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‘‘Chronic respiratory diseases (CRD) which include asthma and chronic obstructive pulmonary diseases (COPD) comprise a major cause of death and disability for all age groups and regions in the world. In the absence of effective interventions, risk factors such as smoking, air pollution, allergen exposure, severe childhood respiratory infection and TB are expected to cause a further rise in the magnitude of these health problems in the coming years, particularly in developing countries. Evidence also indicates that in many countries people with common CRDhave no access to acceptable standards of health care; health systems may also provide inappropriate care due to misdiagnosis arising from respiratory symptoms which are often common for acute and chronic illnesses.’’ (1) In low and middle-income countries, the capacity of health professionals should be expanded to address CRD. Sub-Saharan Africa appears to be an important region of the world that could be used to assess how the CRD program can be modeled and implemented. In these countries, CRD (including allergic diseases) represent only one type of major disease, and in many instances are not the main disease burden. Thus, it is important to propose an integrated management of disease that covers communicable and noncommunicable diseases.

Inflammation of the human bronchial epithelium, as observed in asthmatics, is characterized by the selective death of the columnar epithelial cells, which desquamate from the basal cells. Tissue repair initiates from basal cells that resist inflammation. Here, we have evaluated the extent of apoptosis as well as the Hsp27 level of expression in epithelial cells from bronchial biopsy samples taken from normal and asthmatic subjects. Hsp27 is a chaperone whose expression protects against oxidative stress. We report that in asthmatic subjects the basal epithelium cells express a high level of Hsp27 but no apoptotic morphology. In contrast, apoptotic columnar cells are devoid of Hsp27 expression. Moreover, we observed a decreased resistance to hydrogen peroxide–induced apoptosis in human bronchial epithelial 16–HBE cells when they were genetically modified to express reduced levels of Hsp27.

Chronic inflammation and airway remodelling are two key steps in asthma pathophysiology. The development of chronic airway inflammation depends upon the continuous recruitment of inflammatory cells from the bloodstream towards the bronchial mucosa and by their subsequent functional activation. The release of inflammatory mediators by activated cells contributes to the generation of a complex network which involves mobile inflammatory cells and structural cells such as epithelial cells, fibroblasts and myofibroblasts. This network is responsible for the amplification and persistence of the inflammatory process as well as for the development of a peculiar microenvironment which can directly modulate the survival of inflammatory cells in the inflamed airways. Increased cellular recruitment and activation, enhanced cell survival and cell:cell interactions are therefore the key steps in the development of chronic airway inflammation in asthma and represent the major causes for tissue damage, repair and remodelling.

Glucocorticoids (GC) represent the cornerstone anti-inflammatory treatment of chronic asthma. A small proportion of asthmatics develop a severe form of the disease and require a chronic long-term treatment with oral GC. These patients, ascribed as GC dependent asthmatics, present an ongoing inflammation of the airways. GC dependent asthma should be differentiated from GC resistant asthma. GC resistant asthmatics are defined as patients whose baseline pre-bronchodilation FEV1 of less than 70-80% predicted improves by less than 15% following 1-2 weeks of 40 mg prednisolone daily. The effects of GC are mediated by the GC receptor (GR) alpha. By a process called trans-activation they increase the transcription of genes involved in either beneficial processes or certain side effects. Through trans-repression, they inhibit the transcription factors, including nuclear factor kappa B (NF-kappa B), thereby decreasing the expression of many genes encoding inflammatory mediators. In addition to GR alpha, an isoform deficient in hormone binding has been isolated in humans and termed GR beta, which functions as a dominant negative inhibitor of GR alpha. However, to act as such, GR beta has to be more abundant than GR alpha, and conflicting data have been obtained concerning the relative levels of the two isoforms in cell lines and freshly isolated cells. It seems however that overexpression of GR beta may play a role in GC-resistant asthmatics, whereas in GC-dependent asthmatics, a predominant GR alpha expression has been consistently found. Thus the persistence of inflammation in GC-dependent asthma does not seem to be associated with an overexpression of GR beta but with a dysfunction of the trans-repression or trans-activation processes mediating the anti-inflammatory effects of GR alpha.

