Local Airway Inflammation Research Articles

Bronchoalveolar lavage fluid cytokines and chemokines changes after bronchial thermoplasty in severe asthma.

Bronchial thermoplasty (BT) is a non-pharmacological intervention in severe asthma with a well-known mechanism of reducing airway smooth muscle. However, its effect on airway inflammation remains uncertain. To investigate the effect of BT on bronchoalveolar lavage fluid (BALF) cytokines and chemokines in severe asthma patients before BT, after the first BT, and 12 weeks after BT. Ten severe asthma patients were recruited, and BALF was obtained from right lower lobe before BT, after the first BT, and 12 weeks after BT. BALF analytes were measured and values were compared among the time points. Lung function, asthma control test (ACT), and asthma quality of life questionnaire (AQLQ) were also measured. Tumor necrosis factor (TNF)-α concentration was significantly decreased after the first BT and significantly increased at 12 weeks after BT. Interleukin-6 (IL-6) and TNF-related apoptosis inducing ligand (TRAIL) concentration were significantly increased at 12 weeks after BT. There were no significant changes in Regulated upon activation, normal T-cell expressed and secreted (RANTES) and transforming growth factor-beta1 (TGF-β1) concentration over time after BT. At 12 weeks after BT, there were significantly greater improvements in the scores on AQLQ (3.93 ± 0.88 to 5.3 ± 0.99, p = 0.002) and ACT (13.6 ± 3.27 to 19 ± 4.44, p = 0.002). The lung function did not differ significantly between pre- and post-BT. BT has limited effect on TNF-α, IL-6, TRAIL, RANTES, and TGF- β1 in BALF suggesting that its clinical benefit is not primarily related to this local airway inflammation. The effect on long-term airway inflammation probably needs further studies.

Local and Systemic Production of Pro-Inflammatory Eicosanoids Is Inversely Related to Sensitization to Aeroallergens in Patients with Aspirin-Exacerbated Respiratory Disease.

Aspirin-exacerbated respiratory disease (AERD) is characterized by overproduction of the pro-inflammatory eicosanoids. Although immunoglobulin E-mediated sensitization to aeroallergens is common among AERD patients, it does not belong to the defining disease characteristics. In this study of 133 AERD patients, we sought to find a relationship between sensitization to aeroallergens and local (leukotriene E4, prostaglandin E2 and prostaglandin D2) and/or systemic (leukotriene E4) production of arachidonic acid metabolites. Interestingly, a negative association between pro-inflammatory eicosanoid levels in induced sputum supernatant or urine and sensitization to aeroallergens was observed. This inverse relationship might suggest the presence of a protective effect of atopic sensitization to aeroallergens against stronger local airway inflammation and higher systemic AERD-related inflammatory activity.

Interleukin-26 is associated with the level of systemic inflammation and lung functions in obese and non-obese moderate-to-severe asthmatic patients.

