Changes In Airway Inflammation Research Articles

Landscape fire smoke airway exposure impairs respiratory and cardiac function and worsens experimental asthma

Millions of people are exposed to landscape fire smoke (LFS) globally, and inhalation of LFS particulate matter (PM) is associated with poor respiratory and cardiovascular outcomes. However, how LFS affects respiratory and cardiovascular function is less well understood. We aimed to characterize the pathophysiologic effects of representative LFS airway exposure on respiratory and cardiac function and on asthma outcomes. LFS was generated using a customized combustion chamber. In 8-week-old female BALB/c mice, low (25 μg/m3, 24-hour equivalent) or moderate (100 μg/m3, 24-hour equivalent) concentrations of LFS PM (10 μm and below [PM10]) were administered daily for 3 (short-term) and 14 (long-term) days in the presence and absence of experimental asthma. Lung inflammation, gene expression, structural changes, and lung function were assessed. In 8-week-old male C57BL/6 mice, low concentrations of LFS PM10 were administered for 3 days. Cardiac function and gene expression were assessed. Short- and long-term LFS PM10 airway exposure increased airway hyperresponsiveness and induced steroid insensitivity in experimental asthma, independent of significant changes in airway inflammation. Long-term LFS PM10 airway exposure also decreased gas diffusion. Short-term LFS PM10 airway exposure decreased cardiac function and expression of gene changes relating to oxidative stress and cardiovascular pathologies. We characterized significant detrimental effects of physiologically relevant concentrations and durations of LFS PM10 airway exposure on lung and heart function. Our study provides a platform for assessment of mechanisms that underpin LFS PM10 airway exposure on respiratory and cardiovascular disease outcomes.

Use of physiologically based pharmacokinetic modeling to support development of an acute (24-hour) health-based inhalation guideline for manganese

The toxicokinetics of manganese (Mn) are controlled through homeostasis because Mn is an essential element. However, at elevated doses, Mn is also neurotoxic and has been associated with respiratory, reproductive, and developmental effects. While health-based criteria have been developed for chronic inhalation exposure to ambient Mn, guidelines for short-term (24-h) environmental exposure are also needed. We reviewed US state, federal, and international health-based inhalation toxicity criteria, and conducted a literature search of recent publications. The studies deemed most appropriate to derive a 24-h guideline have a LOAEL of 1500 μg/m3 for inflammatory airway changes and biochemical measures of oxidative stress in the brain following 90 total hours of exposure in monkeys. We applied a cumulative uncertainty factor of 300 to this point of departure, resulting in a 24-h guideline of 5 μg/m3. To address uncertainty regarding potential neurotoxicity, we used a previously published physiologically based pharmacokinetic model for Mn to predict levels of Mn in the brain target tissue (i.e., globus pallidus) for exposure at 5 μg/m3 for two short-term human exposure scenarios. The PBPK model predictions support a short-term guideline of 5 μg/m3 as protective of both respiratory effects and neurotoxicity, including exposures of infants and children.

Airway inflammatory changes in the lungs of patients with asthma-COPD overlap (ACO): a bronchoscopy endobronchial biopsy study

