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Biomedical subjects

Giovanni Bonsignore

Publications and source records attributed to Giovanni Bonsignore.

At least 19 recordsLinked to original sources
PubMed2006

Endurance training damages small airway epithelium in mice.

RATIONALE: In athletes, airway inflammatory cells were found to be increased in induced sputum or bronchial biopsies. Most data were obtained after exposure to cold and dry air at rest or during exercise. Whether training affects epithelial and inflammatory cells in small airways is unknown. OBJECTIVES: To test whether endurance training under standard environmental conditions causes epithelial damage and inflammation in the small airways of mice. METHODS AND MEASUREMENTS: Formalin-fixed, paraffin-embedded lung sections were obtained in sedentary (n = 14) and endurance-trained (n = 16) Swiss mice at baseline and after 15, 30, and 45 days of training. The following variables were assessed (morphometry and immunohistochemistry) in small airways (basement membrane length < 1 mm): (1) integrity, proliferation, and apoptosis of bronchiolar epithelium; and (2) infiltration, activation, and apoptosis of inflammatory cells. MAIN RESULTS: Compared with sedentary mice, bronchiolar epithelium of trained mice showed progressive loss of ciliated cells, slightly increased thickness, unchanged goblet cell number and appearance, and increased apoptosis and proliferation (proliferating cell nuclear antigen) (p < 0.001 for all variables). Leukocytes (CD45(+) cells) infiltrated airway walls (p < 0.0001) and accumulated within the lumen (p < 0.001); however, apoptosis of CD45(+) cells did not differ between trained and sedentary mice. Nuclear factor-kappaB translocation and inhibitor-alpha of NF-kappaB (IkappaBalpha) phosphorylation were not increased in trained compared with sedentary mice. CONCLUSIONS: Bronchiolar epithelium showed damage and repair associated with endurance training. Training increased inflammatory cells in small airways, but inflammatory activation was not increased. These changes may represent an adaptive response to increased ventilation during exercise.

Animals↗
PubMed2006

Noninvasive methods for the detection of upper and lower airway inflammation in atopic children.

BACKGROUND: Exhaled nitric oxide (FE(NO)) and exhaled breath condensate (EBC) are noninvasive methods to assess inflammation. OBJECTIVE: To investigate the role of the FE(NO) and of the EBC pH and IL-5 levels in atopic children. METHODS: We evaluated oral and nasal FE(NO) and the pH and IL-5 of oral and nasal EBC in children with atopic dermatitis (AD; n = 18), allergic rhinitis (AR; n = 18), intermittent asthma (n = 21), moderate persistent asthma (n = 18), and healthy controls (HCs; n = 16). RESULTS: Oral FE(NO) was significantly increased in asthma, whereas the nasal values were increased in AR and asthma in comparison with HCs. The pH of oral EBC was lower in AD and asthma than in AR and HCs, whereas the nasal levels were lower in AD, AR, and asthma than in HCs. The oral IL-5 was higher in AD, AR, and asthma in comparison with HCs, whereas the nasal IL-5 concentrations were higher in asthma and AR than in HCs. In AR, the nasal FE(NO) correlated with the IL-5 values and with the disease duration. In intermittent asthma, oral and nasal pH inversely correlated with the exacerbations, whereas in moderate asthma, the nasal IL-5 positively correlated with exacerbations. In AD, the oral and nasal IL-5 positively correlated with the serum IgE. CONCLUSION: These markers of nasal and bronchial inflammation, accessible with noninvasive techniques, might be useful to identify patients with uncontrolled diseases and to verify the usefulness of new therapeutic approaches. CLINICAL IMPLICATIONS: These markers are useful tools to monitor the upper and lower airway inflammation in atopic children.

Adolescent↗
PubMed2006

Role of prostaglandin E2 in the invasiveness, growth and protection of cancer cells in malignant pleuritis.

