Inflammation Of Airway Mucosa Research Articles

Epithelial immunomodulation by aerosolized Toll-like receptor agonists prevents allergic inflammation in airway mucosa in mice.

Allergic asthma is a chronic inflammatory respiratory disease associated with eosinophilic infiltration, increased mucus production, airway hyperresponsiveness, and airway remodeling. Epidemiologic data reveal that the prevalence of allergic sensitization and associated diseases has increased in the twentieth century. This has been hypothesized to be partly due to reduced contact with microbial organisms (the hygiene hypothesis) in industrialized society. Airway epithelial cells, once considered a static physical barrier between the body and the external world, are now widely recognized as immunologically active cells that can initiate, maintain, and restrain inflammatory responses, such as those that mediate allergic disease. Airway epithelial cells can sense allergens via expression of myriad Toll-like receptors (TLRs) and other pattern-recognition receptors. We sought to determine whether the innate immune response stimulated by a combination of Pam2CSK4 (“Pam2”, TLR2/6 ligand) and a class C oligodeoxynucleotide ODN362 (“ODN”, TLR9 ligand), when delivered together by aerosol (“Pam2ODN”), can modulate the allergic immune response to allergens. Treatment with Pam2ODN 7 days before sensitization to House Dust Mite (HDM) extract resulted in a strong reduction in eosinophilic and lymphocytic inflammation. This Pam2ODN immunomodulatory effect was also seen using Ovalbumin (OVA) and A. oryzae (Ao) mouse models. The immunomodulatory effect was observed as much as 30 days before sensitization to HDM, but ineffective just 2 days after sensitization, suggesting that Pam2ODN immunomodulation lowers the allergic responsiveness of the lung, and reduces the likelihood of inappropriate sensitization to aeroallergens. Furthermore, Pam2 and ODN cooperated synergistically suggesting that this treatment is superior to any single agonist in the setting of allergen immunotherapy.

CD69+ Th2-type CD4+ T Cells are Responsible for Long-term Memory Responses to Allergens in the Lungs

Persistent and recurrent inflammation in airway mucosa plays a central role in allergic airway diseases. However, our knowledge is limited regarding the mechanisms that explain development and maintenance of immunologic memory in the lungs. The goal of this project was to fill this gap by using mouse models.

Respiratory syncytial virus induces NRF2 degradation through a promyelocytic leukemia protein ‐ ring finger protein 4 dependent pathway

Respiratory syncytial virus (RSV) is the most important cause of viral acute respiratory tract infections and hospitalizations in children, for which no vaccine or specific treatments are available. RSV causes airway mucosa inflammation and cellular oxidative damage by triggering production of reactive oxygen species and by inhibiting at the same time expression of antioxidant enzymes, via degradation of the transcription factor NF-E2-related factor 2 (NRF2). RSV infection induces NRF2 deacetylation, ubiquitination, and degradation through a proteasome-dependent pathway. Although degradation via KEAP1 is the most common mechanism, silencing KEAP1 expression did not rescue NRF2 levels during RSV infection. We found that RSV-induced NRF2 degradation occurs in an SUMO-specific E3 ubiquitin ligase - RING finger protein 4 (RNF4)-dependent manner. NRF2 is progressively SUMOylated in RSV infection and either blocking SUMOylation or silencing RNF4 expression rescued both NRF2 nuclear levels and transcriptional activity. RNF4 associates with promyelocytic leukemia – nuclear bodies (PML-NBs). RSV infection induces the expression of PML and PML-NBs formation in an interferon (INF)-dependent manner and also induces NRF2 – PMN-NBs association. Inhibition of PML-NB formation by blocking IFN pathway or silencing PML expression resulted in a significant reduction of RSV-associated NRF2 degradation and increased antioxidant enzyme expression, identifying the RNF4-PML pathway as a key regulator of antioxidant defenses in the course of viral infection.

