial hyperreactivity. This effect correlates with inhibition of leukotriene biosynthesis in the lung. DHT significantly inhibits also other asthma-like features such as airway hyperplasia and mucus production in sensitized female mice. Conversely, DHT does not affect plasma IgE levels as well as CD3+CD4+ IL-4+ cell and IgE+c-Kit+ cell infiltration within the lung but prevents pulmonary mast cell activation. The in vitro study on RBL‐2H3 cells confirms that DHT inhibits mast cell degranulation. In conclusion, our data demonstrate that immunomodulatory effects of DHT on mast cell activation prevent the translation of allergen sensitization into clinical manifestation of asthma.

Longitudinal changes in structural lung abnormalities using MDCT in chronic obstructive pulmonary disease with asthma-like features.

Some patients with chronic obstructive pulmonary disease (COPD) have asthma-like features. However, there have been few reports on the structural lung abnormalities found in this patient population. Multi-detector computed tomography (MDCT) can detect emphysematous low-attenuation areas (LAA) within the lung, airway thickness (wall area percentage, WA%), and the loss of pulmonary vasculature as the percentage of small pulmonary vessels with cross-sectional area (CSA) less than 5 mm2 (%CSA<5). We analyzed differences in structural lung changes over time between patients with COPD and those with COPD with asthma-like features using these CT parameters. We performed pulmonary function tests (PFTs), MDCT, and a COPD assessment test (CAT) in 50 patients with COPD and 29 patients with COPD with asthma-like features at the time of enrollment and two years later. We analyzed changes in clinical parameters and CT indices over time and evaluated differences in structural changes between groups. The CAT score and FEV1 did not significantly change during the follow-up period in either group. Emphysematous LAA regions significantly increased in both groups. The %CSA<5 showed a small but significant increase in COPD patients, but a significant decrease in patients with COPD with asthma-like features. The WA% at the distal bronchi was significantly decreased in COPD, but did not significantly change in COPD with asthma -like features. Emphysematous LAA increased in patients with COPD with and without asthma-like features. The %CSA<5 and WA% at the distal bronchi did not change in parallel with LAA. Furthermore, changes in %CSA<5 were significantly different between patients with COPD and those with COPD with asthma-like features. Patients with COPD with asthma-like features may have different longitudinal structural changes than those seen in COPD patients.

Secretory Inositol Polyphosphate 4-Phosphatase Protects against Airway Inflammation and Remodeling.

The asthma candidate gene inositol polyphosphate 4-phosphatase type I A (INPP4A) is a lipid phosphatase that negatively regulates the PI3K/Akt pathway. Destabilizing genetic variants of INPP4A increase the risk of asthma, and lung-specific INPP4A knockdown induces asthma-like features. INPP4A is known to localize intracellularly, and its extracellular presence has not been reported yet. Here we show for the first time that INPP4A is secreted by airway epithelial cells and that extracellular INPP4A critically inhibits airway inflammation and remodeling. INPP4A was present in blood and BAL fluid, and this extracellular INPP4A was reduced in patients with asthma and mice with allergic airway inflammation. In both naive mice and mice with allergic airway inflammation, antibody-mediated neutralization of extracellular INPP4A potentiated PI3K/Akt signaling and induced airway hyperresponsiveness, with prominent airway remodeling, subepithelial fibroblast proliferation, and collagen deposition. The link between extracellular INPP4A and fibroblasts was investigated in vitro. Cultured airway epithelial cells secreted enzymatically active INPP4A in extracellular vesicles and in a free form. Extracellular vesicle-mediated transfer of labeled INPP4A, from epithelial cells to fibroblasts, was observed. Inhibition of such transfer by anti-INPP4A antibody increased fibroblast proliferation. We propose that secretory INPP4A is a novel "paracrine" layer of the intricate regulation of lung homeostasis, by which airway epithelium dampens PI3K/Akt signaling in inflammatory cells or local fibroblasts, thereby limiting inflammation and remodeling.

ACO: Time to move from the description of different phenotypes to the treatable traits.