Asthma is a disease characterized by a chronic inflammation of the airways and by structural alterations of bronchial tissues, often referred to as airway remodelling. The development of chronic airway inflammation in asthma depends upon the continuous recruitment of inflammatory cells from the bloodstream towards the bronchial mucosa and by their subsequent activation. It is however increasingly accepted that mechanisms involved in the regulation of the survival and apoptosis of inflammatory cells may play a central role in the persistent inflammatory process characterizing this disease. Increased cellular recruitment and activation, enhanced cell survival and cell:cell interactions are therefore the key steps in the development of chronic airway inflammation in asthma, and represent the major causes for tissue damge, repair and remodelling.

The inflammation of chronic asthma appears to be far more complex than a simple eosinophilic inflammation. All cells of the airways—inflammatory and structural—are involved and become activated including T cells, eosinophils, mast cells, macrophages, epithelial cells, fibroblasts, and even bronchial smooth muscle cells. All these cells play an effector role by the release of pro-inflammatory mediators,1 cytotoxic mediators, and cytokines resulting in vascular leakage, hypersecretion of mucus, smooth muscle contraction, epithelial shedding, and bronchial hyperresponsiveness. These cells are also involved in the regulation of inflammation of the airways and initiation of the process of remodelling by the release of cytokines and growth factors. T lymphocytes play a central role in the development of airway inflammation.2 They are present in increased numbers in the airways of patients with fatal asthma3 or in patients with asthma of variable aetiology including occupational asthma.4 Most bear CD4 receptors while CD8 positive cells are more rarely identified, even during exacerbations of asthma.5 T cells are …

Glucocorticoids (GCs) are routinely used as anti-inflammatory drugs in the treatment of asthma. They act through binding to glucocorticoid receptor α (GRα), which represses numerous genes encoding pro-inflammatory mediators. A hormone binding deficient GR isoform named GRβ has been isolated in humans. When overexpressed by transfection, GRβ may function as a dominant negative modulator of GRα. However, to act as such, GRβ has to be more abundant than GRα, and conflicting data have been obtained concerning the relative levels of the two isoforms in cell lines and freshly isolated cells. Moreover, the dominant negative effect was not confirmed by independent laboratories. In GC-resistant asthmatics, GRβ was expressed by an increased number of peripheral blood mononuclear cells (PBMCs), airway T cells, and cells found in skin biopsies of tuberculin responses. However, the relative amounts of GRα and GRβ in these cells were not determined. In GC-dependent asthmatics, PBMCs expressed GRα predominantly. No cells containing higher levels of GRβ than GRα have yet been reported in asthmatics. Even if the existence of such cells is demonstrated, the role of GRβ in asthma will remain a matter of controversy because functional studies have given discrepant data.

Tumor progression results from complex interactions between tumor and tumor-associated host tissue. Basic fibroblast growth factor (bFGF), via activation of its receptor, FGFR-1, has been postulated to be an important inducer of host stromal response and angiogenesis. To assess the putative role of tumor-associated stromal cells and vessels in tumor progression, we studied non-small cell lung cancer (NSCLC) from 84 patients, including 51 squamous cell carcinomas and 33 nonsquamous cell carcinomas, by immunohistochemical detection. bFGF and FGFR-1 immunoreactivity was observed in tumor and in tumor-associated stromal cells and vessels. The expression of bFGF and FGFR-1 in stromal cells was higher in squamous than in non-squamous cell carcinomas (respectively, P = .007 and P = .0004). We found that bFGF and FGFR-1 expression in tumor and tumor-associated stromal cells and vessels was directly correlated with host stromal response, as assessed by intratumoral extension of stroma, but not with angiogenic response, as assessed by microvessel count. Although FGFR-1 expression of tumor cells was directly correlated with T-stage (P = .03), bFGF expressions of tumor-associated stromal cells and vessels were inversely correlated with lymph node metastasis (respectively, P = .0001 and P = .0002) and advanced pathological stage (respectively, P = .03 and P = .01). These findings suggest that bFGF might mediate host stromal response in NSCLC and that the expression of bFGF in tumor-associated stromal cells and vessels might have an inhibitory role in NSCLC progression.

