Local Airway Inflammation Research Articles

Mucosal and systemic inflammatory changes in allergic rhinitis and asthma: a comparison between upper and lower airways

Local airway inflammation and airway remodelling are considered important in the clinical expression of allergic asthma. The aim of this study was to compare airway inflammation and remodelling in nasal and bronchial mucosa of subjects with allergic rhinitis with or without asthma. Four experimental groups were formed: allergic asthma and rhinitis (n = 19); allergic rhinitis, no asthma (n = 18); atopic subjects, no asthma, no rhinitis (n = 8) and non-allergic healthy control subjects (n = 16). Blood samples, nasal and bronchial biopsy specimens were collected during stable disease. Immunohistochemistry was performed for eosinophils (MBP), mast cells (CD117) and vascular endothelium (CD31). Epithelial loss, reticular basement membrane (RBM) thickness and subepithelial vascularity was assessed with a computer-assisted image analysis system. In nasal and bronchial mucosa, numbers of eosinophils were significantly higher in rhinitis patients with and without asthma than in asymptomatic atopics (P < 0.05) and controls (P < or = 0.01). In bronchial mucosa, the RBM was significantly thickened in rhinitis patients with and without asthma compared to asymptomatic atopics (P < 0.05) and controls (P < 0.01), while in nasal mucosa no differences were seen. Patients with asthma and rhinitis had increased numbers of blood eosinophils (P = 0.05) and skin test reactivity (P = 0.01) compared to patients with rhinitis only. No significant differences could be found between the investigated groups with respect to serum IL-5 and eotaxin levels, the number of mucosal mast cells and the degree of epithelial loss and subepithelial vascularity. Epithelial desquamation was significantly increased in the bronchial mucosa compared to nasal mucosa, not only in asthmatics (P < 0.001), but also in atopics without asthma and rhinitis (P = 0.02). This study shows that allergic inflammation, increased basement membrane thickness and epithelial desquamation are present in the lower airways of atopic subjects, even before the onset of clinical symptoms. Despite the presence of inflammatory cells, no structural changes could be assessed in nasal mucosa of allergic patients.

Rhinovirus infection up-regulates eotaxin and eotaxin-2 expression in bronchial epithelial cells.

Human rhinoviruses (RVs) are the most common precipitants of asthma exacerbations. RV infection of bronchial epithelium results in local airway inflammation inducing eosinophil recruitment and activation. Induction of eosinophil chemoattractants could represent a central mechanism, as well as a prime target for intervention. To assess the effect of RV infection on mRNA expression and production of eosinophil chemoattractants by bronchial epithelial cells in-vitro. BEAS-2B cells were infected with major and minor RVs and the mRNA expression of IL-8, RANTES, MIP-1alpha, eotaxin, eotaxin-2, MCP-2, MCP-3 and MCP-4 was assessed by reverse transcription PCR. In cases where mRNA induction was observed, a fluoroimmunoassay was used to confirm protein production. To assess the virus-specificity of the observed reactions, cells were also exposed to inactivated RVs. RV infection was able to up-regulate mRNA expression of IL-8, RANTES, MIP-1alpha, eotaxin and eotaxin-2, did not affect MCP-4, while MCP-2 and MCP-3 were not expressed either at baseline or after virus infection. Protein production was confirmed for IL-8, RANTES and eotaxin, but not for MIP-1alpha. When RVs were inactivated cytokine up-regulation was almost completely lost. Infection of bronchial epithelial cells with RVs results in the production of a wide array of mediators that are able to chemoattract eosinophils. These include the eosinophil-specific molecules eotaxin and eotaxin-2, in addition to IL-8 and RANTES, which are the most abundant. Eosinophil recruitment after RV infection of bronchial epithelium could represent a central event in the pathogenesis of virus-induced asthma exacerbations.