BackgroundAlthough asthma and chronic obstructive pulmonary disease (COPD) are two distinct chronic airway inflammatory diseases, they often co-exist in a patient and the condition is referred to as asthma-COPD overlap (ACO). Lack of evidence regarding the inflammatory cells in ACO airways has led to their poor prognosis and treatment. The objective of this endobronchial biopsy (EBB) study was to enumerate inflammatory cellular changes in the airway wall of ACO compared with asthma, COPD current smokers (CS) and ex-smokers (ES), normal lung function smokers (NLFS), and non-smoker controls (HC).MethodsEBB tissues from 74 patients were immunohistochemically stained for macrophages, mast cells, eosinophils, neutrophils, CD8+ T-cells and CD4+ T-cells. The microscopic images of stained tissues were evaluated in the epithelium, reticular basement membrane (RBM) cells/mm RBM length, and lamina propria (LP) cells/mm2 up to a depth of 120 µM using the image analysis software Image-Pro Plus 7.0. The observer was blinded to the images and disease diagnosis. Statistical analysis was performed using GraphPad Prism v9.ResultsThe tissue macrophages in ACO were substantially higher in the epithelium and RBM than in HC (P < 0.001 for both), COPD-ES (P < 0.001 for both), and -CS (P < 0.05 and < 0.0001, respectively). The ACO LP macrophages were significantly higher in number than COPD-CS (P < 0.05). The mast cell numbers in ACO were lower than in NLFS (P < 0.05) in the epithelium, lower than COPD (P < 0.05) and NLFS (P < 0.001) in RBM; and lower than HC (P < 0.05) in LP. We noted lower eosinophils in ACO LP than HC (P < 0.05) and the lowest neutrophils in both ACO and asthma. Furthermore, CD8+ T-cell numbers increased in the ACO RBM than HC (P < 0.05), COPD-ES (P < 0.05), and NLFS (P < 0.01); however, they were similar in number in epithelium and LP across groups. CD4+ T-cells remained lower in number across all regions and groups.ConclusionThese results suggest that the ACO airway tissue inflammatory cellular profile differed from the contributing diseases of asthma and COPD with a predominance of macrophages.

Airway and systemic biomarkers of health effects after short-term exposure to indoor ultrafine particles from cooking and candles – A randomized controlled double-blind crossover study among mild asthmatic subjects

BackgroundThere is insufficient knowledge about the systemic health effects of exposure to fine (PM2.5) and ultrafine particles emitted from typical indoor sources, including cooking and candlelight burning. We examined whether short-term exposure to emissions from cooking and burning candles cause inflammatory changes in young individuals with mild asthma. Thirty-six non-smoking asthmatics participated in a randomized controlled double-blind crossover study attending three exposure sessions (mean PM2.5 µg/m3; polycyclic aromatic hydrocarbons ng/m3): (a) air mixed with emissions from cooking (96.1; 1.1), (b) air mixed with emissions from candles (89.8; 10), and (c) clean filtered air (5.8; 1.0). Emissions were generated in an adjacent chamber and let into a full-scale exposure chamber where participants were exposed for five hours. Several biomarkers were assessed in relation to airway and systemic inflammatory changes; the primary outcomes of interest were surfactant Protein-A (SP-A) and albumin in droplets in exhaled air – novel biomarkers for changes in the surfactant composition of small airways. Secondary outcomes included cytokines in nasal lavage, cytokines, C-reactive protein (CRP), epithelial progenitor cells (EPCs), genotoxicity, gene expression related to DNA-repair, oxidative stress, and inflammation, as well as metabolites in blood. Samples were collected before exposure start, right after exposure and the next morning.ResultsSP-A in droplets in exhaled air showed stable concentrations following candle exposure, while concentrations decreased following cooking and clean air exposure. Albumin in droplets in exhaled air increased following exposure to cooking and candles compared to clean air exposure, although not significant. Oxidatively damaged DNA and concentrations of some lipids and lipoproteins in the blood increased significantly following exposure to cooking. We found no or weak associations between cooking and candle exposure and systemic inflammation biomarkers including cytokines, CRP, and EPCs.ConclusionsCooking and candle emissions induced effects on some of the examined health-related biomarkers, while no effect was observed in others; Oxidatively damaged DNA and concentrations of lipids and lipoproteins were increased in blood after exposure to cooking, while both cooking and candle emissions slightly affected the small airways including the primary outcomes SP-A and albumin. We found only weak associations between the exposures and systemic inflammatory biomarkers. Together, the results show the existence of mild inflammation following cooking and candle exposure.

Biologics and airway remodeling in severe asthma.

