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Study objectives To investigate whether the bronchodilatory effect of deep inspiration is impaired in subjects with COPD. Methods We measured deep inspiration-induced bronchodilation in 19 patients with COPD and 17 healthy subjects (mean age, 67.8 ± 7.1 years vs 62.5 ± 9.3 years, respectively [± SEM]). Each subject underwent a series of single-dose methacholine provocations to induce at least a 15% reduction in inspiratory vital capacity (IVC). When this was achieved, subjects were asked to perform four consecutive deep inspirations, after which the IVC measurement was repeated and the percentage of bronchodilation by deep inspiration was calculated. Results The percentage of reduction in IVC from baseline prior to the deep inspirations did not differ between the two groups (COPD, 20.1 ± 1.6%; healthy, 22.7 ± 2.4%; p=0.38); median single methacholine doses employed were 20 mg/mL (range, 0.025 to 75 mg/mL) and 25 mg/mL (range, 10 to 75 mg/mL), respectively (p = 0.19). Deep inspirations were not able to reverse bronchoconstriction in patients with COPD (bronchodilation, 3.9 ± 2.6%; p=0.15 by one-sample t test). Bronchodilation by deep inspiration was present in healthy subjects (13.7 ± 3.0%, p=0.0003), and was significantly higher than that of patient with COPD (p = 0.02). In patients with COPD, deep inspiration-induced bronchodilation correlated with the percentage of predicted transfer factor of the lung for carbon monoxide ( r = 0.53, p=0.05), but not with airway obstruction, as assessed by FEV 1 or FEV 1 /FVC. Conclusions The bronchodilatory ability of deep inspiration is lost in mild COPD. We speculate that the absence of deep inspiration-induced bronchodilation contributes to the development and severity of chronic respiratory symptoms in patients with COPD.

Chronic obstructive pulmonary disease (COPD) is a serious and mounting global public health problem. Although its pathogenesis is incompletely understood, chronic inflammation plays an important part and so new therapies with a novel anti-inflammatory mechanism of action may be of benefit in the treatment of COPD. Cilomilast and roflumilast are potent and selective phosphodiesterase (PDE)4 inhibitors, with an improved therapeutic index compared with the weak, non-selective PDE inhibitor, theophylline. Unlike theophylline, which is limited by poor efficacy and an unfavourable safety and tolerability profile, the selective PDE4 inhibitors are generally well tolerated, with demonstrated efficacy in improving lung function, decreasing the rate of exacerbations and improving quality of life, with proven anti-inflammatory effects in patients with COPD. Theophylline is a difficult drug to use clinically, requiring careful titration and routine plasma monitoring due to the risk of toxic side effects, such as cardiovascular and central nervous system adverse events, with dose adjustments required in many patients, including smokers, the elderly and some patients on concomitant medications. In contrast, the selective PDE4 inhibitors are convenient medications for both patient and physician alike. Hence these agents represent a therapeutic advance in the treatment of COPD, due to their novel mechanism of action and potent anti-inflammatory effects, coupled with a good safety and tolerability profile.

Asthma and allergies, including rhinoconjunctivitis and atopic dermatitis, are common throughout the world, with a high burden of morbidity and cost. The nasal and bronchial mucosa present similarities, and most patients with asthma also have rhinitis, suggesting the concept of one airway, one disease. Not all patients with rhinitis present with asthma, however, and there are differences between rhinitis and asthma. For this article, the authors differentiate between chronic rhinosinusitis and nasal polyposis based on the presence of polyps in the nasal cavity or the sinuses during clinical examination or surgery. This approach neglects an ill-defined group of chronic hyperplastic sinusitis, which might represent a transition phase.