The recurrence of pleural effusions is a common event in a variety of neoplastic diseases. The objective of this study was to identify the mechanisms promoting the homing and growth of cancer cells within the pleural space. A cancer cell line recovered from malignant pleural fluids (lung adenocarcinoma cell line) that constitutively expresses cyclooxygenase 2 (COX-2) and all types of prostaglandin receptors was studied. It was first demonstrated using a matrigel system, that malignant pleural fluids increase the invasiveness of adenocarcinoma cells more than congestive heart failure (CHF) pleural fluids. Moreover, exposure to exudative malignant, but not to CHF pleural fluids, increased the mRNA (measured by real-time polymerase chain reaction (PCR)) and protein expression of COX-2 (measured by Western blot), as well as the activation and nuclear translocation of nuclear factor kappaB (NFkappaB) in cancer cells. These events are all actively regulated by prostaglandin E2 (PGE2), since the addition of synthetic PGE2 to cancer cells and the depletion of PGE2 from malignant pleural fluids or the inhibition of COX-2 activity significantly increased and reduced these phenomena, respectively. Moreover, malignant pleural effusions and synthetic PGE2 increased the long-term proliferation of cancer cells and reverted the impairment in long-term proliferation due to talc exposure. This study demonstrates that PGE2 present in malignant effusions contributes to cancer expansion and may protect cancer cells by anti-proliferative effects induced by talc.

Adenocarcinoma↗
PubMed2005

Role of different nocturnal monitorings in the evaluation of CPAP titration by autoCPAP devices.

The aim of the study was to assess how the analysis of different signals recorded during application of automatic continuous positive airway pressure (autoCPAP) devices improves the evaluation of pressure titration in patients with obstructive sleep apnea syndrome (OSAS) naive to treatment. Seventy-two patients underwent nocturnal polysomnography during autoCPAP (Autoset T, ResMed, Sydney, Australia) application. Progressively more complex combinations of signals were analysed in consecutive steps. According to the analysis of oxyhemoglobin saturation (SaO(2)) alone, a fixed CPAP level suitable for treatment could not be identified in 3 subjects. When analysis of posture was added, titration was considered unsatisfactory in 1 more subject, due to a short time spent supine. Further, addition of flow and respiratory movements led to consider titration unsatisfactory in 1 more subject. Analysis of all polysomnographic signals demonstrated a not fully reliable titration in 9 subjects: 1 with short sleep duration, 2 without REM sleep, 4 with a short sleep time spent supine, and 3 subjects (already identified by SaO(2)) with insufficient correction of respiratory disorders even when a relatively high CPAP was administered. Mask leaks did not hamper titration. CPAP titration by automatic devices alone results in imperfect titration in >10% subjects naive to ventilatory treatment. Only polysomnographic recording ensures titration reliability in all patients. Further research is needed to identify simple and economic methods to reliably start the CPAP treatment.

Continuous Positive Airway Pressure↗
PubMed2005

A new method of negative expiratory pressure test analysis detecting upper airway flow limitation to reveal obstructive sleep apnea.

BACKGROUND: Expiratory flow limitation (EFL) by negative expiratory pressure (NEP) testing, quantified as the expiratory flow-limited part of the flow-volume curve, may be influenced by airway obstruction of intrathoracic and extrathoracic origins. NEP application during tidal expiration immediately determines a rise in expiratory flow (V) followed by a short-lasting V drop (deltaV), reflecting upper airway collapsibility. PURPOSES: This study investigated if a new NEP test analysis on the transient expiratory DeltaV after NEP application for detection of upper airway V limitation is able to identify obstructive sleep apnea (OSA) subjects and its severity. METHODS: Thirty-seven male subjects (mean +/- SD age, 46 +/- 11 years; mean body mass index [BMI], 34 +/- 7 kg/m2) with suspected OSA and with normal spirometric values underwent nocturnal polysomnography and diurnal NEP testing at - 5 cm H2O and - 10 cm H2O in sitting and supine positions. RESULTS: deltaV (percentage of the peak V [%Vpeak]) was better correlated to apnea-hypopnea index (AHI) than the EFL measured as V, during NEP application, equal or inferior to the corresponding V during control (EFL), and expressed as percentage of control tidal volume (%Vt). AHI values were always high (> 44 events/h) in subjects with BMI > 35 kg/m2, while they were very scattered (range, 0.5 to 103.5 events/h) in subjects with BMI < 35 kg/m2. In these subjects, AHI still correlated to deltaV (%Vpeak) in both sitting and supine positions at both NEP pressures. CONCLUSIONS: OSA severity is better related to deltaV (%Vpeak) than EFL (%Vt) in subjects referred to sleep centers. DeltaV (%Vpeak) can be a marker of OSA, and it is particularly useful in nonseverely obese subjects.

Adult↗
PubMed2004

Synergistic effects of fluticasone propionate and salmeterol on in vitro T-cell activation and apoptosis in asthma.