Obese asthma is a complex syndrome, which includes different phenotypes of disease. At present, these phenotypes only have started to acquire a sufficient understanding. It was suggested that IL-26 is a potential biomarker of disease severity in asthma without signs of Th2-mediated inflammation. In this study, we investigated the serum and exhaled levels of IL-26 and its associations with the level of systemic inflammation, lung functions, and body weight in obese and non-obese moderate-to-severe asthmatic patients MATERIAL AND METHODS: The study included 10 healthy subjects, 10 obese subjects without lung pathologies, 10 non-obese asthmatics (NOA) (BMI 18.5-24.9 kg/m²), and 40 obese asthmatics (OA) (BMI 25.0-49.9 kg/m²). During the visit, patients' examination and spirometry with the bronchodilator reversibility test were conducted, the exhaled breath condensate (EBC) was obtained, and the blood samples were collected. The level of IL-26, interleukin-1β (IL-1β), interleukin-4 (IL-4), interleukin-6 (IL-6), TNF-α, interleukin-10 (IL-10), total and specific immunoglobulin E (IgE), and high sensitive C reactive protein (hs-CRP) were measured using the ELISA kits. Statistical comparison between 2 groups was analyzed using the Mann-Whitney rank-sum test. Chi-square with Yates' correction was used to compare frequencies. Spearman's rank test was used for correlating nonparametric variables. The Receiver Operating Characteristic (ROC) curve and the area under ROC curve (AUC) were used for evaluating the diagnostic power of IL-26 as a possible biomarker. NOA had a reversible airway obstruction with reduced FEV1, FEV1/FVC, FVC 25/75, and positive post-bronchodilator test (PBT), significantly increased serum levels of IL-10, IL-4, and slightly increased IL-26. NOA had significantly increased exhaled IL-26 in comparison with healthy subjects. The obese subjects had a normal ventilatory pattern without airway obstruction, and differences in serum IL-26, IL-10, and IL-4 concentrations in comparison with healthy subjects. Obese subjects had a significant escalation of hs-CRP and no differences in the levels of exhaled IL-26, IL-10, and hs-CRP as compared with healthy subjects. OA had reduced FEV1, FEV1/FVC, and FEV25-75 in comparison with non-obese asthmatics. OA had elevated IL-26, IL-10, IL-4, and hs-CRP concentrations as compared with healthy subjects. These patients had a partial similarity with both non-obese asthmatics (elevated IL-26, IL-10, and IL-4) and obese subjects (elevated, IL-1β, IL-6, TNF-α, hs-CRP). OA had a reduced concentration of exhaled IL-26 in comparison with NOA and elevated exhaled IL-10 in comparison with obese subjects. Furthermore, OA had an increased concentration of IL-1β and TNF-α in comparison with healthy individuals and NOA. Exhaled IL-26 concentration distinguished non-obese asthmatics from healthy subjects, asthmatic patients from non-asthmatics (healthy and obese subjects), all asthmatic patients from non-asthmatics (healthy and obese subjects). Exhaled IL-26 elevated in obese and non-obese moderate-to-severe asthmatic patients. Exhaled IL-26 might be a perspective biomarker in non-obese and obese asthmatics. The obese asthmatic phenotype comprised the combined systemic and local airway inflammation.

Pediatric Obesity-Related Asthma: The Role of Nutrition and Nutrients in Prevention and Treatment.

Childhood obesity rates have dramatically risen in numerous countries worldwide. Obesity is likely a factor in increased asthma risk, which is already one of the most widespread chronic respiratory pathologies. The pathogenic mechanism of asthma risk has still not yet been fully elucidated. Moreover, the role of obesity-related inflammation and pulmonary overreaction to environmental triggers, which ultimately result in asthma-like symptoms, and the importance of dietary characteristics is well recognized. Diet is an important adjustable element in the asthma development. Food-specific composition of the diet, in particular fat, sugar, and low-quality nutrients, is likely to promote the chronic inflammatory state seen in asthmatic patients with obesity. An unbalanced diet or supplementation as a way to control asthma more efficiently has been described. A personalized dietary intervention may improve respiratory symptoms and signs and therapeutic response. In this narrative review, we presented and discussed more recent literature on asthma associated with obesity among children, focusing on the risk of asthma among children with obesity, asthma as a result of obesity focusing on the role of adipose tissue as a mediator of systemic and local airway inflammation implicated in asthma regulation, and the impact of nutrition and nutrients in the development and treatment of asthma. Appropriate early nutritional intervention could possibly be critical in preventing and managing asthma associated with obesity among children.

Novel non-invasive assessment of upper airway inflammation in obstructive sleep apnea using positron emission tomography/magnetic resonance imaging.

To develop a novel non-invasive technique to quantify upper airway inflammation using positron emission tomography/magnetic resonance imaging (PET/MRI) in patients with obstructive sleep apnea (OSA). Patients with treatment naïve moderate-to-severe OSA underwent [18F]-fluoro-2-deoxy-D-glucose (FDG) PET/MRI. Three readers independently performed tracings of the pharyngeal soft tissue on MRI. Standardized uptake values (SUV) were generated from region of interest (ROI) tracings on corresponding PET images. Background SUV was measured from the sternocleidomastoid muscle. SUV and target-to-background (TBR) were compared across readers using intraclass correlation coefficient (ICC) analyses. SUV from individual image slices were compared between each reader using Bland-Altman plots and Pearson correlation coefficients. All tracings were repeated by one reader for assessment of intra-reader reliability. Five participants completed our imaging protocol and analysis. Median age, body mass index, and apnea-hypopnea index were 41years (IQR 40.5-68.5), 32.7kg/m2 (IQR 28.1-38.1), and 30.7 event per hour (IQR 19.5-48.1), respectively. The highest metabolic activity regions were consistently localized to palatine or lingual tonsil adjacent mucosa. Twenty-five ICC met criteria for excellent agreement. The remaining three were TBR measurements which met criteria for good agreement. Head-to-head comparisons revealed strong correlation between each reader. Our novel imaging technique demonstrated reliable quantification of upper airway FDG avidity. This technology has implications for future work exploring local airway inflammation in individuals with OSA and exposure to pollutants. It may also serve as an assessment tool for response to OSA therapies.