Structural and functional characteristics of bronchial epithelial cells in corticosteroid-dependent asthma are unknown.In bronchial biopsy specimens from 16 control, 9 untreated asthmatic, 9 inhaled corticosteroid-treated asthmatic, and 19 corticosteroid-dependent asthmatic subjects, we evaluated epithelium morphology and patterns of cell apoptosis, proliferation, and activation.We used the terminal deoxynucleotidyl-mediated dUTP nick end labeling (TUNEL) technique to study apoptosis. Immunohistochemistry was used to evaluate the expression of molecules related to apoptosis (such as Bcl-2 and P53), cell proliferation (PCNA), and cell activation (NFkappaB and CD40/CD40-L).Epithelium thickness was higher in corticosteroid-dependent asthmatic and control subjects than in inhaled corticosteroid-treated and untreated asthmatic subjects (P.0001 and P.0003). Very few TUNEL-positive epithelial cells were found in the 4 groups. Bcl-2 expression was higher in all groups of asthmatic subjects than in controls (P.001). In corticosteroid-dependent asthmatic subjects, PCNA, NFkappaB, and CD40-L expression was higher than in inhaled corticosteroid-treated asthmatic (P.001), untreated asthmatic (P.001 and P.04), and control (P.01) subjects. CD40 expression was greater in corticosteroid-dependent asthmatic and untreated asthmatic subjects than in inhaled corticosteroid-treated asthmatic subjects (P.0001 and P.0006) and controls (P.02 and P.03). In corticosteroid-dependent asthma, PCNA expression was correlated with the epithelium thickness (P.007).This study shows that in bronchial epithelial cells of corticosteroid-dependent asthma, markers of cell survival and proliferation are coexpressed with markers of cell activation, suggesting that in this disease epithelium repair is associated with a persistent activation state of epithelial cells.

A chronic inflammatory process is almost invariably associated with tissue damage and healing. Healing results in repair and replacement of dead or damaged cells by viable cells. Repair usually involves 2 distinct processes: regeneration, which is the replacement of injured tissue by parenchymal cells of the same type, and replacement by connective tissue and its eventual maturation into scar tissue. In many instances both processes contribute to the healing response. Chronic inflammatory disease can therefore lead to a wide variety of consequences, from complete or partial restitution of organ structure and function to fibrosis. Asthma is characterized by a chronic inflammatory process of the airways. The ensuing healing process results in structural alterations referred to as a remodeling of the airways. The mechanisms underlying these structural alterations are still largely unknown. They are likely to be heterogeneous, leading-through the highly dynamic process of cell de-differentiation, migration, differentiation, and maturation-to changes in connective tissue deposition and to the altered restitution of airways structure, resulting in mucus gland hyperplasia, neovascularization, fibrosis, and an increase in smooth muscle mass.

Recent evidence shows that 15(S)-hydroxy-eicoisatetraenoic acid (15[S]-HETE) can be released and rapidly reincorporated into cellular lipids. These mechanisms exert several immunoregulatory functions that may be relevant in airway inflammation.Our purpose was to evaluate the levels of both soluble and cell-associated 15(S)-HETE and to examine 15-lipoxygenase (15-LO) messenger RNA (mRNA) expression in sputum samples obtained from 10 control and 18 asthmatic subjects.Levels of 15(S)-HETE were measured by reverse-phase HPLC separation followed by RIA in supernatants and in cell membrane-extracted phospholipids after acid hydrolysis. 15-LO mRNA was evaluated by primed in situ hybridization (PRINS). Combined immunocytochemistry and PRINS was used to identify the phenotype of cells bearing 15-LO transcripts.Levels of both soluble and cell-associated 15(S)-HETE were higher in asthmatic than in control subjects (P.0001). The percentage of cells expressing 15-LO mRNA was higher in asthmatic than in control subjects (P.01). On double staining for specific cell-type markers and 15-LO mRNA, macrophages were the major source for 15-LO.This study shows that the induced sputum technique allows the evaluation of 15-LO activity and that soluble, cell-associated 15(S)-HETE and 15-LO levels are higher in asthmatic than in control subjects. In addition, this study indicates that, in induced sputum, airway macrophages are the major source of 15(S)-HETE in asthma.