BackgroundAsthma-COPD overlap (ACO) is a term that encompasses patients with characteristics of two conditions, smoking asthmatics or COPD patients with asthma-like features such as high bronchodilator response or blood eosinophil count ≥300 cells/μL. The aim of this study was to compare the different phenotypes inside the ACO definition in a real-life population cohort.MethodsWe analyzed patients from the MAJORICA cohort who had a diagnosis of asthma and/or COPD based on current guidelines, laboratory data in 2014 and follow-up until 2015. Prevalence of ACO according to the different criteria, demographic, clinical and functional characteristics, prescriptions and use of health resources data were compared between three groups.ResultsWe included 603 patients. Prevalence of smoking asthmatics was 14%, COPD patients with high bronchodilator response 1.5% and eosinophilic COPD patients 12%. Smoking asthmatics were younger and used more rescue inhalers, corticosteroids and health resources. Conversely, eosinophilic COPD patients were older than the other groups, often treated with corticosteroids and had lower use of health resources. Most of the COPD patients with high bronchodilator response were included in the eosinophilic COPD group.ConclusionsACO includes two conditions (smoking asthmatics and eosinophilic COPD patients) with different medication requirement and prognosis that should not be pooled together. Use of ≥300 blood eosinophils/μL as a treatable trait should be recommended.

Leukotriene-mediated sex dimorphism in murine asthma-like features during allergen sensitization

The incidence and severity of asthma preponderate in women versus men. Leukotrienes (LTs) are lipid mediators involved in asthma pathogenesis, and sex disparities in LT biosynthesis and anti-LT pharmacology in inflammation have recently emerged. Here, we report on sex dimorphism in LT production during allergen sensitization and its correlation to lung function. While high plasma levels of IgE, as sensitization index, were elevated in both sexes, LT levels increased only in lungs of female ovalbumin-sensitized BALB/c mice. Sex-dependent elevated LT levels strictly correlated to an enhanced airway hyperreactivity, pulmonary inflammation and mast cell infiltration/activation in female mice. Importantly, this sex bias was coupled to superior therapeutic efficacy of different types of clinically used LT modifiers like zileuton, MK886 and montelukast in female animals. Our findings reveal sex-dependent LT production as a basic mechanism of sex dimorphism in allergic asthma, and suggest that women might benefit more from anti-LT asthma therapy.

Sex-specific airway hyperreactivity and sex-specific transcriptome remodeling in neonatal piglets challenged with intra-airway acid.

Acute airway acidification is a potent stimulus of sensory nerves and occurs commonly with gastroesophageal reflux disease, cystic fibrosis, and asthma. In infants and adults, airway acidification can acutely precipitate asthma-like symptoms, and treatment-resistant asthma can be associated with gastroesophageal reflux disease. Airway protective behaviors, such as mucus secretion and airway smooth muscle contraction, are often exaggerated in asthma. These behaviors are manifested through activation of neural circuits. In some populations, the neural response to acid might be particularly important. For example, the immune response in infants is relatively immature compared with adults. Infants also have a high frequency of gastroesophageal reflux. Thus, in the current study, we compared the transcriptomes of an airway-nervous system circuit (e.g., tracheal epithelia, nodose ganglia, and brain stem) in neonatal piglets challenged with intra-airway acid. We hypothesized that the identification of parallel changes in the transcriptomes of two neutrally connected tissues might reveal the circuit response, and, hence, molecules important for the manifestation of asthma-like features. Intra-airway acid induced airway hyperreactivity and airway obstruction in male piglets. In contrast, female piglets displayed airway obstruction without airway hyperreactivity. Pairwise comparisons revealed parallel changes in genes directly implicated in airway hyperreactivity ( scn10a) in male acid-challenged piglets, whereas acid-challenged females exhibited parallel changes in genes associated with mild asthma ( stat 1 and isg15). These findings reveal sex-specific responses to acute airway acidification and highlight distinct molecules within a neural circuit that might be critical for the manifestation of asthma-like symptoms in pediatric populations.

Airways exudation of plasma macromolecules: Innate defense, epithelial regeneration, and asthma

