Search

The goal of this project was to determine if different body conditions in late gestation that are due to varying body conditions at mating affect mammary development and mammary gene expression of gilts. Gilts that were fed ad libitum in the growing period were selected based on their backfat depths to form 3 groups at mating, namely, low backfat (LBF; 12-15 mm; = 14), medium backfat (MBF; 17-19 mm; = 15), and high backfat (HBF; 22-26 mm; = 16). During gestation, LBF, MBF, and HBF gilts were fed approximately 1.25, 1.43, and 1.63 times maintenance requirements to maintain their differences in body condition. Feed intake was increased by 1 kg in the last 10 d of gestation. Backfat depths of gilts were ultrasonically measured at mating and on d 30, 50, 70, 100, and 109 of gestation. Blood samples were obtained at mating and on d 109 of gestation to measure concentrations of IGF-1, glucose, insulin, estradiol, urea, free fatty acids, leptin, and adiponectin. Gilts were slaughtered on d 110 of gestation to collect mammary glands for compositional analyses. Mammary extraparenchymal tissue weight was lesser in LBF and MBF gilts than in HBF gilts (1,259.3, 1,402.7, and 1,951.5 ± 70.4 g, respectively; 0.10), but its composition was altered. Concentrations of DNA and RNA decreased as backfat depth increased ( 0.10) with the exception of , which had a greater expression level in LBF gilts than in MFB or HBF gilts ( < 0.05). Percent of Ki-67-positive cells, used to assess mammary cell proliferation rate, was greater in HBF gilts than in LBF gilts ( < 0.05). When differences in body conditions of gilts that were present at mating were maintained throughout gestation, it had an impact on mammary development. Extraparenchymal tissue mass was affected and, more importantly, composition of parenchymal tissue was altered, indicating a beneficial effect of gilts being in the thinner treatment groups at mating.

The impact of body condition at 110 d of gestation on mammary gland development, mammary gene expression, and hormonal and metabolite status of gilts was studied. Thirty-nine gilts were equally divided into 3 groups based on their backfat thickness at the end of gestation: 1) low backfat (LBF; 12-15 mm), 2) medium backfat (MBF; 17-19 mm), or 3) high backfat (HBF; 21-26 mm). Gilts had similar BW (138.1 ± 8.2 kg) and backfat thicknesses (16.4 ± 1.0 mm) at mating and the 3 groups were achieved via ingestion of varying amounts of feed throughout gestation. Jugular blood samples were obtained from all gilts at mating and at 109 d of gestation to assess hormonal and metabolic statuses, and animals were slaughtered on d 110 to collect mammary glands for compositional analyses and for measure of gene expression. The LBF gilts had less extraparenchymal tissue ( 0.10). There was a tendency for circulating leptin concentrations on d 109 of gestation to be lower in LBF gilts than in MBF gilts ( 0.10). Current results demonstrate that being too thin at the end of gestation (12-15 mm backfat) has a negative impact on mammary development in gilts, whereas having backfats varying from 17 to 26 mm seems to have no detrimental effects on mammogenesis. Backfat thickness in late pregnancy must therefore be considered to achieve optimal sow lactation performance.

SUMMARY The pleural space is a virtual compartment between the lung and chest wall that becomes filled with fluid and inflammatory cells during a variety of respiratory diseases. Here, we study the potential role of the eicosanoid metabolite leukotriene B4 (LTB4) in disparate diseases leading to acute (pneumonia) or chronic (tuberculosis, cancer) inflammation of the pleural space. LTB4 concentrations were significantly higher in pleural fluid due to pneumonia, tuberculosis and cancer with respect to congestive heart failure and correlated with neutrophil elastase, which is used as an indication of state of activation of neutrophils in the pleural space. Moreover, pleural LTB4 was biologically active, as an anti-LTB4 antibody partially neutralized the chemotactic activity of parapneumonic, tuberculous and cancer effusions. Macrophages, neutrophils, lymphocytes, mesothelial cells and cancer cells all expressed mRNA for 5-lipoxygenase, the enzyme that initiates leukotriene synthesis leading to the production of LTB4, in exudative pleural effusions. Upon stimulation in transudative pleural effusions, pleural macrophages produced, in a time-dependent fashion, a significantly higher concentration of LTB4 than mesothelial cells. These studies demonstrate that different cell types are capable of producing LTB4 in the inflamed pleural space and that this mediator may play a crucial role in the recruitment of neutrophils into the pleural space.