Exhaled Breath Condensate-A Non-Invasive Approach for Diagnostic Methods in Asthma.

The pathophysiology of asthma has been intensively studied, but its underlying mechanisms such as airway inflammation, control of airway tone, and bronchial reactivity are still not completely explained. There is an urgent need to implement novel, non-invasive diagnostic tools that can help to investigate local airway inflammation and connect the molecular pathways with the broad spectrum of clinical manifestations of asthma. The new biomarkers of different asthma endotypes could be used to confirm diagnosis, predict asthma exacerbations, or evaluate treatment response. In this paper, we briefly describe the characteristics of exhaled breath condensate (EBC) that is considered to be an interesting source of biomarkers of lung disorders. We look at the composition of EBC, some aspects of the collection procedure, the proposed biomarkers for asthma, and its clinical implications. We also indicate the limitations of the method and potential strategies to standardize the procedure of EBC collection and analytical methods.

Regulatory and IgE+ B Cells in Allergic Asthma.

Allergic asthma is triggered by inhalation of environmental allergens resulting in bronchial constriction and inflammation, which leads to clinical symptoms such as wheezing, coughing, and difficulty breathing. Asthmatic airway inflammation is initiated by inflammatory mediators released by granulocytic cells. However, the immunoglobulin E (IgE) antibody is necessary for the initiation of the allergic cascade, and IgE is produced and released exclusively by memory B cells and plasma cells. Acute allergen exposure has also been shown to increase IgE levels in the airways of patients diagnosed with allergic asthma; however, more studies are needed to understand local airway inflammation. Additionally, regulatory B cells (Bregs) have been shown to modulate IgE-mediated inflammatory processes in allergic asthma pathogenesis, particularly in mouse models of allergic airway disease. However, the levels and function of these IgE+ B cells and Bregs remain to be elucidated in human models of asthma. The overall objective for this chapter is to provide detailed methodological, and insightful technological advances to study the biology of B cells in allergic asthma pathogenesis. Specifically, we will describe how to investigate the frequency and function of IgE+ B cells and Bregs in allergic asthma, and the kinetics of these cells after allergen exposure in a human asthma model.

Immune Modulation of Allergic Asthma by Early Pharmacological Inhibition of RIP2.

Exposure to house dust mite (HDM) is highly associated with the development of allergic asthma. The adaptive immune response to HDM is largely Th2 and Th17 dominant, and a number of innate immune receptors have been identified that recognize HDM to initiate these responses. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic sensor of peptidoglycan, which is important for Th2 and Th17 polarization. NOD2 mediates its signaling through its downstream effector kinase, receptor-interacting serine/threonine protein kinase 2 (RIP2). We have previously shown that RIP2 promotes HDM-associated allergic airway inflammation and Th2 and Th17 immunity, acting early in the HDM response and likely within airway epithelial cells. However, the consequences of inhibiting RIP2 during this critical period has not yet been examined. In this study, we pharmacologically inhibited RIP2 activity during the initial exposure to allergen in an acute HDM model of asthma and determined the effect on the subsequent development of allergic airway disease. We show that early inhibition of RIP2 was sufficient to reduce lung histopathology and local airway inflammation while reducing the Th2 immune response. Using a chronic HDM asthma model, we demonstrate that inhibition of RIP2, despite attenuating airway inflammation and airway remodeling, was insufficient to reduce airway hyperresponsiveness. These data demonstrate the potential of pharmacological targeting of this kinase in asthma and support further development and optimization of RIP2-targeted therapies.

Frontline Science: RIP2 promotes house dust mite-induced allergic airway inflammation.