Asthma is a chronic inflammatory airway disease resulting in airflow obstruction, which in part can become irreversible to conventional therapies, defining the concept of airway remodeling. The introduction of biologics in severe asthma has led in some patients to the complete normalization of previously considered irreversible airflow obstruction. This highlights the need to distinguish a "fixed" airflow obstruction due to structural changes unresponsive to current therapies, from a "reversible" one as demonstrated by lung function normalization during biological therapies not previously obtained even with high-dose systemic glucocorticoids. The mechanisms by which exposure to environmental factors initiates the inflammatory responses that trigger airway remodeling are still incompletely understood. Alarmins represent epithelial-derived cytokines that initiate immunologic events leading to inflammatory airway remodeling. Biological therapies can improve airflow obstruction by addressing these airway inflammatory changes. In addition, biologics might prevent and possibly even revert "fixed" remodeling due to structural changes. Hence, it appears clinically important to separate the therapeutic effects (early and late) of biologics as a new paradigm to evaluate the effects of these drugs and future treatments on airway remodeling in severe asthma.

The Roles of Tissue-Resident Memory T Cells in Lung Diseases.

The unique environment of the lungs is protected by complex immune interactions. Human lung tissue-resident memory T cells (TRM) have been shown to position at the pathogen entry points and play an essential role in fighting against viral and bacterial pathogens at the frontline through direct mechanisms and also by orchestrating the adaptive immune system through crosstalk. Recent evidence suggests that TRM cells also play a vital part in slowing down carcinogenesis and preventing the spread of solid tumors. Less beneficially, lung TRM cells can promote pathologic inflammation, causing chronic airway inflammatory changes such as asthma and fibrosis. TRM cells from infiltrating recipient T cells may also mediate allograft immunopathology, hence lung damage in patients after lung transplantations. Several therapeutic strategies targeting TRM cells have been developed. This review will summarize recent advances in understanding the establishment and maintenance of TRM cells in the lung, describe their roles in different lung diseases, and discuss how the TRM cells may guide future immunotherapies targeting infectious diseases, cancers and pathologic immune responses.

The effect of chronic hepatitis-C virus infection on asthma control, severity, and induced sputum analysis in bronchial asthma patients

Background Bronchial asthma is a heterogeneous disease, manifested by chronic airway-inflammatory changes. Viral hepatitis-C infection is a major worldwide illness with about 130–150 million that are chronically infected. Hepatitis-C virus (HCV) is associated with liver pathology and extrahepatic manifestations, which can lead to many indirect and direct pulmonary complications. Alteration of airway inflammation may be the underlying mechanism predisposing asthmatics with chronic HCV to more severe asthma. Discrete inflammatory types have been recognized in the sputum of asthmatics. This study aims to assess the effect of HCV infection on asthma control, asthma severity, and airway inflammation and to analyze sputum in bronchial asthma patients graded according to Global Initiative for Asthma Classification. Patients and methods This study included 60 adult nonsmoking asthmatic patients who were enrolled from the outpatient clinic of Chest and Tropical Departments, Mansoura University Hospital from February 2016 to September 2017. They were classified into two groups. Group A: patients without HCV infection and group B: patients with chronic HCV infection. Analysis of induced sputum to evaluate airway-inflammatory cell type in relation to asthma control, severity, and treatment step. Results Regarding asthma severity and treatment step, there is a significant difference between the two studied groups, while no significant differences in asthma control between the two groups were found. Successfully induced samples illustrated that airway-inflammatory cells varied in both groups; although an eosinophilic phenotype predominates in both groups, a higher percentage was present in group A (50%) than patients in group B (35%), also, paucigranulocytic phenotype was higher in group A than group B. On the other hand, the percentage of neutrophilic and mixed granulocytic phenotypes was more in group B in comparison with group A. Conclusion Patients with asthma and chronic HCV infection had a significant later onset of bronchial asthma, eosinophilic phenotype predominated in all asthmatic patients, especially in patients without HCV. High percentage of neutrophils was present in asthmatics with HCV infection and this suggested more severe airway inflammation.