Interactions between inhalant allergen extracts and airway epithelial cells: Effect on cytokine production and cell detachment

Background: The factors responsible for inducing or maintaining airway inflammation are poorly understood. Various studies have focussed on the mechanisms leading to allergic airway inflammation in patients with asthma and rhinitis. The observation of local airway inflammation in nonallergic patients with asthma or rhinitis, including those with nasal polyposis, suggest that non-IgE–related mechanisms exist that may lead to airway inflammation. Various lines of evidence suggest that epithelial cells may participate in local inflammation of the airways. Objective: This study focused on the interaction of airway epithelial cells with clinically relevant inhalant allergen extracts in vitro. Methods: Cultures of airway epithelial cells were exposed to mite, Timothy grass pollen, and birch pollen extracts. Production of IL-8, IL-6, monocyte-chemotactic protein-1 (MCP-1), and granulocyte-macrophage colony-stimulating factor and cell detachment were monitored while protease inhibitors and chromatography techniques were applied to identify the factors responsible for these effects. Results: With the mite extracts, cytokine production and cell detachment was largely dependent on protease activity. With the pollen extracts, cytokine production without cell detachment seemed to be independent of protease activity. Conclusion: These findings support the view that epithelial cells may contribute to the pathogenesis of airway disease by their interaction with inhalant allergen extracts. Furthermore, allergen extracts may enhance airway inflammation by means other than their IgE-binding activity through both protease-dependent and protease-independent mechanisms. (J Allergy Clin Immunol 1998;102:75-85.)

Cytokine- and virus-stimulated airway smooth muscle cells produce IL-11 and other IL-6-type cytokines.

Inflammation and smooth muscle abnormalities coexist in human airway disorders, and inflammation modulates the proliferative and contractile properties of airway smooth muscle cells. To determine whether human airway smooth muscle (HASM) cells have the ability to regulate local inflammatory processes, we characterized the interleukin (IL)-6-type cytokine production of HASM cells in vitro. We demonstrated that HASM cells are potent producers of IL-11 when stimulated with IL-1 or transforming growth factor-beta 1 (TGF-beta 1) and that IL-11 levels are synergistically increased by IL-1 and TGF-beta 1 in combination. These studies also demonstrated that IL-1 and TGF-beta 1-stimulated HASM cells produce IL-6 and leukemia inhibitory factor but not oncostatin M and that respiratory syncytial virus and parainfluenza virus type 3 stimulate HASM cell IL-11 production. Finally, they demonstrate that, in all cases, the stimulation of HASM cell IL-11 elaboration is pretranslationally mediated since cytokine- and virus-induced alterations in IL-11 protein production were associated with proportionate changes in IL-11 mRNA accumulation. HASM cells are potent producers of IL-11 and other IL-6-type cytokines and may be important regulators of local airway inflammation.

Bacterial-induced release of inflammatory mediators by bronchial epithelial cells.

This review focuses on bacterial induction and release of inflammatory cytokines and adhesion molecules by human bronchial epithelial cells, with special reference to Haemophilus influenzae, a pathogen commonly associated with chronic bronchitis. Studies investigating the mechanisms underlying bacterial colonization of the airways and bacterial-induced chronic airway inflammation have suggested that these are likely to involve localization of bacteria to the site(s) of infection in the respiratory tract and induction of a local airway inflammation resulting in the initiation of epithelial damage. We have hypothesized that the gross airway epithelial damage observed in chronic infective lung disease is an indirect consequence of proteolytic enzymes and toxic oxygen radicals generated by large numbers of neutrophils infiltrating the airways. Furthermore, the infiltration and activation of the neutrophils is a consequence of increased release of proinflammatory mediators from the host respiratory epithelium, induced by bacterial products, such as endotoxin. This hypothesis is based on studies which have demonstrated that the concentrations of circulating cytokines, such as interleukin (IL)-8 and tumour necrosis factor-alpha (TNF-alpha), which have profound effects on neutrophil activity, are increased in endotoxaemia and that airway epithelial cells are a rich source of these cytokines. Support for this hypothesis is provided by studies of cultured human bronchial epithelial cells incubated either in the absence or presence of purified endotoxin preparations from nontypable and type b H. influenzae strains which have demonstrated that these endotoxins lead to significantly increased expression and/or release of proinflammatory mediators, including IL-6, IL-8, TNF-alpha and intercellular adhesion molecule-1 (ICAM-1). Treatment of the cells with steroids can downregulate the expression and/or release of these inflammatory mediators. Additionally, these studies have demonstrated that culture medium collected from endotoxin-treated cultures, 24 h after treatment, significantly increases neutrophil chemotaxis and adhesion to human endothelial cells in vitro.