House dust mites (HDMs) are one of the most significant environmental allergens in the establishment of the so-called "Atopic March." It is known that the immune response to HDM is Th2 dominant, but the innate mechanisms leading to HDM-induced type 2 responses are still not completely understood. A number of innate immune receptors have been implicated in the response to HDM including toll-like receptors, C-type lectin receptors, and protease activated receptors. NOD2 is a member of the NOD-like receptor family, which has been reported to be involved in the establishment of type 2 immunity and in blocking respiratory tolerance. NOD2 mediates its effects through its downstream effector kinase, receptor interacting protein (RIP2). It has not been shown if RIP2 is involved in the innate response to HDM and in the resulting generation of type 2 immunity. Furthermore, the role of RIP2 in modulating allergic airway inflammation has been controversial. In this study, we show that RIP2 is activated in airway epithelial cells in response to HDM and is important for the production of CCL2. Using a murine HDM asthma model, we demonstrate that lung pathology, local airway inflammation, inflammatory cytokines, HDM-specific IgG1 antibody production, and HDM-specific Th2 responses are all reduced in RIP2 knockout mice compared to WT animals. These data illustrate that RIP2 can be activated by a relevant allergic stimulus and that such activation can contribute to allergic airway inflammation. These findings also suggest that RIP2 inhibitors might have some efficacy in down-regulating the inflammatory response in type 2 dominated diseases.

Both fractional exhaled nitric oxide and sputum eosinophil were associated with uncontrolled asthma.

BackgroundSputum eosinophil and fractional exhaled nitric oxide (FeNO), noninvasive biomarkers of local eosinophilic airway inflammation, can be used to assess asthma outcome. Nevertheless, the clinical application of the association between FeNO and sputum eosinophil is controversial. The aim of the study was to investigate the predictive relationship between FeNO and sputum eosinophil in uncontrolled asthmatic patients and the correlation between sputum eosinophil and FeNO in bronchial reversibility and bronchial hyperresponsiveness (BHR).MethodsA total of 69 uncontrolled asthmatic patients were included in the study. All patients underwent a clinical assessment on the same day as follows: FeNO, spirometry with BHR or bronchodilator reversibility test and induced sputum in turn. Eosinophilic airway inflammation was defined as sputum eosinophil percentage (≥2.5%)/FeNO level (≥32 parts per billion [ppb]).ResultsFeNO level and sputum neutrophilic percentage were higher in the sputum eosinophilia group compared to those without (49 versus 27, p=0.011; 71.12 versus 87.67, p=0.012, respectively). Sputum eosinophil percentage was higher with raised FeNO level compared to those without (10.3% versus 2.75%, p=0.03). A significant correlation was observed between sputum eosinophil percentage and FeNO level (r=0.4016; p=0.0006). There were no significant relationships between sputum eosinophilic percentage and provocative dose (PD20)/ΔFEV1 (improvement in a forced expiratory volume in 1 second [FEV1] after 400μg of salbutamol), FeNO levels and PD20/ΔFEV1. The FeNO level of 35.5 ppb was effective in assessing sputum eosinophilia, with a receiver operating characteristic area under curve (AUC) of 0.707 (p=0.011; 95% confidence interval [CI] 0.573–0.841), and 4.36% was the best diagnostic cutoff value of sputum eosinophil percentage for the FeNO level of 32 ppb (AUC 0.721; 95% CI 0.59–0.852).ConclusionFeNO level can accurately detect eosinophilic asthma but has limited value to assess noneosinophilic asthma in uncontrolled stage. Further studies are required to validate the use of FeNO level to determine an optimal cutoff for sputum eosinophilia that could be used in clinical practice.