Acute responses of airway oxidative stress, inflammation, and hemodynamic markers to ambient PM2.5 and their trace metal contents among healthy adolescences: A panel study in highly polluted versus low polluted regions

Particulate air pollutants are known contributors to global cardiorespiratory mortality through several pathways. We examined the effects of varied exposure to PM2.5 and trace metals on biological markers of airway inflammation, oxidative stress, and hemodynamic function of young individuals living in two different exposure settings.We enrolled and followed a panel of 97 healthy nonsmoking participants aged 15–18 years living in a highly polluted metropolitan city of Tabriz (TBZ) and a much less polluted semi-urban town of Hadishahr (HDS). For five consecutive months, the subjects were examined by a physician, and fractional exhaled nitric oxide levels (FENO) were measured. Samples of exhaled breath condensation (EBC) were obtained for measuring interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and total nitric oxide (NOx). We measured daily outdoor PM2.5 mass concentration in a fixed station in each location for all this period. The PM-metal content was analyzed by ICP-MS. The linear mixed-effects regression models were applied for data analysis.The averages of PM2.5 mass and total metals in TBZ were nearly two and four times higher than in HDS, respectively. In TBZ, an increased IQR of PM2.5 mass during 0–5 days was -correlated with a significant rise in diastolic blood pressure, heart rate, TNF-α, FENO, and NOx and reduction of IL-6. Moreover, exposure to low PM2.5 concentration is significantly -correlated with an elevation in diastolic blood pressure in HDS. We also observed that exposure to metal constituents in the highly polluted region is correlated with increased TNF-α and IL-6 with 131.80% (95% CI: 56.01, 244.39) and 47.51% (95% CI: 33.01, 62.05) per IQR of Hg, respectively.This study suggests that exposure to ambient PM2.5 and their metal contents in highly polluted areas may incite significant changes in airway inflammation, oxidative stress, and hemodynamic parameters in healthy subjects.

Resolvin D2 Promotes the Resolution of Lung Inflammation in Allergen-Induced Asthma

Abstract Background: Asthma is a chronic inflammatory disease without complete resolution. The production of specialized pro-resolving mediators (SPMs) is defective in asthma, so they represent a potential therapeutic opportunity. We hypothesize that docosahexaenoic acid derived resolvin D2 (RvD2) can promote the resolution of asthma. Methods: BALB/c mice were challenged intra-tracheally with house dust mite (HDM). Bronchoalveolar lavage (BAL) fluid was collected at predefined protocol endpoints for peak inflammation and during resolution. To determine impact on resolution, some mice were given RvD2 (100 ng, intra-nasally) for 2 days after the last HDM challenge, and the resolution index for eosinophils and other markers were calculated. Results: Airway HDM challenge led to marked increases in BAL eosinophils and BAL fluid pro-inflammatory cytokine and chemokine levels. Histology demonstrated changes in airway inflammation and mucous cell metaplasia in HDM-challenged lungs. NF-κB expression was increased in the lungs of HDM allergic mice. Compared to vehicle, treatment with RvD2 significantly decreased BAL inflammatory macrophage and eosinophil counts, and accelerated the resolution of HDM-evoked inflammation with a marked decrease in the resolution index for BAL eosinophils from 5 days to 1 day. Interestingly, RvD2 attenuation of eosinophils specifically targeted a specific eosinophil population, but not the “resident” eosinophils. The impact of RvD2 on NF-kB activity and its GPR18 receptor-mediated actions is under current investigation to determine mechanisms for RvD2’s pro-resolving actions. Conclusion: RvD2 promotes resolution of allergen-induced inflammation in a murine model of allergic asthma.

Changes in airway inflammation with pseudomonas eradication in early cystic fibrosis