Asthma is a chronic disease and should be treated with both controller and reliever drugs. Asthma controller therapy is not used sufficiently widely, probably due to low compliance with inhaled drugs, lack of response in some patients to low-medium doses of inhaled steroids and possible adverse events. This review analyses a new class of antiasthmatic drugs, leukotriene receptor antagonists (antileukotrienes). At present, two antileukotrienes are available in Italy: zafirlukast and montelukast. Antileukotrienes improve symptoms and also inhibit the effects of some of the inflammatory mediators involved in the pathogenesis of asthma; therefore, antileukotrienes may be used in monotherapy. In addition, the oral administration route is an advantage for compliance. Antileukotrienes significantly improve pulmonary function, asthma symptoms and inhaled and oral steroid and short-acting beta 2-agonist use. Moreover, antileukotrienes produce a 50% mean reduction in the incidence of asthma exacerbations compared with placebo. From the economic point of view, asthma controller therapy using antileukotrienes is associated with a50% (compared with placebo) reduction in healthcare costs (hospitalization due to asthma exacerbation, healthcare contact and absenteeism from work or school), which globally account for 93% of asthma-related costs. Antileukotrienes are indicated in the treatment of persistent mild-to-severe asthma, seasonal allergic asthma, exercise-induced asthma and aspirin-induced asthma. Antileukotrienes are well tolerated independently of the duration of treatment and the incidence of the observed adverse events is substantially similar to that observed using placebo. Owing to good tolerability and compliance and the economic advantages, these agents may be considered a valid therapeutic option for the control and management of asthma as a chronic disease.

Although asthma and rhinitis often coexist, it is still unknown whether they are characterized by a similar inflammatory profile. We studied eosinophilic infiltration, epithelial shedding and reticular basement membrane thickness in nasal and bronchial biopsies of six control subjects, 15 untreated allergic asthmatics with perennial rhinitis, and six corticosteroid-dependent (CSD) asthmatics. In nasal and bronchial biopsies, eosinophils were greater in untreated asthmatics than in control subjects and CSD asthmatics (p = 0.001). In untreated asthmatics, eosinophils were higher in bronchial than in nasal biopsies (p = 0.002). In nasal and bronchial biopsies, reticular basement membrane thickness was greater in untreated and CSD asthmatics than in control subjects (nasal: p0.008 and p0. 004; bronchial: p0.001 and p0.008). In untreated and CSD asthmatics, reticular basement membrane thickness was greater in bronchial than in nasal biopsies (p = 0.001; Wilcoxon's W test). Nasal epithelium was not shed in all the study groups. In untreated asthmatics, bronchial epithelium shedding was greater than in control subjects or CSD asthmatics (p0.005), and it was greater than nasal epithelium shedding (p0.006). This study has shown that, although concomitant, the extent of eosinophilic inflammation of reticular basement membrane thickness and of the epithelium shedding is greater in bronchial than in nasal mucosa of asthmatic patients with perennial rhinitis.

Inflammation represents a localized or systemic response against tissue or cell injury, which, on the one hand, is essential among cell defense mechanisms and, on the other, is involved in a broad spectrum of diseases. According to the initiating event, the inflammatory response may involve, or not, an antigenspecific immune response. In the first case, the initiating agent is generally a microorganism or an antigen of unknown origin, while in the latter, cells may respond to injurious physical agents (foreign bodies, burns, radiations, trauma) or toxic chemicals. Lymphocytes are classically involved in the specific immune response, and phagocytes in its non-specific counterpart.