BACKGROUND: In asthma T cells are characterized by an increased activation state and by reduced apoptosis. OBJECTIVE: Because the clinical efficacy of inhaled corticosteroids combined with long-acting beta 2 -agonists has been widely demonstrated in asthma, we studied, in vitro, the effect of fluticasone propionate (FP) and salmeterol alone and in combination on the activation and apoptosis of peripheral blood T cells (PBTs), on the expression of phosphorylated nuclear factor kappaB inhibitor (IkappaBalpha), and on the nuclear translocation of glucocorticoid receptor (GR) in PBTs from asthmatic subjects. METHODS: Apoptosis was evaluated on the basis of annexin V binding, whereas the expression of caspases 8 and 3 and phosphorylated IkappaBalpha, as well as the nuclear translocation of the GR, were evaluated by means of Western blot analysis. RESULTS: FP alone increases and salmeterol alone does not affect T-cell apoptosis. The combination of FP and salmeterol significantly increases PBT apoptosis in comparison with FP alone. FP at the lower concentration, when combined with salmeterol, is equivalent to FP at the higher concentration in inducing PBT apoptosis. The synergy in the induction of cell apoptosis is associated with more efficient activation of caspases 8 and 3. FP plus salmeterol is also able to synergistically reduce the expression of phosphorylated IkappaBalpha, thus limiting nuclear factor kappaB activation. The synergy was related to an increased nuclear translocation of the GR. CONCLUSION: This study shows that the combination of FP and salmeterol is able to control PBT activation in asthmatic patients more efficiently than FP alone and with a lower concentration of steroids.

Active Transport, Cell Nucleus↗
PubMed2004

Airway cell composition at rest and after an all-out test in competitive rowers.

PURPOSES: This study was designed to assess: a) whether rowing affects airway cell composition, and b) the possible relationship between the degree of ventilation during exercise and airway cells. SUBJECTS AND METHODS: In nine young, nonasthmatic competitive rowers (mean age +/- SD: 16.2 +/- 1.0 yr), induced sputum samples were obtained at rest and shortly after an all-out rowing test over 1000 m (mean duration: 200 +/- 14 s), during which ventilatory and metabolic variables were recorded breath-by-breath (Cosmed K4b, Italy). RESULTS: At rest, induced sputum showed prevalence of neutrophils (60%) over macrophages (40%); after exercise, total cell and bronchial epithelial cell (BEC) counts tended to increase. In the last minute of exercise, mean VE was 158.0 +/- 41.5 L x min(-1), and VO2 x kg(-1) 62 +/- 11 mL x min(-1). Exercise VE correlated directly with postexercise total cell (Spearman rho: 0.75, P < 0.05) an dmacrophage (rho: 0.82, P < 0.05) counts. A similar trend was observed for exercise VE and changes in BEC counts from baseline to postexercise (rho: 0.64, P = 0.11). Exercise VE did not correlate with airway neutrophil counts at rest or after exercise. Expression of adhesion molecules by airway neutrophils, macrophages, and eosinophils decreased after the all-out test. CONCLUSION: Similar to endurance athletes, nonasthmatic competitive rowers showed increased neutrophils in induced sputum compared with values found in sedentary subjects. The trend toward increased BEC postexercise possibly reflected the effects of high airflows on airway epithelium. Airway macrophages postexercise were highest in rowers showing tile most intense exercise hyperpnea, suggesting early involvement of these cells during exercise. However, the low expression of adhesion molecules by all airway cell types suggests that intense short-lived exercise may be associated with a blunted response of airway cells in nonasthmatic well-trained rowers.

Adolescent↗
PubMed2003

Persistent activation of nuclear factor-kappaB signaling pathway in severe uncontrolled asthma.

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.

Adult↗
PubMed2003

Clinical and biological heterogeneity in children with moderate 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.

Adolescent↗
PubMed2003

Biologically active intercellular adhesion molecule-1 is shed as dimers by a regulated mechanism in the inflamed pleural space.

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.

Aged↗
PubMed2003

Increased prostaglandin E2 concentrations and cyclooxygenase-2 expression in asthmatic subjects with sputum eosinophilia.