Asthma represents a chronic inflammatory process of the airways followed by healing, the end-result of which is an altered structure referred to as a remodeling of the airways. Repair usually involves 2 distinct processes: regeneration (which is the replacement of injured tissue by parenchymal cells of the same type) and replacement by connective tissue and its eventual maturation into scar tissue. In many instances both processes contribute to the healing response and inflammation. In asthma the processes of cell dedifferentiation, migration, differentiation, and maturation and connective tissue deposition can be followed either by complete or altered restitution of airway structure and function, the latter often seen as fibrosis and increase in smooth muscle and mucus gland mass. These features result in an increased resistance to airflow, particularly when there is bronchial contraction and bronchial hyperresponsiveness. The effect on airflow is compounded by the presence of increased mucous secretion and inflammatory exudate, which not only blocks the airway passages but also causes an increased surface tension that favors airway closure.

Bronchial brushing is a useful method for morphological and functional studies of bronchial epithelial cells (BECs) in various diseases. This technique has been found to be generally safe, but its safety in asthma and chronic bronchitis has not been fully assessed. The purpose of this study was to determine 1. whether bronchial brushing is a safe method in asthmatic and chronic bronchitis patients of differing severity and 2. to characterize the BECs obtained in terms of number, viability and purity. We evaluated 25 asthmatics of variable severity, 19 chronic bronchitis patients and 26 normal volunteers. Bronchoscopy and bronchial brushing were performed in a standardized manner by the same investigator. Safety was assessed by clinical follow-up of all subjects; continuous monitoring of arterial oxygen saturation during the procedure with a digital oximeter was carried out in a subsample of subjects. No complications were observed clinically during the procedure. There was a minimal fall in arterial oxygen saturation without a significant difference between the three groups of subjects. A consistent number of BECs was recovered and their viability, assessed by the trypan blue exclusion test, in asthmatics and chronic bronchitis patients was significantly lower than in controls (P

Background: Apoptosis regulates inflammatory cell survival, and its reduction contributes to the chronicity of an inflammatory process. Apoptosis is controlled by suppressing or inducing genes, such as bcl-2 and p53 , respectively. Objective: We sought to assess apoptosis of eosinophils, macrophages, and T lymphocytes in bronchial biopsy specimens from asthmatic subjects and to examine its regulation by evaluating the expression of B-cell lymphoma leukemia-2 (Bcl-2) and P53 proteins. We also sought to explore the relationships between cell apoptosis and GM-CSF, a cytokine able to increase eosinophil and macrophage survival. Methods: Apoptosis in eosinophils, macrophages, and T lymphocytes was evaluated in bronchial biopsy specimens obtained from 30 asthmatic subjects, 26 subjects with chronic bronchitis, and 15 control subjects by combining the terminal deoxynucleotidyl transferase–mediated dNTP nick end-labeling technique and immunohistochemistry. The expression of P53, Bcl-2, and GM-CSF was studied through immunohistochemistry by using specific mAbs. Results: The number of apoptotic eosinophils and macrophages was lower in subjects with asthma than in those with chronic bronchitis ( P P P P P = .0001) and with the severity of the disease ( P P P P P Conclusion: Airway inflammation in asthma is associated with an enhanced survival of different cell types caused by reduced apoptosis. (J Allergy Clin Immunol 1999;103:563-73)