15(S)-Hydroxyeicosatetraenoic acid (15[S]-HETE) is a 15-lipoxygenase (15-LO) metabolite that may play an important role in different pulmonary diseases. 15-HETE is synthesized by different epithelial cells and may be subsequently incorporated into cellular phospholipids. We studied the role of interleukin-4 (IL-4) on 15-LO activity and on 15(S)-HETE incorporation into cellular phospholipids by WI-26 pulmonary epithelial cells. 15-LO activity was evaluated by measuring 15(S)-HETE production, through combined reverse-phase-high-pressure liquid chromatography (RP-HPLC) separation and specific radioimmunoassay (RIA), after incubation with arachidonic acid (AA). We also studied 15-LO messenger RNA (mRNA) expression, using primed in situ (PRINS) labeling. IL-4 (10 ng/ml) markedly increased the percentage of 15-LO mRNA-bearing cells as well as 15-LO activity after 24, 48, and 72 h, with a maximal response at 48 h. Uptake and incorporation into cellular phospholipid was studied with [3H]15(S)-HETE, which showed that IL-4 was able to increase significantly 15(S)-HETE incorporation into WI-26 cells, with a maximal effect observed at 72 h. Cellular-lipid-associated [3H]15(S)-HETE, evaluated with RP-HPLC after base-catalyzed hydrolysis, increased concomitantly with disappearance of the radiolabel from the supernatant. Class separation of cellular lipids with normal-phase HPLC (NP-HPLC) showed that IL-4 increased [3H]15(S)- HETE incorporation mainly in the phosphatidylinositol (PI) fraction. The ability of IL-4 to promote 15-LO activity and incorporation into cellular phospholipids of human lung epithelial cells may be important in airway inflammation and in modulation of the potential autocrine function of 15(S)-HETE.

In a cross-sectional study we evaluated the effect of aging (separately from that of duration of disease) on airway obstruction and reversibility by comparing two groups of non-smoker patients with asthma.We compared two groups of patients: group A, which had 50 subjects (8 men and 42 women) aged 59.7+/-4.6 years (mean +/- SD), and group B, comprised of 51 subjects (19 men and 32 women) who were 35.7+/-7.4 years old. The groups were selected because of comparable baseline degree of obstruction (FEV1 % of predicted, 67.8+/-20.3 in group A; 73.0+/-19.6 in group B, NS) and duration of the disease (14.0+/-11.7 years vs 11.2+/-9.1, NS). Spirometric examination, with a bronchodilator test, was performed and subjects not reaching 85% of predicted were submitted to a 4-week course of inhaled steroids.Although a higher number of subjects from group B responded to the acute bronchodilator test (p0.001), the maximum response achievable with treatment (steroid or bronchodilator) (deltaFEV1 expressed as the percent of predicted) was not statistically different between groups (12.0+/-17.5 vs 16.0+/-23.9). The mean FEV1 attainable after treatment (deltaFEV1%PT) was significantly lower in the older group (p = 0.0006). Within groups, the baseline FEV1% did not correlate with age; it was inversely correlated with the duration of the disease (p0.03 and p0.01, respectively). In both groups deltaFEV1 was inversely related with the baseline FEV1, whereas FEV1%PT was correlated with the duration of the disease, with a slope nearly doubled in group B (p0.001).Both the process of aging and the prolonged exposure to disease effects are important factors in determining the functional characteristics of chronic asthma: In particular, aging is associated not only with a reduced acute responsiveness to bronchodilators, but also with a reduced slope of the duration-FEV1%PT relationship that suggests a slowing of the rate of loss of reversibility of uncertain biological meaning.

Neuropeptides act on most of the components of the bronchial environment. They influence bronchomotor tone and bronchial vascular caliber and permeability. To investigate the nonadrenergic, noncholinergic system within the airways in asthma and chronic bronchitis, we performed endobronchial biopsies in 16 normal human volunteers, 49 patients with asthma of varying severity, including 16 patients treated with oral corticosteroids, and 13 patients with chronic bronchitis. Frozen sections of biopsies stained with specific antibodies against the neural marker PGP 9.5, vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), and neuropeptide Y (NPY) were analyzed for the presence of nerves through indirect immunofluorescence. Nerves were present in most of the biopsies and were found within and below the epithelium and adjacent to smooth muscle, glands, and blood vessels. By comparison with those in normal subjects, the numbers of VIP-immunoreactive nerves were not significantly decreased in patients with asthma and chronic bronchitis, but NPY-immunoreactive nerves were significantly decreased in the smooth muscle of these latter two groups of patients (p < 0.005). There was no correlation between disease severity and the number of nerves found in the biopsies. This study does not confirm previous findings in autopsy material of some defects in sensory and VIP-containing nerves in severe asthma.