This review discusses in vivo airway aspects of plasma exudation in relation to current views on epithelial permeability and epithelial regeneration in health and disease. Microvascular-epithelial exudation of bulk plasma proteins characteristically occurs in asthmatic patients, being especially pronounced in those with severe and exacerbating asthma. Healthy human and guinea pig airways challenged by noninjurious histamine-leukotriene–type autacoids also respond through prompt mucosal exudation of nonsieved plasma macromolecules. Contrary to current beliefs, epithelial permeability in the opposite direction (ie, absorption of inhaled molecules) has not been increased in patients with asthma and allergic rhinitis or in acutely exuding healthy airways. A slightly increased subepithelial hydrostatic pressure produces such unidirectional outward perviousness to macromolecules. Lack of increased absorption permeability in asthmatic patients can further be reconciled with occurrence of epithelial shedding, leaving small patches of denuded basement membrane. Counteracting escalating barrier breaks, plasma exudation promptly covers the denuded patches. Here it creates and sustains a biologically active barrier involving a neutrophil-rich, fibrin-fibronectin net. Furthermore, in the plasma-derived milieu, all epithelial cell types bordering the denuded patch dedifferentiate and migrate from all sides to cover the denuded basement membrane. However, this speedy epithelial regeneration can come at a cost. Guinea pig in vivo studies demonstrate that patches of epithelial denudation regeneration are exudation hot spots evoking asthma-like features, including recruitment/activation of granulocytes, proliferation of fibrocytes/smooth muscle cells, and basement membrane thickening. In conclusion, nonsieved plasma macromolecules can operate on the intact airway mucosa as potent components of first-line innate immunity responses. Exuded plasma also takes center stage in epithelial regeneration. When exaggerated, epithelial regeneration can contribute to the inception and development of asthma.

Tumor necrosis factor family member LIGHT acts with IL-1β and TGF-β to promote airway remodeling during rhinovirus infection.

Rhinovirus (RV) can exacerbate allergen-driven asthma. However, it has been suggested that serial infections with RV may also lead to asthma-like features in childhood without prior allergen exposure. We sought to test the effects of RV infection in the absence of allergen challenge on lung tissue remodeling and to understand whether RV induced factors in common with allergen that promote remodeling. We infected C57BL/6 mice multiple times with RV in the absence or presence of allergen to assess airway remodeling. We used knockout mice and blocking reagents to determine the participation of LIGHT (TNFSF14), as well as IL-1β and TGF-β, each previously shown to contribute to lung remodeling driven by allergen. Recurrent RV infection without allergen challenge induced an increase in peribronchial smooth muscle mass and subepithelial fibrosis. Rhinovirus (RV) induced LIGHT expression in mouse lungs after infection, and alveolar epithelial cells and neutrophils were found to be potential sources of LIGHT. Accordingly, LIGHT-deficient mice, or mice where LIGHT was neutralized, displayed reduced smooth muscle mass and lung fibrosis. Recurrent RV infection also exacerbated the airway remodeling response to house dust mite allergen, and this was significantly reduced in LIGHT-deficient mice. Furthermore, neutralizing IL-1β or TGF-β also limited subepithelial fibrosis and/or smooth muscle thickness induced by RV. Rhinovirus can promote airway remodeling in the absence of allergen through upregulating common factors that also contribute to allergen-associated airway remodeling.

Neonatal hyperoxia promotes asthma-like features through IL-33–dependent ILC2 responses

Premature infants often require oxygen supplementation and, therefore, are exposed to oxidative stress. Following oxygen exposure, preterm infants frequently develop chronic lung disease and have a significantly increased risk of asthma. We sought to identify the underlying mechanisms by which neonatal hyperoxia promotes asthma development. Mice were exposed to neonatal hyperoxia followed by a period of room air recovery. Agroup of mice was also intranasally exposed to house dust mite antigen. Assessments were performed at various time points for evaluation of airway hyperresponsiveness, eosinophilia, mucus production, inflammatory gene expression, and TH and group 2 innate lymphoid cell (ILC2) responses. Sera from term- and preterm-born infants were also collected and levels of IL-33 and type 2 cytokines were measured. Neonatal hyperoxia induced asthma-like features including airway hyperresponsiveness, mucus hyperplasia, airway eosinophilia, and type 2 pulmonary inflammation. In addition, neonatal hyperoxia promoted allergic TH responses to house dust mite exposure. Elevated IL-33 levels and ILC2 responses were observed in the lungs most likely due to oxidative stress caused by neonatal hyperoxia. IL-33 receptor signaling and ILC2s were vital for the induction of asthma-like features following neonatal hyperoxia. Serum IL-33 levels correlated significantly with serum levels of IL-5 and IL-13 but not IL-4 in preterm infants. These data demonstrate that an axis involving IL-33 and ILC2s is important for the development of asthma-like features following neonatal hyperoxia and suggest therapeutic potential for targeting IL-33, ILC2s, and oxidative stress to prevent and/or treat asthma development related to prematurity.