The goal of this project was to determine if different body conditions in late gestation that are due to varying body conditions at mating affect mammary development and mammary gene expression of gilts. Gilts that were fed ad libitum in the growing period were selected based on their backfat depths to form 3 groups at mating, namely, low backfat (LBF; 12-15 mm; = 14), medium backfat (MBF; 17-19 mm; = 15), and high backfat (HBF; 22-26 mm; = 16). During gestation, LBF, MBF, and HBF gilts were fed approximately 1.25, 1.43, and 1.63 times maintenance requirements to maintain their differences in body condition. Feed intake was increased by 1 kg in the last 10 d of gestation. Backfat depths of gilts were ultrasonically measured at mating and on d 30, 50, 70, 100, and 109 of gestation. Blood samples were obtained at mating and on d 109 of gestation to measure concentrations of IGF-1, glucose, insulin, estradiol, urea, free fatty acids, leptin, and adiponectin. Gilts were slaughtered on d 110 of gestation to collect mammary glands for compositional analyses. Mammary extraparenchymal tissue weight was lesser in LBF and MBF gilts than in HBF gilts (1,259.3, 1,402.7, and 1,951.5 ± 70.4 g, respectively;0.01). The weight of parenchymal tissue was not affected by treatment (0.10), but its composition was altered. Concentrations of DNA and RNA decreased as backfat depth increased (0.05), whereas percent fat and DM increased (0.05). Circulating concentrations of leptin tended to be lower at mating (0.10) and were lower on d 109 of gestation (0.05) in LBF gilts than in HBF gilts. On d 109 of gestation, concentrations of insulin (0.01) and IGF-1 (0.05) were lower in LBF and MBF gilts than in HBF gilts, whereas those of urea were greater (0.05). The mRNA abundance in parenchymal tissue for all genes studied was not affected by treatments (0.10) with the exception of , which had a greater expression level in LBF gilts than in MFB or HBF gilts (0.05). Percent of Ki-67-positive cells, used to assess mammary cell proliferation rate, was greater in HBF gilts than in LBF gilts (0.05). When differences in body conditions of gilts that were present at mating were maintained throughout gestation, it had an impact on mammary development. Extraparenchymal tissue mass was affected and, more importantly, composition of parenchymal tissue was altered, indicating a beneficial effect of gilts being in the thinner treatment groups at mating.

The impact of body condition at 110 d of gestation on mammary gland development, mammary gene expression, and hormonal and metabolite status of gilts was studied. Thirty-nine gilts were equally divided into 3 groups based on their backfat thickness at the end of gestation: 1) low backfat (LBF; 12-15 mm), 2) medium backfat (MBF; 17-19 mm), or 3) high backfat (HBF; 21-26 mm). Gilts had similar BW (138.1 ± 8.2 kg) and backfat thicknesses (16.4 ± 1.0 mm) at mating and the 3 groups were achieved via ingestion of varying amounts of feed throughout gestation. Jugular blood samples were obtained from all gilts at mating and at 109 d of gestation to assess hormonal and metabolic statuses, and animals were slaughtered on d 110 to collect mammary glands for compositional analyses and for measure of gene expression. The LBF gilts had less extraparenchymal tissue (0.01) and parenchymal tissue (0.05) than HBF gilts. Mammary parenchyma from LBF gilts also tended to contain less DM (0.10), contained more protein (0.05), and had greater RNA concentrations (0.01) than that from HBF gilts. None of the 15 genes studied in mammary parenchymal tissue differed in terms of expression level, and the rate of mammary cell proliferation was similar among treatments (0.10). There was a tendency for circulating leptin concentrations on d 109 of gestation to be lower in LBF gilts than in MBF gilts (0.10), whereas values for HBF gilts did not differ from those of the other treatments (0.10). Current results demonstrate that being too thin at the end of gestation (12-15 mm backfat) has a negative impact on mammary development in gilts, whereas having backfats varying from 17 to 26 mm seems to have no detrimental effects on mammogenesis. Backfat thickness in late pregnancy must therefore be considered to achieve optimal sow lactation performance.

BACKGROUND: Smoking induces structural changes in the airways, and is considered a major factor in the development of airflow obstruction in chronic obstructive pulmonary disease. However, differences in inflammatory cell distribution between large airways (LA) and small airways (SA) have not been systematically explored in smokers. Hypothesis: The content of cells infiltrating the airway wall differs between LA and SA. AIMS: To compare the content of neutrophils, macrophages, lymphocytes and mast cells infiltrating LA and SA in smokers who underwent surgery for lung cancer. METHODS: Lung tissue from 15 smokers was analysed. Inflammatory cells in the lamina propria were identified by immunohistochemical analysis, quantified by digital image analysis and expressed as number of cells per surface area. RESULTS: The number of neutrophils infiltrating the lamina propria of SA (median 225.3 cells/mm(2)) was higher than that in the lamina propria of LA (median 60.2 cells/mm(2); p

The reaction of lithium salts of ring-fused ligands (L), where the ring fused to the cyclopentadienyl moiety is a saturated one (six, seven, or eight carbon atoms), with YCl3 in THF in 2:1 and 1:1 molar ratios affords complexes of formula [L2YCl]2 and [(LYCl2·THF)2LiCl·2THF], respectively. Here we report the synthesis, spectroscopic characterization, and X-ray crystal structure of [(L′YCl2·THF)2LiCl·2THF] (L′ = 2-phenyl-4,5,6,7,8-hexahydroazulenyl), together with the crystal structure of the hexameric species [{L′YCl(OH)}6·2THF], which was quite unexpectedly isolated during the attempted crystallization of the latter complex and is probably formed by partial hydrolysis of that complex. The activity of the new complexes towards ethylene and 1-hexene polymerization reactions was also tested. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