The severity of asthma can be graded from mild intermittent to severe persistent. Airway inflammation is a feature of persistent asthma. We compared several markers of inflammation in mucosal biopsies and bronchoalveolar lavage fluid (BAL fluid) from 12 healthy control subjects, 24 patients with intermittent asthma, and 18 patients with mild-to-moderate persistent asthma. Epithelial shedding, eosinophil (EG2-positive cells), and activated T-cell (UCHL1) counts in biopsies, and ECP levels in BAL fluids were significantly increased in patients with intermittent asthma by comparison with control subjects and this increase was significantly greater for patients with persistent asthma. Alveolar macrophage activation (percentage of hypodense cells) and the thickness of the basement membrane were significantly increased in asthmatic subjects as compared with controls but there was no difference between the two asthmatic groups. Hyaluronic acid levels in BAL fluids were significantly increased in patients with persistent asthma by comparison with control subjects and patients with intermittent asthma. Mast cell numbers (toluidine blue) in biopsies and histamine or levels in BAL fluids were similar in the three groups. This study shows that airways inflammation is present in patients with intermittent asthma but to a lesser extent than in patients with persistent asthma.

The aim of this study was to evaluate the role of ageing on variability of airflow obstruction and on the specific pattern of nocturnal exacerbations ("morning dipping" of peak expiratory flow (PEF)) in asthma. Two groups of stable asthmatics (Group A: 23 patients, aged 14-47 yrs; Group B: 20 patients, aged 53-74 yrs), that were similar for duration of disease, degree of obstruction and response to bronchodilators, were studied. PEF was monitored four times daily for 2 weeks, and amplitude of variation and "morning dip" were calculated. Both PEF amplitude and "morning dip" were greater in the older patients (p

Allergy rhinitis results from an IgE-mediated allergy associated with nasal inflammation of variable intensity. The mechanisms of allergic rhinitis have been clarified using nasal challenge with allergen or proinflammatory mediators and measuring cells and mediators released during the early- and late-phase allergic reaction. However, the priming effect of the nasal mucosa is of importance since a single challenge does not perfectly mimic the ongoing allergic reactions induced by repeated allergen exposure. In seasonal and chronic allergic rhinitis, the same cells and mediators are of importance but nonspecific nasal hyperreactivity develops. The regulation of the inflammation of allergic rhinitis is dependent on adhesion molecules and cytokines.

Platelet-derived growth factor (PDGF) controls cellular growth, migration, and differentiation. It is secreted by various cell types, including macrophages, and participates in tissue repair and epithelial regeneration. PDGF may therefore be involved in airway remodeling in asthma. This study compared the immunoreactivity of PDGF and its receptors (R alpha and R beta) in bronchial biopsies and the levels of PDGF in bronchoalveolar lavage (BAL) fluid of asthmatics and control subjects. Bronchial biopsies were done in a subsegmental bronchus of 11 asthmatics and 11 control subjects by flexible bronchoscope. PDGF AA and BB, and PDGF receptors R alpha and R beta were studied with monoclonal antibodies and revealed by immunoperoxidase staining. The percentage of subjects presenting positive staining with PDGFs and its receptors was studied in the epithelium and submucosa. PDGF AA, AB, and BB were measured in BAL fluid of 18 asthmatics and 10 controls by specific ELISA. In biopsies, there was no significant difference between asthmatics and controls for PDGF AA, BB, PDGF-R alpha and R beta (Fisher's exact test and Bonferroni's correction). Moreover, the levels of PDGF, AA, AB, and BB were similar in asthmatics and controls. This study does not support a role for PDGF in the repair processes of asthma.