BACKGROUND: Prostaglandin E2 (PGE2) is known to be produced within human airways, but it is not clear whether in airway diseases it can play a deleterious or a beneficial role. Recently it has been reported that PGE2 can enhance eosinophil survival in vitro. OBJECTIVE: To evaluate whether the concentrations of PGE2 in asthmatic airways correlate with the number of eosinophils and can be responsible for eosinophil-enhanced survival and to identify the cyclooxygenase isoform contributing to the synthesis of PGE2 by cells present in asthmatic airways. METHODS: Reversed-phase high-performance liquid chromatography and/or specific radioimmunoassay was used to measure PGE2 concentrations in induced sputum supernatants from 14 control and 30 asthmatic subjects. Correlations between concentrations of PGE2 and the number of eosinophils in induced sputum were evaluated. Expression of cyclooxygenase-2 (COX-2) in induced sputum cells was determined by immunocytochemistry, and the effect of COX-2 inhibition on PGE2 production was evaluated with the use of radiolabeled arachidonic acid. The effects on eosinophil apoptosis by PGE2 or induced sputum supernatants were studied by using peripheral blood eosinophils obtained by negative immunomagnetic selection. RESULTS: PGE2 concentrations resulted in elevated samples from asthmatic subjects and directly correlated with the percentage of eosinophils and the concentrations of eosinophilic cationic protein. Immunostaining for COX-2 showed enhanced expression in macrophages of asthmatic subjects when compared with control subjects, and the use of a specific COX-2 inhibitor provided evidence that PGE2 synthesis was the result of COX-2 enzymatic activity in asthma-induced sputum cells. Supernatant from induced sputum of asthmatic subjects with high eosinophil counts caused a decreased apoptosis of peripheral blood eosinophils when compared with control subjects, and immunoprecipitation of PGE2 significantly reverted this phenomenon, suggesting that PGE2 was present in biologically relevant concentrations in induced sputum. CONCLUSIONS: The results obtained suggest that COX-2 expression in alveolar macrophages from asthmatic subjects may contribute to enhanced eosinophil survival through an increased PGE2 production.

Adult↗
PubMed2003

Non-specific bronchial hyper-responsiveness in children with allergic rhinitis: relationship with the atopic status.

An increased prevalence of bronchial hyper-responsiveness (BHR) has been demonstrated in children from a general population, and in non-asthmatic adults with allergic rhinitis. Thus, also children with allergic rhinitis are expected to be at higher risk of BHR. We evaluated the prevalence of BHR in a sample of non-asthmatic children with allergic rhinitis by means of the methacholine (Mch) bronchial challenge, and by monitorizing the airway patency using the daily peak expiratory flow variability (PEFv). Fifty-one children (ranged 6-15 years of age) with allergic rhinitis, ascertained by skin prick test to inhalant allergens, underwent a 14-day peak expiratory flow monitoring, and a Mch bronchial provocation challenge. Thirty healthy children matched for age, and sex served as control group. Thirty-one children in the rhinitis group (61%), and six (20%) in the control group were Mch+ (Mch provocative dose causing a 20% fall of forced expiratory volume in 1 s respect to baseline <2250 microg, equivalent to 11.50 micromol). In rhinitic children the PEFv did not significantly differ between Mch+ and Mch- subjects, but the total serum immunoglobulin E (IgE) were higher among Mch+. The persistent form of rhinitis was significantly associated to Mch positivity. Non-asthmatic children with allergic rhinitis displayed a high prevalence of BHR. The BHR was significantly associated with persistent rhinitis and with higher total IgE levels. Nevertheless, the spontaneous changes in airway patency, as expressed by PEFv, were within normal limits both in Mch+ and Mch- children.

Adolescent↗
PubMed2003

Airway cells after swimming outdoors or in the sea in nonasthmatic athletes.