This consensus document is aimed at reviewing evidence that the rhinitis-asthma links have peculiar features in athletes. Beside a review of epidemological data on the high prevalence of rhinitis and asthma in athletes, the effects on intense physical exercise on the immune system and repiratory functions are discussed, with special reference to the role of allergens and pollutants. In extending the Allergic Rhinitis and its Impact on Asthma (ARIA) recommendations to athletes, the issue is addressed of adapting diagnosis and management to criteria set by the International Olympic Committee (IOC) and regulations adopted by the World Anti-Doping Agency (WADA).

We evaluated the aberrant promoter methylation profile of a panel of 3 genes in DNA from tumor and sputum samples, in view of a complementary approach to spiral computed tomography (CT) for early diagnosis of lung cancer. The aberrant promoter methylation of RARbeta2, p16(INK4A) and RASSF1A genes was evaluated by methylation-specific PCR in tumor samples of 29 CT-detected lung cancer patients, of which 18 had tumor-sputum pairs available for the analysis, and in the sputum samples from 112 cancer-free heavy smokers enrolled in a spiral CT trial. In tumor samples from 29 spiral CT-detected patients, promoter hypermethylation was identified in 19/29 (65.5%) cases for RARbeta2, 12/29 (41.4%) for p16(INK4A) and 15/29 (51.7%) for RASSF1A. Twenty-three of twenty-nine (79.3%) samples of the tumors exhibited methylation in at least 1 gene. In the sputum samples of 18 patients, methylation was detected in 8/18 (44.4%) for RARbeta2 and 1/18 (5%) for both RASSF1A and p16(INK4A). At least 1 gene was methylated in 9/18 (50%) sputum samples. Promoter hypermethylation in sputum from 112 cancer-free smokers was observed in 58/112 (51.7%) for RARbeta2 and 20/112 (17.8%) for p16, whereas methylation of the RASSF1A gene was found in only 1/112 (0.9%) sputum sample. Our study indicates that a high frequency of hypermethylation for RARbeta2, p16(INK4A) and RASSF1A promoters is present in spiral CT-detected tumors, whereas promoter hypermethylation of this panel of genes in uninduced sputum has a limited diagnostic value in early lung cancer detection.

The reaction between [LNYX]2 [X = Cl, OTf; LN = 2,6-pyridinediylbis(methylcyclopentadienyl] and L'Na2 [L' = LN = 2,6-pyridinediylbis(methylcyclopentadienyl; LSi = dimethylsilanediylbis(cylopentadienyl); LO = 2,5-furanediylbis(methylcyclopentadienyl)] in a 2:1 molar ratio affords dinuclear complexes of formula (LY)2(μ-L'), in which the ansa-bis(cyclopentadienyl) ligands simultaneously act both in a chelating and bridging mode. The X-ray crystal structure of (LNY)2(μ-LN), determined at 193 K shows an arrangement close to trigonal planar of the centroids Cg of the three Cp ligands around the Y atoms. The reactivity of the (LNLn)2(μ-L') species containing different bridging ansa-bis(cyclopentadienyl) groups with an additional free donor atom was tested to verify the possibility of coordination of a third lanthanide ion. The rearrangement reactions that occur, finally leading to the formation of the only [LNLnX]2 species, are likely to depend on the presence of the further coordinating atom in the ligand bridging the two metal ions. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Effector memory T-cells (CD45RO+) may provide pro-inflammatory signals that contribute to the persistent airway inflammation that is characteristic of asthma, and reduced apoptosis of these cells may prolong their effects. The present authors compared apoptosis of CD45RO+ T-cells in the inner airway wall in nonfatal asthma (n = 7), fatal asthma (n = 7) and control (n = 8) cases. Apoptotic cells were identified using both the terminal deoxynucleotidyl transferase dNTP nick end-labelling (TUNEL) technique and cell morphology. The percentage of CD45RO+ T-cells that were apoptotic was significantly greater in control cases compared with nonfatal and fatal cases of asthma, respectively, in small (42+/-19, 16+/-9, 7+/-6%), medium (40+/-12, 15+/-11, 12+/-8%) and large airways (42+/-15, 23+/-18, 18+/-12%). The reduction in the percentage of apoptotic CD45RO+ cells in the cases of asthma was observed in both blood vessels and the interstitium in large airways. In conclusion, these data suggest that reduced apoptosis may prolong the active life of effector memory T-cells in the airways. It is possible that survival signals may be received before cells migrate into the interstitium of the inner airway wall.