Theophylline (1,3 dimethylxanthine) is one of the most widely used drugs in the therapy of bronchial asthma and chronic obstructive pulmonary diseases. It is now being increasingly recognized that theophylline is able to down-regulate, both in-vitro and in-vivo, a variety of inflammatory and immune cell functions, such as the late-phase reaction after challenge with the occupational agent toluene diisocyanate and the bronchial responsiveness. The suppressive activity of theophylline is due to its ability to decrease the release of inflammatory mediators and might have important implications with regards to its therapeutic activity in asthma. In this report we summarize the effects of theophylline on TNF-α release, an inflammatory mediator which plays a key role in the pathogenesis of airways inflammation associated with bronchial asthma, by human peripheral blood monocytes (BM) and alveolar macrophages (AM) as well as on the activation and the proliferation of lymphocytes.

Although the first pathologic observations, made just after the turn of the century, of patients who died from an asthma attack described eosinophil inflammation and shedding of the epithelium, for many years the major basic mechanism of asthma was believed to be bronchial obstruction, with bronchospasm, mucosal edema and mucous hypersecretion playing a major role. However, in the early 1980s, bronchoalveolar lavage (BAL) studies and immunohistochemistry of post-mortem bronchial specimens [1, 2] led to the concept of chronic desquamative bronchitis with eosinophilia. This concept has been extended and in the 1990s it has been shown that many cell types are involved in asthma. Our understanding of the pathophysiology of asthma has been improved by the pathologic examination of bronchi in living asthmatics, readily done using fiberoptic bronchoscopy. The information obtained has been considerably enhanced by electron microscopy [3], immunohistochemistry [2, 4] and, more recently, molecular biology techniques [5]. Thus, combining results of BAL and biopsies [6] it is possible to better examine the inflammation and the remodeling of the bronchi.

Background: Interleukin (IL)-4 is involved in IgE upregulation and downregulates cytokine release by mononuclear phagocytes. Mononuclear cells release greater amounts of IL-1, tumor necrosis factor-α, and IL-6 in patients with asthma than in control subjects, but the effect of IL-4 on cells from patients with asthma is unknown. The effects of IL-4 on the release of IL-1, tumor necrosis factor-α, and IL-6 by monocytes and alveolar macrophages were compared in 19 patients with asthma and 18 control subjects. Methods: The release of IL-1, tumor necrosis factor-α, and IL-6 from unstimulated and lipopolysaccharide stimulated monocytes and alveolar macrophages was measured by ELISA. The effect of 30 U of IL-4 on the release of these cytokines was studied. Results: Lipopolysaccharide-stimulated monocytes released significantly fewer cytokines in patients with asthma than in control subjects. IL-4 significantly inhibited cytokine release by monocytes of both groups. Unstimulated alveolar macrophages from patients with asthma released more cytokines than those of control subjects. Lipopolysaccharide induced a significantly greater increase in cytokine release in alveolar macrophages of control subjects in comparison with asthmatic subjects. IL-4 abolished the release of cytokines in alveolar macrophages from control subjects and had a minimal inhibitory effect on alveolar macrophages from patients with asthma. Conclusions: Alveolar macrophages from patients with asthma are hyperreactive but less prone to lipopolysaccharide stimulation and IL-4-downregulation than those from normal subjects. (J ALLERGY CLIN IMMUNOL 1994;94:997-1005.)

The generation of nitric oxide by human monocytes has long been a subject of controversy because of the difficulty of rationalizing this production. In this work we evaluated the capacity of human monocytes to produce nitric oxide (NO) as measured by nitrite (NO2-) release. Resting unstimulated monocytes (2 106 cells/ml) were found to produce significant amounts of NO2- after 8 to 12 days in culture. This production appeared to be highly heterogeneous. Indeed, approximatively, 75% of monocytes from the different donors produced up to 10 μM NO2- and were considered low producers; the last 25% produced higher amounts of NO2- (from 10 to 110 μM) and were considered high producers. In any case the spontaneous production of NO2- by monocytes was overcome in the presence of 1 mM Nω-monomethyl-l-arginine (LNMMA). This inhibitory effect was reversed in the presence of an excess of l-arginine (5 mM), indicating that this process is effectively dependent on l-arginine metabolism. Because interleukin-4 (IL-4) is considered an important NO-regulatory cytokine, its regulatory effect on this spontaneous production of NO was also evaluated. In the presence of a defined dose of IL-4 (1 to 100 ng/ml) the spontaneous production of the high-producing population of monocytes was abrogated, whereas IL-4 stimulated the production by the low-producing population of monocytes, which was suppressed in the presence of LNMMA. The present data indicate that NO production by human monocytes is heterogeneous and that IL-4 can be a potent inducer or inhibitor of this production, suggesting a variability in the activation state of these cells. J. Leukoc. Biol. 56: 15–20; 1994.