BACKGROUND: Marathon runners and elite swimmers showed increased inflammatory cells in the airways at baseline. Although airway neutrophils increase further after a marathon race, the airway response to swimming is unknown. The aim of this study was to assess the effects of swimming on airway cells. To avoid the concomitant effects of chronic exposure to chlorine, the study was conducted in seven nonasthmatic swimmers [mean age (SD): 23.3 +/- 7.7 yr, training: 32 +/- 15 km.wk-1] habitually training in an outdoor pool (OP), i.e., a low-chlorine environment. METHODS: Spirometry, exhaled nitric oxide (NO), induced sputum, and peripheral blood samples were obtained at baseline, after a 5-km trial in OP, and after a 5-km race in the sea (S), i.e., hypertonic airway exposure. RESULTS: Airway neutrophil differential counts at baseline were higher in swimmers than in sedentary controls (N = 10), but cell counts, neutrophil elastase, and eosinophil cationic protein were unaffected by 5-km swimming. After swimming, L-selectin expression on airway cells decreased, suggesting exercise-induced cell mobilization into the airways and/or direct effects of hyperventilation on airway cells. After S, airway eosinophil differential counts increased slightly. Exhaled NO concentration was 19 +/- 6 ppb at baseline, 8 +/- 4 ppb after OP, and 21 +/- 7 ppb after S (P < 0.005 for OP vs baseline and S). CONCLUSIONS: In swimmers not chronically exposed to high chlorine concentrations, data obtained at baseline suggest a direct relationship between airway neutrophilia and endurance training. The low L-selectin expression by airway cells postexercise suggests hyperventilation-induced cell recruitment or modulation of cell function. Hypertonic exposure of airways during exercise may slightly increase airway eosinophils and exhaled NO. Overall, 5-km swimming exerted smaller effects on airway cells than running a marathon.

Adolescent↗
PubMed2003

Airway remodeling in asthma.

Chronic inflammation and remodeling may follow acute inflammation or may begin insidiously as a low-grade smoldering response, especially in the case of immune reactions. The histologic hallmarks of chronic inflammation and remodeling are as follows: (1) infiltration by macrophages and lymphocytes; (2) proliferation of fibroblasts that may take the form of myofibroblasts; (3) angiogenesis; (4) increased connective tissue (fibrosis); and (5) tissue destruction. It is clear that changes in the extracellular matrix, smooth muscle, and mucous glands have the capacity to influence airway function and reactivity in asthma patients. However, it is not known how each of the many structural changes that occur in the airway wall contributes to altered airway function in asthma. In asthma, remodeling is almost always present in biopsy specimens (eg, collagen deposition on basement membrane) but is not always clinically demonstrated. Destruction and subsequent remodeling of the normal bronchial architecture are manifested by an accelerated decline in FEV(1) and bronchial hyperresponsiveness. This irreversible component of airway obstruction is more prominent in patients with severe disease and even persists after aggressive anti-inflammatory treatment. Airway remodeling appears to be of great importance for understanding the long-term follow-up of asthmatic patients, but there are major gaps in our knowledge. Physiologic correlations with pathology represent a major missing link that should be filled. More long-term studies are needed to appreciate the prevention and treatment of remodeling. Future research therefore should provide better methods for limiting airway remodeling in asthma patients.

Asthma↗
PubMed2002

Continuous positive airway pressure treatment improves baroreflex control of heart rate during sleep in severe obstructive sleep apnea syndrome.

The role of the arterial baroreflex in the cardiovascular changes associated with the obstructive sleep apnea syndrome (OSAS), and the effect of nasal continuous positive airway pressure (CPAP) treatment on baroreflex function during sleep are unknown. Baroreflex control of heart rate was studied in 29 normotensive patients with OSAS under no treatment, in 11 age-matched control subjects, and in 10 patients at CPAP withdrawal after 5.5 +/- 3.7 (range 3-14) months of treatment. Baroreflex control of heart rate was assessed by "sequence method" analysis of continuous blood pressure recordings (Finapres) obtained during nocturnal polysomnography. In untreated OSAS, baroreflex sensitivity (BRS) was low during wakefulness and non-rapid eye movement (REM) stage 2 sleep compared with control subjects, and correlated inversely with mean lowest Sa(O(2)) and the blood pressure increase after apneas. After CPAP treatment, the apnea-hypopnea index was lower, and mean lowest Sa(O(2)) higher than before treatment. After CPAP, patients were more bradycardic, blood pressure and its standard deviation decreased as Sa(O(2)) improved in non-REM stage 2 sleep, and BRS increased (nocturnal wakefulness: +59%; non-REM stage 2 sleep: +68% over pretreatment values). Our data suggest that baroreflex dysfunction in OSAS may be at least partly accounted for by nocturnal intermittent hypoxemia, and can be reversed by long-term CPAP treatment.

Adult↗
PubMed2002

Leukotriene B4 production in human mononuclear phagocytes is modulated by interleukin-4-induced 15-lipoxygenase.

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 microM) or opsonized zymosan. 15(S)-hydroxyeicosatetraenoic acid [15(S)-HETE], LTB4, and arachidonic acid (AA) release were measured by high-performance liquid chromatography/radioimmunoassay, liquid chromatography/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.

Anti-Inflammatory Agents, Non-Steroidal↗