Corticosteroids play an important role in inflammation and remodelling of airways and are considered an important therapeutic target in asthma. Inflammation in asthma is characterized by a dysregulation of eosinophil apoptosis and of markers of airways remodelling. We evaluated the ability of flunisolide to inhibit in vitro the release of metalloproteinases-9 (MMP-9), tissue inhibitor metalloproteinases-1 (TIMP-1), transforming growth factor (TGF-beta) and fibronectin by sputum cells (SC) as well as to induce sputum eosinophil apoptosis.The SC, isolated from induced sputum samples of 12 mild-to-moderate asthmatics, were cultured for 24 h in the presence or absence of flunisolide (1, 10 and 100 microM). The release of mediators was assessed by enzyme-linked immunosorbent assay (ELISA) whereas apoptosis was studied by TUNEL technique.Flunisolide (10 microM) significantly reduced MMP-9 and TIMP-1 (P = 0.0011 and P0.0001 respectively) and increased MMP-9/TIMP-1 molar ratio (P = 0.004). In addition, flunisolide decreased TGF-beta and fibronectin release by SC (P = 0.006; and P0.0001 respectively) and increased eosinophil apoptosis (P0.001).These results demonstrate that flunisolide may play an important role in the inhibition of airway inflammation and remodelling, by promoting the resolution of eosinophilic inflammation and by inhibiting the release of MMP-9, TIMP-1, TGF-beta and fibronectin.

The possible roles of dietary protein level and feed restriction in regulating mammary development of prepubertal gilts were investigated. Cross-bred gilts were fed a commercial diet until 90 d of age and then divided into four nutritional regimens based on two pelleted diets (as-fed basis): a high-protein diet (HP = 13.8 MJ of ME, 1.0% total lysine, 18.7% CP) and a low-protein diet (LP = 13.8 MJ of ME, 0.7% total lysine, 14.4% CP). Nutritional regimens were as follows: 1) HP ad libitum until slaughter (n = 22, T1); 2) HP ad libitum until 150 d of age followed by LP until slaughter (n = 20, T2); 3) LP ad libitum until slaughter (n = 21, T3); and 4) HP with a 20% feed restriction until slaughter (n = 19, T4). Gilts were weighed, their backfat thickness was measured, and jugular blood samples were obtained on d 90, 150, and at slaughter to determine concentrations of prolactin, IGF-I, leptin, and glucose. Gilts were slaughtered 8+/-1 d after their first or second estrus (202.7+/-14.5 d of age). Mammary glands were excised, parenchymal and extraparenchymal tissues were dissected, and composition of parenchymal tissue (protein, fat, DM, DNA, protein/DNA) was determined. The T4 gilts weighed less (P < 0.01) and had less backfat (P < 0.01) than did gilts on other treatments on d 150 and at slaughter. Treatments had no significant effects on prolactin, IGF-I, or glucose concentrations, but there was a treatment x day interaction (P < 0.01) for leptin, with concentrations being lower at slaughter in restricted-fed (T4) vs. LP (T3) gilts (P < 0.05). There was less extraparenchymal mammary tissue (P < 0.01) in T4 gilts than in gilts from the other groups and a tendency (P = 0.13) for the amount of parenchymal tissue to be lower in T4 gilts. In conclusion, a lower lysine intake during prepuberty did not hinder mammary development of gilts, but a 20% feed restriction decreased mass of parenchymal and extraparenchymal tissues. The effect of feed restriction on extraparenchymal tissue is most likely associated with the lower fat deposition.

Background: Anti-IgE therapy could be particularly beneficial for patients with concomitant disease as it targets a common factor in both diseases. The aim of this study was to evaluate the efficacy and safety of omalizumab in patients with concomitant moderate-to-severe asthma and persistent allergic rhinitis. Methods: This multicentre, randomized, double-blind, parallel-group, placebocontrolled trial evaluated the safety and efficacy of omalizumab. A total of 405 patients (12–74 years) with a stable treatment (‡ 400 lg budesonide Turbuhaler � )a nd‡ 2 unscheduled medical visits for asthma during the past year or ‡ 3 during the past 2 years were enrolled. Patients received omalizumab (‡ 0.016 mg/kg/IgE [IU/ml] per 4 weeks) or placebo for 28 weeks. Results: Fewer patients treated with omalizumab experienced asthma exacerbations (20.6%) than placebo-treated patients (30.1%), P ¼ 0.02. A clinically significant (‡ 1.0 point) improvement in both Asthma Quality of Life Questionnaire and Rhinitis Quality of Life Questionnaire occurred in 57.7% of omalizumab patients compared with 40.6% of placebo patients (P < 0.001). Omalizumab reduced Wasserfallen symptom scores for asthma (P ¼ 0.023), rhinitis (P < 0.001) and the composite asthma/rhinitis scores (P < 0.001) compared with placebo. Serious adverse events were observed in 1.4% of omalizumab-treated patients and 1.5% of placebo-treated patients. Conclusion: Omalizumab is well tolerated and effective in preventing asthma exacerbations and improving quality of life in patients with concomitant asthma and persistent allergic rhinitis.