IL-4 modulates the synthesis of IgE, the expression of CD23, and the release of 15(S)-hydroxyeicosatetraenoic (15[S]-HETE).We evaluated the release of 15(S)-HETE by IL-4-stimulated monocytes and verified whether the observed increase in 15(S)-HETE release after passive sensitization and anti-IgE challenge of IL-4-treated monocytes was secondary to an increased CD23 expression.Human monocytes were incubated for 24, 48, and 72 hours with IL-4 (10 ng/mL) with or without an IgE-anti-IgE stimulation. We evaluated CD23 expression by immunocytochemistry and 15(S)-HETE release by HPLC and RIA. To prove that the increase in 15(S)-HETE release was due to the effect of IL-4 on CD23, we performed experiments with an anti-CD23 blocking mAb.CD23 expression and 15(S)-HETE release were significantly increased by IL-4, reaching a peak after 72 hours (P.02). After passive sensitization with human IgE and anti-IgE challenge, IL-4-stimulated monocytes released higher amounts of 15(S)-HETE than IL-4-unstimulated monocytes (P.02). Pretreatment with the anti-human B-cell CD23 MHM6 mAb caused a dose-dependent inhibition of 15(S)-HETE release.This study shows that immunologic challenge of IL-4-treated, passively sensitized monocytes results in a CD23-dependent additional increase of 15(S)-HETE release, indicating the presence of a synergistic effect of IL-4 on CD23 expression and 15(S)-HETE production.

Summary Asthma is a chronic inflammatory disease of the airways followed by healing whose end-result is an altered structure referred to as a remodelling of the airways. All the structures of the bronchi are involved in asthma, and inflammation and remodelling processes seems to occur both in large and peripheral airways. In patients with chronic asthma airways inflammation has been widely demonstrated and correlated to the clinical severity of the disease, and the involvement of several cells, such as epithelial cells, eosinophils, mast-cells, lymphocytes and macrophages has been widely demonstrated. Although it the bronchial tree, the site of the airways inflammation is still a matter of controversy, recent studies suggest that inflammation is not restricted to bronchi being almost homogeneously distributed in both central and peripheral airways.

Resume Nous possedons beaucoup d'arguments pour penser que le remodelage bronchique est une realite dans l'asthme. Cette phase de reparation fait intervenir des cellules de structures et de l'inflammation ainsi que la matrice extracellulaire. Tous ces elements sont presents et actives dans les bronches de l'asthmatique. Les consequences cliniques de ces phenomenes sont possibles mais non directement demontrees. L'action des therapeutiques anti-asthmatiques et des corticosteroides en particulier demande a etre appreciee sur de longues etudes prospectives.

BACKGROUND AND AIM: Endothelin has bronchoconstrictive, vasoactive, and inflammatory properties and may be involved in the pathogenesis of asthma. We have studied the involvement of endothelin in asthma by examining its expression and release by mononuclear phagocytes obtained from 56 patients with asthma and 32 control subjects and the activation of mononuclear phagocytes by endothelin. METHODS: Endothelin immunoreactivity was studied by using immunocytochemistry on monocytes and alveolar macrophages. Spontaneous and lipopolysaccharide-induced endothelin release from monocytes and alveolar macrophages was studied by radioimmunoassay. The proportion of intracellular endothelin was assessed after cell disruption by Triton (Union Carbide Corp., Bound Brook, N.J.). The release of fibronectin and tumor necrosis factor-α induced by endothelin was studied in alveolar macrophages by enzyme immunoassay. RESULTS: Endothelin immunoreactivity was significantly increased in cells from patients with asthma in comparison with those from the control group, but its release by alveolar macrophages was similar in both groups. Levels in the cell lysates and supernatants were similar for patients with asthma and normal subjects. Endothelin significantly increased the release of tumor necrosis factor-α and fibronectin by alveolar macrophages from normal subjects and patients with stable asthma, but it significantly decreased their release in patients with unstable asthma. CONCLUSION: This study suggests a role for endothelin in airway inflammation in asthma. Endothelin may act in a different fashion on alveolar macrophages, depending on the degree of stability of the disease. (J ALLERGY CLIN IMMUNOL 1996;98:412-20.)