SUMMARY An increased expression of HLA-DR and lCAM-1 molecules on bronchial epithelial cells has been observed in asthmatic patients. The aim of this study was to evaluate the localization and to quantify the spontaneous expression of HLA-DR and ICAM-1 on bronchial epithelial cells recovered by bronchial brushing of nine asthmatics and nine controls. Epithelial cells constituted over 95% of cells recovered as shown using an anticytokeralin MoAb. Expression of HLA-DR and ICAM-1 was studied using indirect immunofluorescence and confocal microscopy. The intensity of fluorescence of epithelial cells expressing HLA-DR and lCAM-1 was significantly (P< 0·003) increased in asthmatics. In asthmatics, but not in controls, the expression of both molecules was localized in the cytoplasm on the apicolateral portions of the cells. This study shows an up-regulation in the expression of HLA-DR and ICAM-1 molecules by bronchial epithelial cells from asthmatics and a localization of these molecules within the cell.

In the airways inflammation observed in asthma, activated macrophages are present in increased numbers. Adhesion molecules are required for the cell: cell contacts between leukocytes and endothelial cells or other leukocytes, and they are induced by inflammatory stimuli. We studied the expression of two adhesion molecules (ICAM-1 and LFA-1) on alveolar macrophages recovered by bronchoalveolar lavage from 11 normal subjects and 13 asthmatic patients by using immunocytochemistry. Two specific monoclonal antibodies were used, and the reaction was revealed by the alkaline phosphatase-antialkaline phosphatase (APAAP) method. The percentage of cells expressing ICAM-1 or LFA-1 was significantly increased in asthmatic patients, as compared with normal subjects (P < 0.001 and P < 0.002, respectively; Mann-Whitney U test), and there was a significant correlation with the percentage of cells expressing both markers in asthma (P < 0.03, Spearman rank test). This study highlights the importance of macrophages in the inflammation of asthma and suggests that macrophage interactions with other cells play a role in this inflammation.

Histamine is a major mediator of the mast cells that are present between epithelial cells in asthma. In asthma, there is an increased expression of ICAM-1 and HLA-DR and an increased spontaneous release of fibronectin. The effect of histamine was tested on bronchial epithelial cells obtained by bronchial brushing from 22 nonasthmatic subjects. The activation of epithelial cells was assessed by immunocytochemical analysis of the expression of membrane markers (ICAM-1 and HLA-DR) using the alkaline phosphatase-anti-alkaline phosphatase method and the release of fibronectin (enzyme immunoassay). Time-response (three experiments) and dose-response (six experiments) curves showed that the maximal effect was obtained after an incubation time of 24 h and a dose of 1 microM of histamine. For this time course and concentration, there was a highly significant increase in the number of cells expressing ICAM-1 (before histamine: 10 +/- 11%; after histamine: 32 +/- 20%; P0.001) and HLA-DR (before histamine: 8 +/- 7%; after histamine: 23 +/- 20%; P0.001) and in the release of fibronectin (before histamine: 30 +/- 20 ng/10(5) viable cells; after histamine: 61 +/- 35 ng/10(5) viable cells; P0.003). Cycloheximide blocked these effects, suggesting that histamine requires protein synthesis for its action. Pyrilamine (H1-blocker) and ranitidine (H2-blocker) at a concentration of 10 microM decreased the effect of histamine. However, there was no additive effect when both antagonists were added. This study suggests that mast cells present in the airways have a role in the activation of epithelial cells.