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.

Background: To investigate whether nasal and bronchial inflammation coexists in chronic obstructive pulmonary disease (COPD), nasal and bronchial biopsy specimens from seven control subjects, seven smokers without COPD, and 14 smokers with COPD were studied. Methods: Nasal and bronchial biopsy specimens were taken from the same patients during bronchoscopy and squamous cell metaplasia and the thickness of the epithelium and basement membrane were measured. The numbers of eosinophils (EG2), neutrophils (elastase), macrophages (CD68), and CD8 T lymphocytes (CD8/144B) were assessed by immunohistochemistry. Results: Smokers with and without COPD had squamous metaplasia in the nasal and bronchial epithelium. In all groups the thickness of the nasal epithelium was greater than that of the bronchial epithelium. The thickness of the basement membrane was similar in nasal and bronchial biopsy specimens from smokers with and without COPD, but was greater in the bronchi than in the nasal epithelium of controls. Eosinophil number was higher in the nasal and bronchial mucosa of smokers without COPD than in smokers with COPD or controls. Neutrophil number was higher in the nasal and bronchial mucosa of smokers with COPD than in smokers without COPD or controls. CD8 T lymphocyte numbers were similar in smokers with and without COPD and higher than in controls. There were fewer macrophages in nasal and bronchial biopsy specimens from smokers without COPD than in those with COPD. Conclusion: Nasal and bronchial inflammation coexists in smokers and is characterised by infiltration of CD8 T lymphocytes. In smokers without COPD this feature is associated with an increased number of eosinophils, while in those with COPD it is linked to an increased number of neutrophils in both nasal and bronchial biopsy specimens.

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.

Asthma has been associated with an exaggerated T-helper type 2 (Th2) over Th1 responses to allergic and nonallergic stimuli, which leads to chronic airway inflammation and airway remodeling. In the present article, we propose that many of the genes involved in IgE synthesis and airways (re)modeling in asthma are persistent or reminiscent fetal genes which may not be silenced during early infancy (or late pregnancy). Genes of the embryologic differentiation of ectodermic and endodermic tissues may explain some of the patterns of airway remodeling in asthma. In utero programming leads to gene expression, the persistence of which may be associated with epigenetic inheritance phenomena induced by nonspecific environmental factors. Clear delineation of these issues may yield new information on the mechanisms of asthma and new targets for therapeutic intervention and primary prevention.

The paper analyses the Made in Italy effect on Chinese consumer buying behavior regarding three specific product categories: wine, shoes and ceramic tiles. A research model aimed at testing the multidimensional dimensions featuring Country of Origin (COO) – overall Country Image (CI), Product Country Image (PCI) and Country Related Product Image (CRPI) – on the Chinese consumer intention to buy these Italian products is applied, verifying the level of consistency (FIT) between the products investigated and the country in which these products originated (Italy). Four-hundred and fifty questionnaires on Chinese consumers were collected and the data processed to test the model by applying structural equations modelling. Results show that Made in Italy influences the Chinese consumers’ intention to buy the Italian products observed through causal links: the Italy country image (CI) impacts on buying intentions through the mediating role of the Italian ability to manufacture products – in general (PCI) and regarding a specific product category (CRPI). Results also confirm the consistency (FIT) between the products investigated and the Italian origin. Scientific and managerial implications are derived.

The transcription factor nuclear factor-kappaB (NF-kappaB) is inactive when bound to its inhibitory protein IkappaBalpha. On cell stimulation with inflammatory signals, IkappaBalpha is phosphorylated by IkappaB kinases and subsequently degraded. Freed NF-kappaB then induces expression of cytokines such as granulocyte-macrophage colony-stimulating factor, interleukin-8, and regulated upon activation, normal T cell expressed and secreted. These mediators are overexpressed in asthma and are downregulated by glucocorticoids through NF-kappaB activity repression. However, high levels of granulocyte-macrophage colony-stimulating factor, interleukin-8, and regulated upon activation, normal T cell expressed and presumably secreted are released by peripheral blood mononuclear cells isolated from patients with severe asthma despite continuous systemic glucocorticoid treatment. We report that these mediators are markedly decreased by pyrrolidinedithiocarbamate, an inhibitor of NF-kappaB activation. To further characterize the persistent NF-kappaB activation in severe asthma, we analyzed the expression of various components of this activation pathway in healthy subjects and in asthmatics with mild controlled, and moderate and severe uncontrolled disease. We found high amounts of phosphorylated IkappaBalpha characterizing the three asthmatic groups. Western blot analyses indicated that in peripheral blood mononuclear cells the IkappaB kinase beta and p65 levels were greater in moderate and severe asthmatics than in normal subjects. Electrophoretic mobility shift assay and immunocytochemistry showed a greater activation status of p65 in severe asthmatics. Our data suggest that exaggerated NF-kappaB activation perpetuates inflammatory mediators production in severe asthma.