Imaging allergen-invoked airway inflammation in atopic asthma with [18F]-fluorodeoxyglucose and positron emission tomography

Summary Background Airway inflammation is a feature of asthma and can be quantified invasively with bronchial lavage and endobronchial histology. Inflammatory foci can be imaged non-invasively with positron emission tomography (PET) and [18F]-fluorodeoxyglucose (18FDG) to quantify glucose uptake in activated granulocytes. We used this technique to study airway inflammation in asthma. Methods Nine men with mild atopic asthma were studied. In five, we studied the effect of bronchoscopic segmental allergen challenge on 18FDG uptake. Allergen was instilled into the posterior segment of the right upper lobe; a similar volume (20 mL) of isotonic saline was instilled into the posterior segment of the left upper lobe. At 1-32 h after instillation, PET with 18FDG was done. In the other four patients, we administered aerosolised allergen. Findings 18FDG uptake was increased four-fold in the right compared with the left upper lobe (geometric mean of ratios 4·30, 95% Cl 2·39-7·72, p=0·002). Aerosolised administration of allergen did not significantly increase 18FDG uptake. Interpretation These data show that local allergen-invoked airway inflammation can be visualised with 18FDG and PET in asthma. The cellular localisation of the 18FDG signal remains to be determined.

Cell surface antigen expression by peripheral blood monocytes in allergic asthma: results of 2.5 years therapy with inhaled beclomethasone dipropionate

At present, inhaled glucocorticoids are widely accepted as the therapy of choice in chronic asthma. Treatment with inhaled glucocorticoids significantly suppresses local airway inflammation in asthmatics, but may also have systemic effects, e.g. a reduction of the number of circulating hypodense eosinophils or a down-modulation of HLA-DR antigen (Ag) expression by T lymphocytes in peripheral blood. However, the effect of long-term therapy with inhaled glucocorticoids on peripheral blood monocytes (PBM), which are the precursors of the most numerous cell type in the lung, the alveolar macrophage, have not yet been evaluated. We therefore investigated the expression of various cell surface Ag on PBM from non-smoking patients with allergic asthma who were treated for 2.5 years with a β2-receptor agonist plus either an inhaled glucocorticoid (beclomethasone dipropionate, BDP) (n = 4) or an anticholinergic or placebo (n = 8). We compared the results with healthy volunteers (n = 7). Long-term treatment of allergic asthmatics with inhaled BDP, but not anticholinergic or placebo therapy, was associated with a significantly lower CDllb Ag expression (p < 0.04) and higher expression of CD13, CD14 and CD18 Ag (p < 0.05, p < 0.02 and p < 0.04, respectively) when compared with the healthy control subjects (n = 7). Most interestingly, PBM of asthmatics treated with inhaled BDP expressed an almost two-fold higher level of CD14 Ag on their cell surface than PBM of patients treated with anticholinergic or placebo (p < 0.03). No significant differences in the expression of CD16, CD23, CD25, CD32 and CD64 Ag or HLA-DR were observed between PBM from the different patient groups or healthy controls. Taken together, this study shows that long-term local therapy with inhaled BDP coincides with an altered expression of at least one cell surface Ag on PBM from allergic asthmatics.