Activation of Activin receptor-like kinases curbs mucosal inflammation and proliferation in chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a widespread disease causing obstruction of the nasal cavity. Its cause remains unclear. The transforming growth-factor beta (TGF-β) superfamily and their receptors, termed Activin receptor-like kinases (ALKs), have recently been suggested to play a role in local airway inflammation, but have so far not been evaluated in human nasal epithelial cells (HNECs) from CRSwNP patients. We demonstrated that ALK1–7 were expressed in the nasal polyp epithelium, and the expression of ALK1-6 was markedly elevated in polyps compared to nasal mucosa from healthy controls. Stimulation with the ALK ligand TGF-β1 decreased Ki67 expression in HNECs from CRSwNP patients, not evident in controls. Likewise, TGF-β1, Activin A and Activin B, all ALK ligands, decreased IL-8 release and Activin A and Activin B reduced ICAM1 expression on HNECs from CRSwNP patients, not seen in controls. Pre-stimulation with TGF-β1, Activin A, BMP4 and Activin B attenuated a TNF-α-induced ICAM1 upregulation on HNECs of CRSwNP. No effect was evident in controls. In conclusion, an increased expression of ALK1-6 was found on polyp epithelial cells and ligand stimulation appeared to reduce proliferation and local inflammation in polyps.

Atopic asthmatic immune phenotypes associated with airway microbiota and airway obstruction.

BackgroundDifferences in asthma severity may be related to inflammation in the airways. The lower airway microbiota has been associated with clinical features such as airway obstruction, symptom control, and response to corticosteroids.ObjectiveTo assess the relationship between local airway inflammation, severity of disease, and the lower airway microbiota in atopic asthmatics.MethodsA cohort of young adult, atopic asthmatics with intermittent or mild/moderate persistent symptoms (n = 13) were assessed via bronchoscopy, lavage, and spirometry. These individuals were compared to age matched non-asthmatic controls (n = 6) and to themselves after six weeks of treatment with fluticasone propionate (FP). Inflammation of the airways was assessed via a cytokine and chemokine panel. Lower airway microbiota composition was determined by metagenomic shotgun sequencing.ResultsUnsupervised clustering of cytokines and chemokines prior to treatment with FP identified two asthmatic phenotypes (AP), termed AP1 and AP2, with distinct bronchoalveolar lavage inflammatory profiles. AP2 was associated with more obstruction, compared to AP1. After treatment with FP reduced MIP-1β and TNF-α and increased IL-2 was observed. A module of highly correlated cytokines that include MIP-1β and TNF-α was identified that negatively correlated with pulmonary function. Independently, IL-2 was positively correlated with pulmonary function. The airway microbiome composition correlated with asthmatic phenotypes. AP2, prior to FP treatment, was enriched with Streptococcus pneumoniae. Unique associations between IL-2 or the cytokine module and the microbiota composition of the airways were observed in asthmatics subjects prior to treatment but not after or in controls.ConclusionThe underlying inflammation in atopic asthma is related to the composition of microbiota and is associated with severity of airway obstruction. Treatment with inhaled corticosteroids was associated with changes in the airway inflammatory response to microbiota.

EPO modified MSCs can inhibit asthmatic airway remodeling in an animal model.

There was no effective measures can be obtained at present to reverse or prevent airway remodeling. We investigated the therapeutic effect of Erythropoietin (EPO) gene modified mesenchymal stem cells (MSCs) on asthmatic airway remodeling and the possible underlied molecular mechanisms. EPO gene was transfected into MSCs via lentivirus vector. The transfected cells (EPO-MSCs) were identified by flow cytometry and the EPO secreting function was detected by PCR and Western blot. MSCs or EPO-MSCs were administrated to albumin (OVA)-induced chronic asthmatic mouse model via tail veins. The asthmatic phenotype was analyzed. Number of cells in bronchoalveolar lavage fluid (BALF) was counted using a hemocytometer. Histological findings of airways were evaluated by microscopic examination. The concentrations of interleukin 4(IL-4), interleukin 5(IL-5), and interleukin 13(IL-13) in lung homogenate were determined by ELISA. The activation state of transforming growth factor-β 1 (TGF-β1), Transforming growth factor beta-activated kinase 1 (TAK1), and p38 Mitogen Activated Protein Kinase (p38MAPK) signaling was detected by Real-Time PCR and Western blotting. EPO-MSCs were successfully constructed. EPO-MSCs showed a more potently suppressive effect on local asthmatic airway inflammation and the level of IL-4, IL-5, and IL-13 in lung tissue than MSCs. Moreover, the numbers of goblet cells, the thicknesses of smooth muscle layer, collagen density, percentage of proliferating cell nuclear antigen positive (PCNA+ ) mesenchymal cells, and von Willebrand factor positive(vWF+ ) vessels were also significantly inhibited by EPO-MSCs. Furthermore, EPO-MSCs could downregulate the expression of TGF-β1, TAK1, and p38MAPK in lung tissue both in mRNA level and in protein level. EPO gene modified MSCs may more efficiently attenuate asthmatic airway remodeling, which maybe related with the downregulation of TGF-β1-TAK1-p38MAPK pathway activity.