It has been suggested that hyperosmolarity may be one of the stimuli that provoke exercise-induced asthma and rhinitis. We investigated whether changes in osmolarity could result in increased levels of mediator release from nasal cells. Cells were dispersed from nasal polyps by enzymatic digestion and were incubated for 15 minutes with solutions of varying osmolarity obtained by the addition of mannitol to Hanks' balanced salt solution. After incubation was performed, cell supernatants were removed, and the release of 15-hydroxyeicosatetraenoic acid, prostaglandin 2 leukotriene B 4 , and fibronectin was measured. Lactate dehydrogenase was measured to assess cell viability. Epithelial cells made up 40% to 60% of cells and mononuclear cells 40% to 65%. At 900 mOsm/kg H 2 O, which has been suggested as the osmolarity of the fluid lining the airways during exercise, we observed a significant increase (Wilcoxon W test) in the release of 15-hydroxyeicosatetraenoic acid ( p 4 ( p 2 ( p J Allergy Clin Immunol 1995;96:980–5.)

Urinary leukotriene E4 (LTE4) is a marker of the body's production of cysteinyl LTs, important mediators of airway inflammation. The role of the latter in nocturnal asthma is a topic of increasing interest.This investigation was aimed at determining whether nighttime attacks are associated with increased release of LTs, expressed by urinary LTE4, and the relationship between the two phenomena.Three groups were studied: group A, seven control subjects; group B, nine asthmatic patients without nocturnal attacks; and group C, nine asthmatic patients with a comparable daytime FEV1 but who were experiencing nocturnal exacerbations (morning dips in peak expiratory flow greater than 20%). Urine was collected over 24 hours in three samples (9:00 AM to 3:00 PM; 3:00 PM to 9:00 PM; and 9:00 PM to 9:00 AM). LTE4 was measured by high-performance liquid chromatography and radioimmunoassay and expressed as nanograms per millimole of creatinine.No significant differences between urinary LTE4 were noticed within groups A and B. Conversely, in group C urinary LTE4 at night (geometric mean with 95% confidence interval; 35.16 with 28.77-42.85) was significantly higher than that of the other samples (respectively 23.12 with 17.78-30.06, p less than 0.05; and 25.18 with 21.03-30.13, p less than 0.02); it was also significantly higher than in all the samples of other groups. A significant (p less than 0.02) linear correlation was observed between morning dip in peak expiratory flow and the log urinary LTE4 in the nocturnal sample.These results indicate the role of LTs in nocturnal asthma and suggest that urinary LTE4 may be a useful marker of this condition.

Several aspects of tryptophan (Trp) metabolism are dependent upon pyridoxine (B 6 ) status. The present experiment aimed to determine if Trp metabolism and the eventual growth responses to dietary supplementation of Trp is modulated by dietary B 6 . Exploratory measurements related to the modulation of the immune system were also made. Piglets weaned at 15 to 18 days of age ( n = 544) were grouped in 32 pens of 17 animals and distributed in a factorial arrangement of treatments with two dietary additions of B 6 [0 (B 6 −) or 5 mg/kg (B 6 +)] and two dietary additions of synthetic Trp [0 (Trp−) or 0.5 g/kg (Trp+)]. Basal dietary concentrations of B 6 varied according to age, between 2.1 and 3.5 mg/kg, and for Trp, between 1.9 and 2.5 g/kg. Growth performance was recorded every week from 2 to 9 weeks of age. Blood samples were taken from two piglets in each pen at 2, 4, 6 and 8 weeks of age. Another piglet in each pen was immunized twice with ovalbumin emulsified with incomplete Freund adjuvant to evaluate the antibody response. No treatment effect was observed on feed intake, body weight gain or feed conversion ratio for the whole experimental period but feed conversion increased more drastically in Trp− than in Trp+ piglets during the last week of experiment (B 6 × Trp × age, P 6 vitamer, was 19% lower in red blood cells of B 6 − than B 6 + piglets (B 6 × age, P 6 + than in B 6 − piglets. The percentage of B lymphocyte population at 4 and 6 weeks of age dropped in B 6 − animals whereas it remained stable in B 6 + piglets (B 6 × age, P 6 × Trp × age), the results indicate that, globally, within the present dietary levels, pyridoxine is not a major factor for Trp metabolism and therefore, for Trp requirements of post-weaning piglets. The absence of interaction between B 6 and Trp on the present immunological indicators suggest that each nutrient modulates the immune response through independent mechanisms.