Bronchial rupture related to endobronchial stenting in relapsing polychondritis

To the Editor: Relapsing polychondritis is a rare multi-systemic disease characterised by recurrent episodes of inflammation and destruction of cartilaginous structures [1]. Airway involvement by relapsing polychondritis, which results in tracheobronchomalacia and airway stenosis, is associated with a poor prognosis. Several reports have suggested that endobronchial intervention can be beneficial in these subjects [2, 3]. Herein, we describe a case of bronchial rupture related to endobronchial intervention in a patient with relapsing polychondritis. A 47-yr-old male nonsmoker was referred for management of progressive dyspnoea, stridor and cough evolving over 12 months. He had been considered to have severe asthma and was treated with a fixed combination of inhaled corticosteroids and long-acting β-agonists, and short courses of oral corticosteroids. Spirometry showed fixed airflow limitation with a post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity of 22% and an FEV1 of 22% predicted. A thoracic computed tomography (CT) scan revealed marked thickening and narrowing of trachea and mainstem bronchi (fig. 1). A diagnosis of relapsing polychondritis was suggested; the patient had no auricular or nasal chondritis and no ocular symptoms. Fluorodeoxyglucose positron emission tomography showed no cartilaginous tracer uptake. Bronchoscopy showed marked thickening and inflammation of airway mucosa. Severe tracheobronchomalacia, …

Airway involvement in relapsing polychondritis

Relapsing Polychondritis (RP) is an uncommon, chronic, and potentially life-threatening multisystem disorder characterized by recurrent inflammatory episodes affecting the cartilaginous tissues of the external ears, nose, peripheral joints, larynx and tracheobronchial tree, sometimes leading to their destruction. RP can also inflame other proteoglycan-rich structures, such as the eye, heart, blood vessels and inner ears. Systemic symptoms are common, and vasculitis affecting skin or internal organs may occur. The etiology of RP is still unknown, but the pathogenetic role of the autoimmunity is suggested by frequent overlaps with various autoimmune diseases, and by the presence of autoantibody against cartilage in the serum of patients with RP. Although several reports have demonstrated the clinicopathologic manifestations and radiologic findings of RP, there are no specific features of RP. Therefore, it is difficult to show the diagnosis of RP. Airway involvements are major causes of morbidity and mortality, and they have accounted for most of the deaths due to RP. To suppress the inflammation of airway mucosa and cartilage is extremely important in the successful treatment for RP. Above all, earlier diagnosis would lead to better outcomes.

Respiratory echovirus 30 and coxsackievirus B5 can induce production of RANTES, MCP-1 and IL-8 by human bronchial epithelial cells

Human Enteroviruses (HEV) ( picornaviridae) are considered as one the major viral causes of childhood acute respiratory wheezing illnesses including bronchiolitis and asthma exacerbation. To identify the mechanisms that can regulate the development of airway mucosa inflammation during HEV respiratory lower tract infection, we investigated the profile and the levels of mRNA and protein secretion for CC and CXC human chemokines by HEV-infected primary human bronchial epithelial cells (SAE cells) using RT-PCR array and Bio-Plex assay. Cultures of SAE cells were infected by reference and wild-type HEV respiratory strains, demonstrating a replicative and productive viral infection. We observed that the replicative infection of the SAE cells by reference and wild-type HEV strains induced specific dose and time-dependent increases in mRNA and protein secretion only for RANTES, MCP-1 and IL-8 and not for all other CC and CXC human chemokines tested. The protein secretion of these chemokines appeared to be significantly increased at 48 or 72 h post-infection in cultures treated by low-doses of IFN-γ comparatively to mock-infected cells ( P < 0.001), and was correlated to the viral replication activity. In conclusion, our findings demonstrated a selective production of RANTES, IL-8 and MCP-1 released by HEV-infected epithelial cells of the small bronchioles along with mechanisms of amplification mediated by IFN-γ.