Anti-Citrullinated Protein Antibodies Are Associated With Neutrophil Extracellular Traps in the Sputum in Relatives of Rheumatoid Arthritis Patients.

Studies suggest that rheumatoid arthritis (RA)-related autoimmunity is initiated at a mucosal site. However, the factors associated with the mucosal generation of this autoimmunity are unknown, especially in individuals who are at risk of future RA. Therefore, we tested anti-cyclic citrullinated peptide (anti-CCP) antibodies in the sputum of RA-free first-degree relatives (FDRs) of RA patients and patients with classifiable RA. We evaluated induced sputum and serum samples from 67 FDRs and 20 RA patients for IgA anti-CCP and IgG anti-CCP, with cutoff levels for positivity determined in a control population. Sputum was also evaluated for cell counts, neutrophil extracellular traps (NETs) using sandwich enzyme-linked immunosorbent assays for protein/nucleic acid complexes, and total citrulline. Sputum was positive for IgA and/or IgG anti-CCP in 14 of 20 RA patients (70%) and 17 of 67 FDRs (25%), including a portion of FDRs who were serum anti-CCP negative. In the FDRs, elevations of sputum IgA and IgG anti-CCP were associated with elevated sputum cell counts and NET levels. IgA anti-CCP was associated with ever smoking and with elevated sputum citrulline levels. Anti-CCP is elevated in the sputum of FDRs, including seronegative FDRs, suggesting that the lung may be a site of anti-CCP generation in this population. The association of anti-CCP with elevated cell counts and NET levels in FDRs supports a hypothesis that local airway inflammation and NET formation may drive anti-CCP production in the lung and may promote the early stages of RA development. Longitudinal studies are needed to follow the evolution of these processes relative to the development of systemic autoimmunity and articular RA.

Lung sound analysis helps localize airway inflammation in patients with bronchial asthma.

PurposeAirway inflammation can be detected by lung sound analysis (LSA) at a single point in the posterior lower lung field. We performed LSA at 7 points to examine whether the technique could identify the location of airway inflammation in patients with asthma.Patients and methodsBreath sounds were recorded at 7 points on the body surface of 22 asthmatic subjects. Inspiration sound pressure level (ISPL), expiration sound pressure level (ESPL), and the expiration-to-inspiration sound pressure ratio (E/I) were calculated in 6 frequency bands. The data were analyzed for potential correlation with spirometry, airway hyperresponsiveness (PC20), and fractional exhaled nitric oxide (FeNO).ResultsThe E/I data in the frequency range of 100–400 Hz (E/I low frequency [LF], E/I mid frequency [MF]) were better correlated with the spirometry, PC20, and FeNO values than were the ISPL or ESPL data. The left anterior chest and left posterior lower recording positions were associated with the best correlations (forced expiratory volume in 1 second/forced vital capacity: r=−0.55 and r=−0.58; logPC20: r=−0.46 and r=−0.45; and FeNO: r=0.42 and r=0.46, respectively). The majority of asthmatic subjects with FeNO ≥70 ppb exhibited high E/I MF levels in all lung fields (excluding the trachea) and V50%pred <80%, suggesting inflammation throughout the airway. Asthmatic subjects with FeNO <70 ppb showed high or low E/I MF levels depending on the recording position, indicating uneven airway inflammation.ConclusionE/I LF and E/I MF are more useful LSA parameters for evaluating airway inflammation in bronchial asthma; 7-point lung sound recordings could be used to identify sites of local airway inflammation.

