Biomedical subjects

Emanuele Crimi

Publications and source records attributed to Emanuele Crimi.

10 recordsLinked to original sources

PubMed2006

Cysteinyl-leukotrienes in the regulation of beta2-adrenoceptor function: an in vitro model of asthma.

BACKGROUND: The response to beta2-adrenoceptor agonists is reduced in asthmatic airways. This desensitization may be in part due to inflammatory mediators and may involve cysteinyl-leukotrienes (cysteinyl-LTs). Cysteinyl-LTs are pivotal inflammatory mediators that play important roles in the pathophysiology of asthma, allergic rhinitis, and other inflammatory conditions. We tested the hypothesis that leukotriene D4 (LTD4) and allergen challenge cause beta2-adrenoceptor desensitization through the activation of protein kinase C (PKC). METHODS: The isoproterenol-induced cAMP accumulation was evaluated in human airway smooth muscle cell cultures challenged with exogenous LTD4 or the PKC activator phorbol-12-myristate-13-acetate with or without pretreatments with the PKC inhibitor GF109203X or the CysLT1R antagonist montelukast. The relaxant response to salbutamol was studied in passively sensitized human bronchial rings challenged with allergen in physiological salt solution (PSS) alone, or in the presence of either montelukast or GF109203X. RESULTS: In cell cultures, both LTD4 and phorbol-12-myristate-13-acetate caused significant reductions of maximal isoproterenol-induced cAMP accumulation, which were fully prevented by montelukast and GF109203X, respectively. More importantly, GF109203X also prevented the attenuating effect of LTD4 on isoproterenol-induced cAMP accumulation. In bronchial rings, both montelukast and GF109203X prevented the rightward displacement of the concentration-response curves to salbutamol induced by allergen challenge. CONCLUSION: LTD4 induces beta2-adrenoceptor desensitization in human airway smooth muscle cells, which is mediated through the activation of PKC. Allergen exposure of sensitized human bronchi may also cause a beta2-adrenoceptor desensitization through the involvement of the CysLT1R-PKC pathway.

Adrenergic beta-Agonists↗

PubMed2006

Allergic airway inflammation and beta-adrenoceptor dysfunction.

A reduced response to beta-adrenoceptor agonists has been reported in airways of asthmatic subjects. Mechanisms for beta-adrenoceptor dysfunction are (1) inactivation or downregulation of beta-adrenoceptors by specific agonists (homologous desensitization) or by inflammatory mediations (heterologous desensitization), (2) inactivation or downregulation of second messengers of beta-adrenoceptor pathway. Studies from our laboratory have shown that allergen challenge of passively sensitized human bronchi causes a beta-adrenoceptor dysfunction as a result of reduced activity of the receptor-coupled Gs protein. The dysfunction was prevented by leukotriene-receptor antagonists or a cell membrane stabilizer, but not by an antihistimine or indomethacin, suggesting a central role of leukotrienes released from resident inflammatory cells in its genesis. Furthermore, the beta-adrenoceptor response and Gs protein function after allergen exposure were restored by short-term (3 h) incubation with beclomethasone dipropionate, suggesting an effect independent of gene transcription. Restoration of the intracellular beta-adrenoceptor effector pathway may contribute to the efficacy of corticosteroids in the acute treatment of asthma.

Adrenergic beta-Agonists↗

PubMed2005

A model of allergen-driven human airway contraction: beta2 pathway dysfunction without cytokine involvement.

BACKGROUND: In our previous in vitro model, allergen incubation of passively sensitized human airways reduced the response to salbutamol. However, whether cytokines play a role in this model is still unknown. OBJECTIVE: To investigate interleukin 1beta and tumor necrosis factor a expression in allergen-challenged human airways. METHODS: Nonasthmatic airways (n = 13) were passively sensitized by overnight atopic serum incubation and then challenged with allergen for 1 hour (n = 9). After repeated washouts, airways were immersed in physiologic salt solution for 6 hours and finally in formaldehyde for immunohistochemical studies. The effect of co-incubation in anti-interleukin 1beta and anti-tumor necrosis factor a specific neutralizing antibodies on salbutamol response was also studied (n = 4). RESULTS: No differences were found among control, sensitized, and challenged rings in the number of inflammatory cells. The percentage of basement membrane covered by epithelium was similar in the different conditions. There was a higher percentage of degranulating to total mast cells in allergen-challenged rings than in sensitized rings (P < .001). A significant correlation was observed between allergen-induced contraction and mast cell degranulation (r = 0.88; P < .001). The sensitization procedure was validated by paired allergen-induced contractions. No expression of the 2 cytokines was detectable up to 6 hours after allergen challenge, and specific neutralizing antibodies did not attenuate the impaired response to salbutamol in allergen-challenged rings. CONCLUSION: These data suggest that in our in vitro model of allergic inflammation, beta2 pathway dysfunction can occur without cytokine involvement, thus supporting previous results that suggest a role for leukotrienes.

Adrenergic beta-Agonists↗

PubMed2005

Supplemental oxygen and heliox: 'new' tools for exercise training in chronic obstructive pulmonary disease.