TRPA1 ion channels: a gateway to airway irritation and reflex responses induced by inhaled oxidants

TRPA1 ion channels: a gateway to airway irritation and reflex responses induced by inhaled oxidants

Role of chemokine receptor 5 during respiratory syncytial virus infection

Lower respiratory tract disease caused by respiratory syncytial virus (RSV) is characterized by profound airway mucosa inflammation, both in infants with naturally acquired infection and in experimentally inoculated animal models. Chemokines are central regulatory molecules in inflammatory, immune and infectious processes of the lung. Previously we have shown that the depletion of MIP-1α/CCL3 reduces lung inflammation and chemokine expression in RSV-infected lung tissue. In this study, we demonstrate that depletion of CCR5 as a receptor for MIP-1α results in upregulation of chemokines and cytokines in RSV-infected lung tissue but had no influence on viral clearance or histopathology compared with the wild type animals. Genetically altered mice with additional deletion of the MIP-1α/CCL3 gene demonstrated an upregulation in the chemokine mRNA expression paralleled by comparable cytokine expression following RSV infection, compared with wild type mice. There was no difference in lung inflammation or viral clearance. Pathology scores were only reduced in mice depleted for MIP-1α/CCL3. These results provide some evidence that the pattern of chemokine expressed in lung tissue determines the severity of lung inflammation during RSV infection.

Perflubron Reduces Lung Inflammation in Respiratory Syncytial Virus Infection by Inhibiting Chemokine Expression and Nuclear Factor–κB Activation

Airway mucosa inflammation plays a critical role in the pathogenesis of lower respiratory tract infections caused by respiratory syncytial virus (RSV), the major etiologic agent of bronchiolitis in infancy. Type and intensity of cellular infiltration are dictated by inflammatory chemokines, which are rapidly and abundantly induced in lung tissue by RSV. This process is, to a large extent, transcriptionally regulated by RSV-mediated activation of the nuclear factor-kappa B. The administration of a perfluorocarbon (PFC) liquid, such as perflubron, during partial liquid ventilation improves lung function and also reduces inflammation. In this study we demonstrate that treatment of BALB/c mice with perflubron intranasally 6 hours after RSV infection significantly inhibited lung cellular inflammation as well as the expression of the chemokines RANTES, MIP-1 alpha, MIP-1 beta, and MIP-2, compared with phosphate-buffered saline-treated control mice. However, perflubron treatment did not affect RSV replication. Strikingly, treatment with perflubron abrogated nuclear factor-kappa B activation in lung of RSV-infected mice. These results demonstrate a novel mechanism by which PFC may exert antiinflammatory activity and suggest that partial liquid ventilation with PFC may be considered in future clinical trials for infants with severe RSV infections requiring mechanical ventilation.

Measuring plasma exudation in nasal lavage fluid and in induced sputum as a tool for studying respiratory tract inflammation

We performed nasal lavage (NAL) combined with induced sputum to determine exudative inflammation in the upper and lower airways in patients with chronic sinusitis and in controls. To monitor plasma exudation into the respiratory lumen and loss of size-selectivity of the mucosa, we determined the sample-to-serum ratio of albumin and alpha-2-macroglobulin, Qa1b and Qa2m, and the dilution independent Relative Coefficient of Excretion, RCE=Qa2m/Qa1b. To detect low protein levels in NAL and induced sputum we adapted an ELISA system for alpha-2-macroglobulin described by Out et al. [Clin. Chim. Acta, 165 (1987) 277–288], and modified this into a sensitive ELISA for albumin. Dithiothreitol, added to increase sputum solubility, did not interfere with the analysis, nor did N-ethylmaleimide, added to block dithiothreitol. In this study plasma exudation in induced sputum is significantly increased in patients with chronic sinusitis, compared to controls. Plasma exudation in NAL is also increased in patients, although not significant. The RCE in NAL and sputum is well-correlated in one of the three study visits. There is much variation in sample protein-levels partly due to differences in dilution and the heterogeneity of the studied population. Determination of plasma exudation together with RCE in NAL and induced sputum is a good, non-invasive way to quantify inflammation of airway mucosa.

Inducible expression of inflammatory chemokines in respiratory syncytial virus-infected mice: role of MIP-1alpha in lung pathology.