Lung injury and inflammation response by chronic intermittent hypoxia in rats

BackgroundChronic intermittent hypoxia is the primary pathophsiological feature of obstructive sleep apnea/hypopnea syndrome. The characteristics of CIH can be imitated by animal experiment models thus to study CIH related systemic organ injuries, including respiratory systems.MethodsSixteen male SD rats were randomly divided into two groups: CIH group (n = 8) and control group (n = 8). The CIH group was exposed to intermittent hypoxia circumstance for 5 weeks (8 h/day) and control group was placed in the same animal chamber exposed to normal air circumstance. Between the two groups, the inflammatory factors of IL-6 and TNF-α within serum and BALF were measured by ELISA; the structure and ultrastructure of lungs were evaluated by HE staining and electronmicroscopy. The nuclear factor-κB (NF-κB) in lung tissue was detected by Western blot.ResultsThe concentration of IL-6 and TNF-α in serum in CIH group increased significantly (138.63 ± 43.82 vs. 41.82 ± 5.24 pg/ml and 126.62 ± 34.81 vs. 73.43 ± 5.72 pg/ml, both P < 0.05). The concentration of IL-6 and TNF-α in BALF in CIH group was higher than that in control group (67.1 ± 24.2 pg/ml vs 39.8 ± 21.5 pg/ml and 36.61 ± 19.17 pg/ml vs 20.31 ± 8.44 pg/ml, respectively, P < 0.05). In the HE staining of lung tissue, results showed that severe inflammatory cell infiltration in alveolar walls and alveolar spaces was found in CIH group and the histological score of CIH group is higher significantly (6.857 ± 0.553 vs. 2.286 ± 0.286 g, P < 0.05); In the electronmicroscopy of TypeIIalveolar cells, results showed that karyotheca and endoplasmic reticulum were damaged obviously in Type II alveolar cells. The NF-κB increased significantly in the CIH group compared with control group (0.43 ± 0.1 vs 0.22 ± 0.05, P < 0.05).ConclusionsAnimal experiment model can be used to imitate the pathophysiologic changes of CIH. There are systematic and local airway inflammation coexisting in CIH rats. CIH leads to inflammatory cell infiltration and organelle damages within lung tissues. We speculated that there was some correlation between inflammation and lung damages in CIH rats.

High Pulmonary Levels of IL-6 and IL-1β in Children with Chronic Suppurative Lung Disease Are Associated with Low Systemic IFN-γ Production in Response to Non-Typeable Haemophilus influenzae.

Non-typeable Haemophilus influenzae (NTHi) is commonly associated with chronic suppurative lung disease in children. We have previously shown that children with chronic suppurative lung disease have a reduced capacity to produce IFN-γ in response to NTHi compared with healthy control children. The aim of this study was to determine if deficient NTHi-specific IFN-γ production is associated with heightened systemic or airway inflammation. We measured a panel of cytokines (IFN-γ, IL-1β, IL-6, IL-8, IL-12 p70), antimicrobial proteins (LL-37, IP-10) as well as cellular and clinical factors associated with airway and systemic inflammation in 70 children with chronic suppurative lung disease. IFN-γ was measured in peripheral blood mononuclear cells challenged in vitro with live NTHi. Regression analysis was used to assess the association between the systemic and airway inflammation and the capacity to produce IFN-γ. On multivariate regression, NTHi-specific IFN-γ production was significantly negatively associated with the BAL concentrations of the inflammatory cytokines IL-6 (β=-0.316; 95%CI -0.49, -0.14; p=0.001) and IL-1β (β=-0.023; 95%CI -0.04, -0.01; p=0.001). This association was independent of bacterial or viral infection, BAL cellularity and the severity of bronchiectasis (using modified Bhalla score on chest CT scans). We found limited evidence of systemic inflammation in children with chronic suppurative lung disease. In summary, increased local airway inflammation is associated with a poorer systemic cell-mediated immune response to NTHi in children with chronic suppurative lung disease. These data support the emerging body of evidence that impaired cell-mediated immune responses and dysregulated airway inflammation may be linked and contribute to the pathobiology of chronic suppurative lung disease.