Since severe asthma is a poorly understood, major health problem, 12 clinical specialist centres in nine European countries formed a European Network For Understanding Mechanisms Of Severe Asthma (ENFUMOSA).In a cross-sectional observational study, a total of 163 subjects with severe asthma were compared with 158 subjects whose asthma was controlled by low doses of inhaled corticosteroids (median dose of beclomethasone equivalents 666 mug). Despite being treated with higher doses of inhaled corticosteroids; (median dose 1773 mug) and for a third of the severe asthmatics also being treated with regular, oral-steroid therapy (median daily dose 19 mg), the subjects with severe asthma met the inclusion criteria. The criteria required subjects to have undergone at least one asthma exacerbation in the past year requiring oral steroid treatment. Females dominated the severe asthma group (female/male ratio 4.4:1 versus 1.6:1 in the controlled asthmatics), and compared with controlled asthmatics, they had a predominantly neutrophilic inflammation (sputum neutrophils, 36 versus 28%) and evidence of ongoing mediator release but less atopy.From these findings and other physiological and clinical data reported in this paper, it is suggested that severe asthma might be a different form of asthma rather than an increase in asthma symptoms. The findings prompt for longitudinal studies and interventions to define the mechanisms in severe asthma.

To evaluate the relationship between inflammatory markers and severity of asthma in children, the amount of interleukin-8 (IL-8) and granulocyte/macrophage colony-stimulating factor (GM-CSF) released by peripheral blood mononuclear cells, exhaled nitric oxide (FE NO) levels, p65 nuclear factor-kappaB subunit, and phosphorylated IkBalpha expression by peripheral blood mononuclear cells were assessed in six control subjects, 12 steroid-naives subjects with intermittent asthma, and 17 children with moderate asthma. To investigate their predictive value, biomarker levels were correlated with the number of exacerbations during a 18-month follow-up period. We found that GM-CSF release was higher in moderate and intermittent asthmatics than in control subjects, whereas IL-8 release was higher in moderate than in intermittent asthmatics and control subjects. FE NO levels were similar among study groups. In moderate asthmatics, IL-8, GM-CSF, and FE NO significantly correlated with the exacerbation numbers. Moreover, p65 and phosphorylated IkBalpha levels were greater in moderate than in intermittent asthmatics and control subjects. According to GM-CSF, IL-8, and FE NO levels, two distinct subgroups of moderate asthmatics (low and high producers) were identified. High producers experienced more exacerbations than low producers. This study shows ongoing inflammation associated with biological and clinical heterogeneity in moderate asthmatics despite regular treatment and proposes that large prospective studies confirm the importance of biomarkers to assess inflammation and asthma control in children with asthma.

Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that plays a crucial role in cell-cell interactions involved in the recruitment of cells and immune responses. Under some circumstances, ICAM-1 is found as a soluble protein that has the potential to influence the nature of immunoinflammatory responses. By examining cells and fluid from the pleural compartment of patients with cancer, tuberculosis, and congestive heart failure, the cellular source, conformation, control, and biological activity of soluble ICAM-1 (sICAM-1) were investigated. The results suggest that dimeric sICAM-1 was released locally in the pleural compartment of tuberculous and malignant effusions. sICAM-1 was shed from preexpressed surface ICAM-1 rather than produced de novo, and both CD45-positive leukocytes and cytokeratin-positive epithelial and mesothelial cells expressed ICAM-1, suggesting multiple cellular sources for sICAM-1. The expression of sICAM-1 was regulated because pleural macrophages caused release of sICAM-1 via a tumor necrosis factor-alpha-dependent mechanism. The functional significance of sICAM-1 was demonstrated by showing that pleural sICAM-1 interfered with conjugate formation between LAK cells and K562 cells, suggesting that pleural sICAM-1 plays an immunosuppressive role by inhibiting adhesion of cytotoxic lymphocytes and tumor cells. Thus, sICAM-1 is shed from the surface of cells in a regulated manner and has the potential to influence the immune response in the pleural space.

Summary Most patients with asthma also have rhinitis, and the same inflammatory cells and mechanisms are present in bronchial and nasal mucosa, thus leading to the concept of ‘one airway, one disease’. This concept is further substantiated by evidence of nasal inflammation in asthma, and bronchial inflammation and hyperresponsiveness in rhinitis. Endobronchial allergen challenge induces nasal and bronchial symptoms as well as reductions in pulmonary function and nasal patency. Likewise, treating rhinitis can improve the symptoms of asthma. There are some notable pathophysiological differences between the nose and the bronchi, for example airway remodelling appears to be less extensive in the nasal mucosa than in the bronchial mucosa. But, in spite of this, it is widely recognized that interrelated mechanisms contribute across the asthma–rhinitis disease spectrum. Of particular note is that the same pro-inflammatory mediators (e.g. cysteinyl leukotrienes, cytokines, histamine) are involved in nasal and bronchial inflammation, in patients with rhinitis and asthma. It appears there are ‘bidirectional’ relationships between nasal and bronchial inflammation, and that biological events occurring in the nose or lung promote widespread responses, thus mimicking a systemic disease.