Background: Neutrophil elastase is a significant risk factor for structural lung disease in cystic fibrosis, and Pseudomonas aeruginosa airway infection is linked with neutrophilic inflammation and substantial respiratory morbidity. We aimed to evaluate how neutrophil elastase (NE) activity changes after P. aeruginosa eradication and influences early disease outcomes.Methods: We assessed participants in the AREST CF cohort between 2000 and 2018 who had P. aeruginosa cultured from their routine annual bronchoalveolar lavage (BAL) fluid and who underwent eradication treatment and a post eradication BAL. Factors associated with persistent P. aeruginosa infection, persistent neutrophilic inflammation following eradication and worse structural lung disease one year post-eradication were evaluated.Results: Eighty-eight episodes (3 months to 6 years old) of P. aeruginosa infection were studied. Eradication was successful in 84.1% of episodes. Median activity of NE was significantly reduced post-eradication from 9.15 to 3.4 nM (p = 0.008) but persisted in 33 subjects. High post-eradication NE levels were associated with an increased risk for P. aeruginosa infection in the next annual visit (odds ratio=1.7, 95% confidence interval 1.1–2.7, p = 0.014). Post-eradication NE levels (difference, 0.8; 95% confidence interval, 0.1–1.5) and baseline bronchiectasis computed tomography (CT) score (difference, 0.4; 95% confidence interval, 0.1–0.8) were the best predictors of bronchiectasis progression within 1 year (backward stepwise linear regression model, R2= 0.608, P<0.001), independent of eradication.Conclusion: In children with CF, NE activity may persist following successful P. aeruginosa eradication and is significantly associated with bronchiectasis progression. Evaluating strategies to diminish neutrophilic inflammation is essential for improving long-term outcomes.

CFTR Modulator Therapy Enhances Peripheral Blood Monocyte Contributions to Immune Responses in People With Cystic Fibrosis.

BackgroundCFTR modulators decrease some etiologies of CF airway inflammation; however, data indicate that non-resolving airway infection and inflammation persist in individuals with CF and chronic bacterial infections. Thus, identification of therapies that diminish airway inflammation without allowing unrestrained bacterial growth remains a critical research goal. Novel strategies for combatting deleterious airway inflammation in the CFTR modulator era require better understanding of cellular contributions to chronic CF airway disease, and how inflammatory cells change after initiation of CFTR modulator therapy. Peripheral blood monocytes, which traffic to the CF airway, can develop both pro-inflammatory and inflammation-resolving phenotypes, represent intriguing cellular targets for focused therapies. This therapeutic approach, however, requires a more detailed knowledge of CF monocyte cellular programming and phenotypes.Material and MethodsIn order to characterize the inflammatory phenotype of CF monocytes, and how these cells change after initiation of CFTR modulator therapy, we studied adults (n=10) with CF, chronic airway infections, and the CFTR-R117H mutations before and 7 days after initiation of ivacaftor. Transcriptomes of freshly isolated blood monocytes were interrogated by RNA-sequencing (RNA-seq) followed by pathway-based analyses. Plasma concentrations of cytokines and chemokines were evaluated by multiplex ELISA.ResultsRNAseq identified approximately 50 monocyte genes for which basal expression was significantly changed in all 10 subjects after 7 days of ivacaftor. Of these, the majority were increased in expression post ivacaftor, including many genes traditionally associated with enhanced inflammation and immune responses. Pathway analyses confirmed that transcriptional programs were overwhelmingly up-regulated in monocytes after 7 days of ivacaftor, including biological modules associated with immunity, cell cycle, oxidative phosphorylation, and the unfolded protein response. Ivacaftor increased plasma concentrations of CXCL2, a neutrophil chemokine secreted by monocytes and macrophages, and CCL2, a monocyte chemokine.ConclusionsOur results demonstrate that ivacaftor causes acute changes in blood monocyte transcriptional profiles and plasma chemokines, and suggest that increased monocyte inflammatory signals and changes in myeloid cell trafficking may contribute to changes in airway inflammation in people taking CFTR modulators. To our knowledge, this is the first report investigating the transcriptomic response of circulating blood monocytes in CF subjects treated with a CFTR modulator.