Bronchial epithelial cells may be involved in the pathogenesis of asthma releasing several inflammatory mediators such as interleukins and lipoxygenase products. In this study we evaluated the spontaneous and A23128-induced release of 15-HETE, PGE2 and fibronectin as well as the spontaneous expression of HLA-DR and ICAM-1 molecules by bronchial epithelial cells obtained by bronchial brushing from 35 asthmatic and 27 normal subjects. The release of fibronectin and 15-HETE was studied using the EIA and RIA techniques. The expression of HLA-DR and ICAM-1 molecules was studied using the APAAP and the immunofluorescence methods. Bronchial epithelial cells from asthmatics released higher amounts of 15-HETE and fibronectin both spontaneously (p < 0.002, p < 0.05, respectively) or after stimulation with calcium ionophore compared with normals. On the other hand, PGE2 release was significantly higher only after stimulation with calcium ionophore (p < 0.002). The spontaneous expression of HLA-DR and ICAM-1 (p < 0.001) was significantly higher on epithelial cells from asthmatics than in normal subjects. Finally, the severity of asthma significantly correlated with the release of 15-HETE (p < 0.02) and the expression of HLA-DR and ICAM-1 respectively (p < 0.001 and p < 0.002, respectively). This study indicates that bronchial epithelial cells are in an activated state in asthma and that the degree of activation is correlated to the severity of the disease.

Spanevello and colleagues claim that a methacholine inhalation challenge carried out one hour before sputum induction in patients with stable asthma does not significantly alter the cellular, eosinophil cationic protein (ECP), or albumin constituents of sputum.1 These results, if correct, are important for both clinical practice and clinical trials where information regarding airway hyperresponsiveness and inflammation is needed. Being able to perform a methacholine challenge and sputum induction on the same day would be convenient. Sixteen subjects with asthma were studied on …

L'asthme est l'une des affections chroniques les plus frequentes et represente un probleme de sante publique mondial. L'apport de la recherche epidemiologique, fondamentale et clinique a abouti a une reduction de la severite de l'asthme au cours de ces dix dernieres annees. L'asthme est un syndrome multifactoriel a determinisme genetique dans lequel interviennent des facteurs de l'environnement dont les allergenes. L'allergie est la cause la plus frequente de l'asthme et les premiers travaux de genetique se sont focalises sur les genes de la reponse immune a l'allergene. Les cytokines de type Th2, representees par les interleukines IL-4, IL-5 et IL-13, sont responsables de l'allergie dans l'asthme. L'inflammation bronchique est complexe mettant en jeu l'ensemble des cellules de l'arbre bronchique et des cellules inflammatoires. Il existe des similitudes entre asthme allergique et non allergique comme le demontrent les etudes de biopsies bronchiques dans lesquelles les eosinophiles et le recepteur des IgE sont presents. La severite de l'asthme est liee a court terme au bronchospasme, a moyen terme a l'inflammation bronchique et, a long terme, au remodelage anormal des voies aeriennes. Les tres nombreux travaux de recherche qui ont ete realises depuis 20ans ont permis d'apprecier l'importance de l'inflammation et du remodelage bronchique et d'orienter la strategie therapeutique vers le traitement anti-inflammatoire.

Deep inspirations have the ability to dilate constricted airways. The impairment of this function has been associated with the occurrence of asthmatic symptoms. We evaluated whether the bronchodilatory effect of deep inspiration (DI) is affected by aging. We tested 25 healthy subjects (median age: 54 yrs, range: 25–83 yrs). Single dose methacholine (Mch) provocations were performed in the absence of DI, which induced at least 15% reduction in inspiratory vital capacity (IVC) from baseline. The post-Mch IVC measurement was followed by 4 DIs and by another IVC (post-DI IVC). The fractional difference between post-DI IVC and post-Mch IVC represented the % bronchodilation by DI. The % bronchodilation significantly diminished with aging (r=0.65, P=0.0005). The bronchodilatory ability of DI was also positively associated with the degree of Mch-induced reduction in IVC (r=0.84, P