Background: The recovery of mediator metabolites from urine has the potential to provide a rapid, safe, and easily available index of release of mediators. We aimed to determine urinary metabolites of both histamine and leukotrienes (LTs) in patients affected by chronic urticaria (CU). Methods: Twenty patients with CU were studied. They were selected on the basis of double-blind placebo-controlled challenge (DBPC) with acetyl salicylic acid (ASA) and food additives. Ten patients (group B) were negative to both challenges. Ten patients (group C) presented urticaria and/or the appearance of angioedema during or 24 h after challenge, with reactions to ASA (five patients) or food additives (five patients). We recruited 15 healthy volunteers as controls (group A). During a second challenge, groups B and C were challenged double-blind with a single dose of ASA, or a specific food additive, or placebo. The healthy group was challenged only with a placebo (talc capsule). Patients in groups B and C were challenged twice: with placebo (as groups B1 and C1) and with ASA (groups B2 and C2) or food additives (C2). Four samples of urine were collected; one during the night before the specific or sham challenge (baseline), and three at 2, 6 and 24 h after the challenge. Urinary methylhistamine (N-MH) and LTE4 were analyzed and normalized for urinary creatinine. Results: For urinary N-MH at baseline, there was a significant difference only between group A and groups B1, B2, C1 and C2 (A vs. B1, P

The aim of this study was to evaluate the consequences of interleukin (IL)-4-induced 15-lipoxygenase (15-LO) expression on leukotriene B4 (LTB4) synthesis in human monocytes. Human monocytes incubated for 24, 48, and 72 h with IL-4 (10 ng/ml) were stimulated with Ca2+-ionophore A23187 (calcimycin; 5 μM) or opsonized zymosan. 15( S )-hydroxyeicosatetraenoic acid [15( S )-HETE], LTB4, and arachidonic acid (AA) release were measured by high-performance liquid chromotography/radioimmunoassay, liquid chromotography/tandem mass spectrometry (LC/MS/MS), or gas chromatography/mass spectrometry. 15-LO activity was evaluated in AA-treated monocytes. 15-LO, 5-lipoxygenase (5-LO) and 5-LO activating protein (FLAP) expression were analyzed by reverse transcription-polymerase chain reaction. Neutrophil chemotactic activity was evaluated using a microtaxis chamber assay. A23187-induced synthesis of 15( S )-HETE was significantly increased after treatment with IL-4 (10 ng/ml) for 48 and 72 h ( p < 0.001). Concomitant decrease of LTB4 release was observed after 72 h of incubation with IL-4 ( p < 0.001). LC/MS/MS analysis confirmed the production of 15( S )-HETE and the significant inhibition of LTB4 synthesis in IL-4-treated monocyte after challenge with opsonized zymosan. IL-4 treatment induced 15-LO enzymatic activity as well as 15-LO mRNA, but did not affect either 5-LO or FLAP mRNA expression in monocytes. Supernatant from IL-4-treated monocytes showed significantly lower neutrophil chemotactic activity than controls. 15( S )-HETE significantly inhibited LTB4 production induced by A23187-stimulated human monocytes without affecting AA release. IL-4-induced expression of 15-LO in monocytes caused a significant reduction of LTB4 production. Whereas this effect did not reflect changes in 5-LO and FLAP mRNA expression, synthetic 15( S )-HETE was able to significantly inhibit the synthesis of LTB4, without affecting AA release.

Apoptosis is an important mechanism allowing inflammation to be limited. Glucocorticoids are the most effective anti-inflammatory agents in asthma therapy and induce cell apoptosis. Since T-lymphocytes are critically involved in airway inflammation in asthma, the effects of fluticasone propionate (FP) on apoptosis in unstimulated and in interleukin (IL)-2 stimulated peripheral blood T-lymphocytes (PBTs) isolated from 14 normal and 19 mild-to-moderate asthmatic subjects were evaluated. Apoptosis was evaluated by: deoxyribonucleic acid (DNA) fragmentation electrophoresis, DNA content, annexin V binding, apoptosis related markers (Fas, B-cell lymphona leukaemia-2 (Bcl-2), Bax, and CD25), and by electron microscopy. FP induced apoptosis in unstimulated PBTs of normal and asthmatic subjects in a time-dependent fashion. In asthma, this effect was associated with a significant decrease of Bcl-2 expression, and with an increase of Bax/Bcl-2 ratio. In PBTs of asthmatics, FP also reduced Fas and CD25 expression. Moreover, in IL-2-stimulated PBTs from both asthmatics and normal subjects, FP was able to induce apoptosis and to reduce Bcl-2, Fas and CD25 expression, whereas negligible effects were detected on Bax expression. This study shows that the glucocorticosteroid, fluticasone, increases apoptosis and modulates expression of apoptosis-related markers in unstimulated and in interleukin-2 stimulated T-lymphocytes. This points towards a potential mechanism by which fluticasone exerts its anti-inflammatory effects.