Resolvin D2 Promotes the Resolution of Allergen-Induced Lung Inflammation

Abstract Background Asthma is a chronic inflammatory disease without complete resolution. The production of specialized pro-resolving mediators (SPMs) is defective in asthma, so they represent a potential therapeutic opportunity. We hypothesize that docosahexaenoic acid derived resolvin D2 (RvD2) can promote the resolution of asthma. Methods BALB/c mice were challenged intra-tracheally with house dust mite (HDM). Bronchoalveolar lavage (BAL) fluid was collected at predefined protocol endpoints for peak inflammation and during resolution. To determine impact on resolution, some mice were given RvD2 (100 ng, intra-nasally) for 2 days after the last HDM challenge, and the resolution index for eosinophils and other markers were calculated. Results Airway HDM challenge led to marked increases in BAL eosinophils and BAL fluid pro-inflammatory cytokine and chemokine levels. Histology demonstrated changes in airway inflammation and mucous cell metaplasia in HDM-challenged lungs. NF-κB and Nrf2 expression were increased the lungs of HDM allergic mice. Compared to vehicle, treatment with RvD2 significantly decreased BAL inflammatory macrophage and eosinophil counts, and accelerated the resolution of HDM-evoked inflammation with a marked decrease in the resolution index for BAL eosinophils from 5 days to 1 day. Interestingly, RvD2 attenuation of eosinophils specifically targeted the inflammatory eosinophil population, but not the resident eosinophils. The impact of RvD2 on cytokine expression and NF-kB and Nrf2 activity is under current investigation to determine mechanisms for RvD2’s pro-resolving actions. Conclusion RvD2 promotes resolution of allergen-induced inflammation in a murine model of allergic asthma.

Blockade of interleukin-2-inducible T-cell kinase signaling attenuates acute lung injury in mice through adjustment of pulmonary Th17/Treg immune responses and reduction of oxidative stress

Acute lung injury (ALI) is linked with considerable morbidity and mortality. ALI can be caused by various agents, one of them being sepsis. ALI is characterized by injury to vascular endothelium and alveolar epithelium that results in edema, pulmonary immune cells infiltration and hypoxemia. Neutrophils and T cells particularly play a huge role in amplification of pulmonary inflammation through release of multiple inflammatory mediators. Recent reports suggest a strong involvement of Th17 cells and oxidative stress in initiation/amplification of pulmonary inflammation during ALI. Interleukin-2-inducible T-cell kinase (ITK) plays a key role in Th17 cell development through control of several transcription factors. Therefore, our study explored the role of ITK on airway inflammation (total/neutrophilic cell counts, myeloperoxidase activity, E-cadherin expression, histopathological analyses) and effect of its inhibition on various inflammatory/anti-inflammatory pathways during ALI [phosphorylated-ITK (p-ITK), NFATc1, IL-17A, STAT3, Foxp3, IL-10, iNOS, nitrotyrosine, lipid peroxides). ALI was associated with increased total/neutrophilic cell counts and myeloperoxidase activity, and decreased E-cadherin expression in airway epithelial cells (AECs) which was concurrent with upregulation of p-ITK, NFATc1, IL-17A, STAT3 in CD4+ T cells and iNOS/nitrotyrosine in AECs. Treatment with ITK inhibitor reversed ALI-induced changes in airway inflammation and Th17 cells/oxidative stress. Treatment with ITK inhibitor further expanded Treg cells in mice with ALI. In short, our study proposes that ITK signaling plays a significant role in sepsis-induced ALI through upregulation of Th17 cells and oxidative stress. Further, findings provide evidence that ITK blockade could be a potential treatment strategy to attenuate airway inflammation associated with ALI.

An Exploratory Study to Characterise Changes in Airway Inflammation, Symptoms, Lung Function and Reliever Use in Adult Asthma Patients

An Exploratory Study to Characterise Changes in Airway Inflammation, Symptoms, Lung Function and Reliever Use in Adult Asthma Patients

The loss of DGK protects against allergic airway inflammation and airway hyperresponsiveness

Abstract Asthma is a chronic allergic inflammatory airway disease that is caused by aberrant immune responses to inhaled allergens, which leads to airflow obstruction driven in part by increased sensitivity of airway smooth muscle to contractile agonists, a process known as airway hyperresponsiveness (AHR). The inflammation of allergic asthma is driven by type 2 cytokines released by Th2 CD4+ T cells and group 2 innate lymphoid cells (ILC2) in the lung. Here, we report that targeting DAG kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protects against allergic asthma. DGKζ knockout (KO) mice exhibited reduced type 2 airway inflammation and were completely resistant to AHR induction in a mouse model of allergic asthma. Surprisingly, the mechanism by which DGKζ protected against airway inflammation and AHR were separable. Targeted deletion of DGKζ in T cells led to decreased type 2 inflammation with no attenuation of AHR. In contrast, conditional deletion of DGKζ in airway smooth muscle cells led to decreased AHR despite no changes in airway inflammation. Importantly, the pharmacological inhibition of DGK provided protection against airway inflammation and AHR in mice, and also reduced bronchoconstriction of human airways. Together, our data suggest that DGKζ is potentially a novel therapeutic target for allergic asthma. Moreover, the targeted deletion of DGKζ reveals that the inflammatory and AHR components of allergic asthma are not as interdependent, as generally believed.