Pulmonary and Atherogenic Effects of Multi-Walled Carbon Nanotubes (MWCNT) in Apolipoprotein-E-Deficient Mice

Rapid growth in nanotechnology has raised concerns regarding adverse health effects due to human exposure to manufactured nanoparticles. Carbon nanotubes (CNT) are among the most extensively used nanoparticles. This study examined pulmonary and atherosclerotic effects of multiwalled CNT (MWCNT) in a mouse model of atherosclerosis. Female apolipoprotein E-deficient (apoE–/–) mice were exposed to 40 μg MWCNT, once each week for 16 consecutive weeks by pharyngeal aspiration. On d 1 after the last administration, tissues were extracted from half the group, while the remaining animals were sacrificed at d 7. Bronchoalveolar lavage (BAL) was performed to obtain BAL fluid. In addition, plasma, lung, and aortas were extracted to assess pulmonary inflammation and atherosclerotic lesion formation. Polymorphonuclear leukocytes and total BAL cell number increased significantly in MWCNT-exposed mice on d 1 and 7 postexposure. Cell-free BAL fluid obtained from MWCNT-exposed mice at d 1 and 7 postexposure contained significantly elevated levels of total protein, lactate dehydrogenase (LDH), surfactant protein-D, and mucin. Although MWCNT exposure increased pulmonary injury and inflammation, the aortic intimal surface covered by atherosclerotic lesions was not significantly different between control apoE–/– mice and apoE–/– MNCNT-treated animals. Total plasma cholesterol concentrations also were not markedly affected by MWCNT exposure. These results demonstrate that pulmonary exposure to MWCNT affects local airway inflammation but did not appear to augment progression of atherosclerosis in female apoE–/– mice.

Autocrine hemokinin-1 functions as an endogenous adjuvant for IgE-mediated mast cell inflammatory responses

Efficient development of atopic diseases requires interactions between allergen and adjuvant to initiate and amplify the underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal through the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 after FcεRI cross-linking by antigen-IgE complexes (FcεRI-activated mast cells [FcεRI-MCs]). Additionally, MCs express the NK1R, suggesting an adjuvant role for NK1R agonists in FcεRI-MC-mediated pathologies; however, in-depth research addressing this relevant aspect of MC biology is lacking. We sought to investigate the effect of NK1R signaling and the individual roles of SP and HK-1 as potential adjuvants for FcεRI-MC-mediated allergic disorders. Bone marrow-derived mast cells (BMMCs) from C57BL/6 wild-type (WT) or NK1R(-/-) mice were used to investigate the effects of NK1R signaling on FcεRI-MCs. BMMCs generated from Tac1(-/-) mice or after culture with Tac4 small interfering RNA were used to address the adjuvancy of SP and HK-1. WT, NK1R(-/-), and c-Kit(W-sh/W-sh) mice reconstituted with WT or NK1R(-/-) BMMCs were used to evaluate NK1R signaling on FcεRI-MC-mediated passive local and systemic anaphylaxis and on airway inflammation. FcεRI-activated MCs upregulated NK1R and HK-1 transcripts and protein synthesis, without modifying SP expression. In a positive signaling loop HK-1 promoted TNF and IL-6 secretion by MC degranulation and protein synthesis, the latter through the phosphoinositide 3-kinase/Akt/nuclear factor κB pathways. Invivo NK1R signaling was necessary for the development of passive local and systemic anaphylaxis and airway inflammation. FcεRI stimulation of MCs promotes autocrine secretion of HK-1, which signals through NK1R to provide adjuvancy for efficient development of FcεRI-MC-mediated disorders.

Allergic rhinitis and asthma: epidemiology and common pathophysiology.

Allergic rhinitis and asthma are common diseases that frequently occur together. This concept has been referred to in the literature as united airway disease. Epidemiological studies have shown that the majority of patients with asthma have concomitant rhinitis and the presence of rhinitis is an increased risk factor for development of asthma. Patients with asthma and rhinitis share common physiology including heightened bronchial hyperresponsiveness and heightened reactivity to a variety of stimuli. Immunopathology of allergic rhinitis is also similar with the predominance of T-helper type 2 inflammation and tissue eosinophilia. Although several mechanisms have been proposed to explain the united airway theory, some of the best lines of evidence suggest that local airway inflammation can result in a systemic inflammatory response. Pharmacotherapeutic studies have shown that the treatment of rhinitis can improve asthma and vice versa. Nevertheless, systemic approaches such as immunotherapy lead to better outcomes for treating both disease states simultaneously. This article will focus on the data supporting the common epidemiology, shared pathophysiology, and therapeutic interventions aimed at allergic rhinitis and asthma as united airway diseases.