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.

The inflammatory and remodelling processes that underlie asthma result from a highly complex interaction between various cell types. Apart from inflammatory cells, such as eosinophils, activated T cells, mast cells and macrophages, structural tissue cells such as epithelial cells, fibroblasts and smooth muscle cells can also play an important effector role through the release of a variety of mediators, cytokines and chemokines. This results in an acute inflammatory response that is characterized by vascular leakage, mucus hypersecretion, epithelial shedding and widespread airway narrowing. At the same time, through the release of mediators, cytokines, chemokines and growth factors, epithelial and mesenchymal cells cause persistence of the inflammatory infiltrate and induce structural changes in the airway wall, such as increased thickness of the basement membrane, increased collagen deposition, changes in bronchial microcirculation, and smooth muscle hypertrophy and hyperplasia. The end result of airway inflammation and remodelling is an increased thickness of the airway wall, leading to a reduced baseline airway calibre and exaggerated airway narrowing.

Background: Adhesion molecules are involved in inflammatory and repair processes of the bronchial epithelium. ICAM-1 is mainly involved in inflammatory reactions, whereas integrins, such as α3β1, are mainly involved in repair processes. Methods: Using bronchial biopsies from 10 asthmatics and eight controls, we first evaluated by immunohistochemistry expression of α3β1 and ICAM-1 in intact and damaged epithelium. Then, using the human pulmonary epithelial cell line WI-26 VA, we studied, by flow-cytometry, the modulation of ICAM-1 and α3β1 expression, and, by ELISA, the release of fibronectin by proinflammatory cytokines, such as IL-5, and anti-inflammatory cytokines, such as IL-4, TGF-β, and EGF. Results: α3β1 expression was slightly higher in asthma than in controls, as well as in damaged epithelium than in undamaged epithelium. ICAM-1 expression was higher in asthma than in controls, and similarly distributed in intact or damaged epithelium. In vitro, α3β1 was significantly increased by TGF-β, EGF, and IL-4, and significantly decreased by IL-5. Fibronectin release was significantly increased by TGF-β and IL-4, unchanged by EGF, and slightly but significantly decreased by IL-5. ICAM-1 expression was significantly decreased by TGF-β and IL-4, unchanged by EGF, and significantly increased by IL-5. Conclusions: These differences in adhesion molecule expression and fibronectin release may be important in epithelial cell inflammation and repair.

Patients with glucocorticoid (GC)-dependent asthma present an ongoing inflammation of the airways despite chronic long-term treatment with oral GC. Interleukin (IL)-8 and granulocyte/macrophage colony-stimulating factor (GM-CSF) have been implicated in airway inflammation in severe asthma and their synthesis is normally repressed by GC. To further characterize the inflammatory process in GC-dependent asthma, we measured the release of IL-8 and GM-CSF by peripheral blood mononuclear cells (PBMC) of eight normal subjects, six untreated controlled asthmatics, six untreated uncontrolled asthmatics, and nine GC-dependent asthmatics. We show that PBMC from GC-dependent asthmatics released high amounts of these cytokines despite chronic in vivo exposure to GC (p < 0.001 versus normal subjects). In contrast, when untreated uncontrolled asthmatics were given a short course of oral GC, IL-8 and GM-CSF production was inhibited (p = 0.0078). Release of IL-8 and GM-CSF by PBMC of GC-dependent asthmatics was reduced af...

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.

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.

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

The pleural space is a potential compartment between the lung and chest wall that becomes filled with fluid and inflammatory cells in a number of respiratory diseases. In an attempt to understand one aspect of the inflammatory process in the pleural space, we compared the responses in three different diseases (congestive heart failure [CHF], tuberculosis [TB], and cancer). Large concentrations of interleukin-8 (IL-8) were detected in cancer and TB effusions, but not in CHF. Surprisingly, the concentration of IL-8 correlated best with lymphocyte recruitment and not with neutrophil recruitment. Pleural fluid from cancer and TB patients was chemotactic for lymphocytes, and this activity was partly blocked by an anti-IL-8 antibody in cancer and completely blocked in TB. To determine whether there was the potential for a chemotactic gradient into the pleural space, pleural effusion cells were analyzed for the expression of IL-8. Cells in the effusions of cancer patients expressed IL-8, whereas IL-8 could not be detected from the cells of TB and CHF effusions. To explore the possible role of pleural macrophages in the regulation of IL-8, pleural effusion cells were treated with culture supernatants from stimulated pleural macrophages. Stimulated pleural macrophages were able to induce expression of messenger RNA (mRNA) for IL-8 and IL-8 protein production, and this activity was abrogated by blocking tumor necrosis factor-alpha. These findings suggest that soluble IL-8 is an important factor for the recruitment of lymphocytes into the pleural space, and that this cytokine is produced by both pleural structural and cancer cells after their activation by macrophage-derived, cytokine-mediated signals.

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.