Lower respiratory tract disease caused by respiratory syncytial virus (RSV) is characterized by profound airway mucosa inflammation, both in infants with naturally acquired infection and in experimentally inoculated animal models. Chemokines are central regulatory molecules in inflammatory, immune, and infectious processes of the lung. In this study, we demonstrate that intranasal infection of BALB/c mice with RSV A results in inducible expression of lung chemokines belonging to the CXC (MIP-2 and IP-10), CC (RANTES, eotaxin, MIP-1beta, MIP-1alpha, MCP-1, TCA-3) and C (lymphotactin) families. Chemokine mRNA expression occurred as early as 24 h following inoculation and persisted for at least 5 days in mice inoculated with the highest dose of virus (10(7) PFU). In general, levels of chemokine mRNA and protein were dependent on the dose of RSV inoculum and paralleled the intensity of lung cellular inflammation. Immunohisthochemical studies indicated that RSV-induced expression of MIP-1alpha, one of the most abundantly expressed chemokines, was primarily localized in epithelial cells of the alveoli and bronchioles, as well as in adjoining capillary endothelium. Genetically altered mice with a selective deletion of the MIP-1alpha gene (-/- mice) demonstrated a significant reduction in lung inflammation following RSV infection, compared to control littermates (+/+ mice). Despite the paucity of infiltrating cells, the peak RSV titer in the lung of -/- mice was not significantly different from that observed in +/+ mice. These results provide the first direct evidence that RSV infection may induce lung inflammation via the early production of inflammatory chemokines.

Perception of bronchial obstruction in asthmatic patients. Relationship with bronchial eosinophilic inflammation and epithelial damage and effect of corticosteroid treatment.

We studied the perception of bronchoconstriction in asthmatic subjects who were randomly treated with inhaled beta 2 agonist given either alone (n = 9) or associated with inhaled corticosteroids (n = 9). Methacholine and bradykinin challenges, bronchoalveolar lavage, and bronchial biopsies were performed in all subjects. After each dose of agonist, breathlessness was assessed using a visual analog scale (VAS) and the forced expiratory volume in 1 s (FEV1) was measured. The relationship between VAS scores and FEV1 and the slope of the regression line of VAS scores on the corresponding FEV1 (VAS/FEV1 slope) were analyzed for each agonist. Subjects without corticosteroids had good perception of methacholine but poor perception of bradykinin-induced bronchoconstriction. In subjects with corticosteroids, bronchoconstriction was well perceived whatever the agonist. VAS/FEV1 slopes for bradykinin but not for methacholine correlated negatively with the magnitude of eosinophilic inflammation in airway mucosa. VAS/FEV1 slopes for each agonist correlated positively with the percentage of basement membrane covered by airway epithelium. We conclude that in asthmatic patients perception of bronchoconstriction is related to eosinophilic inflammation and to epithelial damage in airways and that corticosteroid treatment is associated with improved perception of bronchoconstriction induced by bradykinin, a mediator endogenously produced in asthma.

Canine Chronic Bronchitis

Eighteen dogs with chronic bronchitis were studied using physiologic, radiologic, microbiologic, and pathologic techniques. Twelve of these dogs were evaluated before and after two weeks of oral bronchodilator administration. Thoracic radiographs, tidal breathing flow-volume loops, radioaerosol ventilation scans, airway appearance at bronchoscopy, and airway pathology were abnormal in the majority of dogs studied. There was a significant relationship between abnormal ventilation scans and abnormal results for PaO2 and end-tidal airflow. Bronchoscopy revealed excessive mucus and inflammation of airway mucosa in all 16 dogs undergoing this procedure. Endoscopically obtained aerobic bacterial cultures grew mixed bacterial flora in only three dogs. Increased numbers of neutrophils in 14 dogs were detected by airway lavage cytology. A large number of eosinophils were seen in airway lavages obtained from two dogs; these two dogs also had evidence for eosinophilic bronchitis on endobronchial biopsy. Oral bronchodilator administration resulted in clinical and expiratory airflow improvements in most dogs, but had no effect on PaO2 or on the radioaerosol-scan abnormalities. The presence of both the physiologic and pathologic airway abnormalities of chronic bronchitis in dogs presented to a veterinary hospital with chronic unexplained cough was confirmed, suggesting that aerobic bacteria do not play an etiologic role in most cases.