Characteristics of lower airway inflammatory changes in the minimal persistent inflammation of allergic rhinitis in mice

ABSTRACTObjective: This study aims to establish an experimental mouse model of minimal persistent inflammation (MPI), observe the features of inflammation and hyper-responsiveness of the upper/lower airways, and explore the relationship between inflammation and hyper-responsiveness in the upper/lower airways. Methods: Sixty-four female BALB/c mice were randomly divided into four groups: allergic rhinitis (AR) group as positive control, MPI group, negative control group and blank control group. Mice were given high and low-concentrated ovalbumin solution after basic and intensive sensitization to establish AR model and MPI model. Nasal mucosa and lung tissues were stained to observe eosinophil infiltration, goblet cell hyperplasia, and expression of intercellular adhesion molecule 1 (ICAM-1). Airway hyper-responsiveness was assessed. Levels of specific immunoglobulin E (sIgE), interleukin (IL)-4 and IL-5 in peripheral blood, nasal lavage fluid (NLF), and bronchoalveolar lavage fluid (BALF) were detected by Enzyme-linked immunosorbent assay. Results: The eosinophil infiltration and expression of ICAM-1 on nasal mucosa and in lung tissues in the AR and MPI groups were significantly elevated compared to control groups. Goblet cells count increased only in the nasal mucosa and not in lung tissues. Eosinophil and neutrophil count of NLF and BALF in the AR and MPI groups increased significantly compared to control groups. Level of IL-4 did not increase significantly, but sIgE and IL-5 did. Conclusions: Mice in the MPI status exhibits lower airway inflammation and hyper-responsiveness with increase in eosinophil count, goblet cells, ICAM-1, IL-4, and IL-5. These results provide further evidence for the importance of MPI of AR in lower airway diseases.

Intranasal administration of mesenchymoangioblast‐derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease

Structural changes known as airway remodeling (AWR) characterize chronic/severe asthma and contribute to lung dysfunction. Thus, we assessed the in vivo efficacy of induced pluripotent stem cell and mesenchymoangioblast-derived mesenchymal stem cells (MCA-MSCs) on AWR in a murine model of chronic allergic airways disease (AAD)/asthma. Female Balb/c mice were subjected to a 9-wk model of ovalbumin (Ova)-induced chronic AAD and treated intravenously or intranasally with MCA-MSCs from weeks 9 to 11. Changes in airway inflammation (AI), AWR, and airway hyperresponsiveness (AHR) were assessed. Ova-injured mice presented with AI, goblet cell metaplasia, epithelial thickening, increased airway TGF-β1 levels, subepithelial myofibroblast and collagen accumulation, total lung collagen concentration, and AHR (all P < 0.001 vs. uninjured control group). Apart from epithelial thickness, all other parameters measured were significantly, although not totally, decreased by intravenous delivery of MCA-MSCs to Ova-injured mice. In comparison, intranasal delivery of MCA-MSCs to Ova-injured mice significantly decreased all parameters measured (all P < 0.05 vs. Ova group) and, most notably, normalized aberrant airway TGF-β1 levels, airway/lung fibrosis, and AHR to values measured in uninjured animals. MCA-MSCs also increased collagen-degrading gelatinase levels. Hence, direct delivery of MCA-MSCs offers great therapeutic benefit for the AWR and AHR associated with chronic AAD.-Royce, S. G., Rele, S., Broughton, B. R. S., Kelly, K., Samuel, C. S. Intranasal administration of mesenchymoangioblast-derived mesenchymal stem cells abrogates airway fibrosis and airway hyperresponsiveness associated with chronic allergic airways disease.

Asthma and smoking-induced airway disease without spirometric COPD.

Due to the high prevalence rates of cigarette smoking and asthma, current and ex-smokers frequently develop chronic airway disease without spirometric evidence of chronic obstructive pulmonary disease (COPD), either alone or associated with asthma. This review considers the classification, clinical outcomes, inflammatory and imaging variables, phenotypes, and management of current and ex-smokers with airway disease without COPD, focusing on overlaps in those with and without asthma. These individuals have more respiratory symptoms, worse quality of life, increased exacerbation rates, reduced lung function and more comorbidities than never-smokers with asthma or healthy never-smokers. As well as clinical features, airway inflammatory and structural changes in smoking-induced airway disease without COPD overlap with those found in smokers with asthma. Cigarette smoking is associated with worse clinical outcomes in some phenotypes of asthma. Management involves public health measures to control exposure to tobacco smoke, personal advice on smoking cessation and the use of appropriate targeted therapies, although evidence is limited on their effectiveness. Understanding the mechanisms, natural history and management of current and ex-smokers with asthma and smoking-induced airway disease without COPD is a priority for future research.

Ligustrazine attenuates inflammation and the associated chemokines and receptors in ovalbumine-induced mouse asthma model.

Ligustrazine which is isolated from Chinese herb ligusticum chuanxiong hort, has been widely used in traditional Chinese medicine (TCM) for asthma treatment. In this study, we aim to observe the effect of ligustrazine on inflammation and the associated chemokines and receptors in ovalbumin (OVA)-induced mouse asthma model. Our data demonstrates that ligustrazine suppresses airway hyperresponsiveness to methacholine and lung inflammation in OVA-induced mouse asthma model. Ligustrazine also induces inhibition of inflammatory cells including neutrophils, lymphocytes and eosinophils. In addition, ligustrazine significantly reduces IL-4, IL-5, IL-17A, CCL3, CCL19 and CCL21 level in BALF of asthma mice. Furthermore, ligustrazine induces down-regulation of CCL19 receptor CCR7, STAT3 and p38 MAPK protein expression. Collectively, these results suggest that ligustrazine is effective in attenuation of allergic airway inflammatory changes and related chemokines and receptors in OVA-induced asthma model, and this action might be associated with inhibition of STAT3 and p38 MAPK pathway, which indicates that ligustrazine may be used as a potential therapeutic method to treat asthma.

Changes in airway inflammation during pulmonary exacerbations in patients with cystic fibrosis and primary ciliary dyskinesia

Lung disease in patients with both primary ciliary dyskinesia (PCD) or cystic fibrosis (CF) is associated with impaired mucociliary clearance; however, clinical outcomes are typically worse in CF patients. We assessed whether CF and PCD patients differ in inflammatory response in the airways during pulmonary exacerbation.We first studied clinically stable PCD patients with a spectrum of bacterial pathogens to assess inflammatory response to different pathogens. Subsequently, PCD and CF patients with similar bacterial pathogens were studied at the time of a pulmonary exacerbation and after 21 days of antibiotics treatment. Qualitative and quantitative microbiology, cell counts, interleukin-8 concentrations, and neutrophil elastase activity were assessed in sputum samples obtained before and after treatment.In stable PCD patients, no significant differences were found in sputum inflammatory markers between individuals colonised with different bacterial pathogens. Pulmonary exacerbation severity assessed by a pulmonary exacerbation score and lung function decline from their previous baseline did not differ between CF and PCD patients. Bacterial density for Staphylococcus aureus and Haemophilus influenzae was higher in CF versus PCD (p<0.05), but absolute neutrophil counts were higher in PCD patients (p=0.02). While sputum elastase activity was similar in PCD and CF at the time of exacerbation, it decreased with antibiotic therapy in PCD (p<0.05) but not CF patients.PCD patients differ from those with CF in their responses to treatment of pulmonary exacerbations, with higher neutrophil elastase activity persisting in the CF airways at the end of treatment.