PURPOSE OF REVIEW: Chronic obstructive pulmonary disease (COPD) is a condition characterized by airflow obstruction only partially reversible with usual bronchodilator therapy. Inability of gas to move freely in and out of the lungs causes dyspnea and exercise intolerance. Putative mechanisms of exercise limitation under these conditions are the occurrence of expiratory airflow limitation and dynamic lung hyperinflation developing with the increase in minute ventilation during exercise. This review will examine the results of recent studies using nonpharmacological interventions to improve exercise tolerance in COPD and their relevance to rehabilitation programs. RECENT FINDINGS: Decreasing ventilatory demands and/or gas density have been recently shown to be beneficial to improve exercise tolerance, symptoms, and quality of life. For instance, breathing supplemental oxygen was capable of reducing exercise ventilation, thus allowing expiratory flow limitation within the tidal breathing range to be minimized, and operational lung volumes to be accommodated at lower levels. As a result, dyspnea was decreased for the elastic work of breathing was decreased, and patients were able to increase exercise intensity and/or duration. Manipulating gas density has also been shown to be beneficial in relieving symptoms and improving exercise capacity, for it facilitates gas emptying during expiration. As a result, the amount of expiratory flow limitation and operational lung volumes decreased, thus ultimately leading to greater exercise tolerance. SUMMARY: Nonpharmacological interventions aimed at modifying physical gas properties appear to open new perspectives in exercise rehabilitation programs for COPD.

Administration, Inhalation↗

PubMed2004

Attenuation of induced bronchoconstriction in healthy subjects: effects of breathing depth.

The effects of breathing depth in attenuating induced bronchoconstriction were studied in 12 healthy subjects. On four separate, randomized occasions, the depth of a series of five breaths taken soon (approximately 1 min) after methacholine (MCh) inhalation was varied from spontaneous tidal volume to lung volumes terminating at approximately 80, approximately 90, and 100% of total lung capacity (TLC). Partial forced expiratory flow at 40% of control forced vital capacity (V(part)) and residual volume (RV) were measured at control and again at 2, 7, and 11 min after MCh. The decrease in V(part) and the increase in RV were significantly less when the depth of the five-breath series was progressively increased (P < 0.001), with a linear relationship. The attenuating effects of deep breaths of any amplitude were significantly greater on RV than V(part) (P < 0.01) and lasted as long as 11 min, despite a slight decrease with time when the end-inspiratory lung volume was 100% of TLC. In conclusion, in healthy subjects exposed to MCh, a series of breaths of different depth up to TLC caused a progressive and sustained attenuation of bronchoconstriction. The effects of the depth of the five-breath series were more evident on the RV than on V(part), likely due to the different mechanisms that regulate airway closure and expiratory flow limitation.

Adult↗

PubMed2003

Modulation of cholinergic responsiveness through the [beta]-adrenoceptor signal transmission pathway in bovine trachealis.

The effects of pharmacological stimulation at different levels of the beta-adrenoceptor (AR) pathway, including the receptor, the receptor-coupled Gs protein, and adenylyl cyclase, were studied by simultaneous measurements of acetylcholine (ACh) release and isometric force evoked by electric stimulation in isolated bovine trachealis. The beta-AR agonists isoproterenol (10-6 and 10-5 M) and salbutamol (10-7 to 10-5 M) significantly attenuated both ACh release and contractile force. Forskolin, at 10-6 M, significantly increased ACh release without effect on contractile force, whereas at 10-5 M it increased ACh release but significantly decreased force. Activation of Gs protein by cholera toxin (10 microg/ml) significantly attenuated both ACh release and contractile force, but its effect on ACh release was abolished by calcium-activated potassium (KCa)-channel blocker iberiotoxin (10-7 M). The KCa-channel opener NS-1619 (10-4 M) attenuated significantly both ACh release and contractile force. It is concluded that beta-AR agonists attenuate cholinergic neurotransmission in isolated bovine trachealis model by a mechanism not involving cAMP but KCa channels.

Acetylcholine↗

PubMed2003

Airway reactivity and diving in healthy and atopic subjects.

BACKGROUND: The short- and long-term effects of self-contained underwater breathing apparatus (SCUBA) dives on airway responsiveness in nonasthmatic atopic subjects have not been systematically investigated. PURPOSE: To compare the effect of SCUBA diving at 50-m depth on lung function and airway responsiveness to methacholine (MCh) in atopic nonasthmatics and healthy subjects. METHODS: We studied 15 atopic nonasthmatic subjects and 15 controls who underwent the visit for the professional SCUBA-diving license at the Navy Medical Center, La Spezia, Italy. All subjects underwent spirometry and skin-prick test for common environmental allergens. MCh challenge was performed 24 h before, and 20 min and 24 h after a standardized SCUBA-dive test and after hyperbaric-chamber test. RESULTS: At 20 min, the provocative dose of MCh causing 20% fall of the forced expiratory volume at the first second (MCh PD20 - FEV1) was significantly reduced in atopic, asymptomatic subjects from 1712 x 2.6 microg (mean x geometric standard deviation) to 1202 x 2.2 microg (P < 0.0005) after the hyperbaric-chamber test and to 1204 x 2.3 microg (P < 0.005) after SCUBA diving. In healthy subjects, the baseline value of MCh PD20 was 2977 x 1.1 microg, and this value did not change significantly after the hyperbaric-chamber test (2575 x 1.4 microg) and after SCUBA dives (2553 x 1.4 microg, P > 0.1 for both comparisons). In atopic subjects, the MCh PD20 returned near to the baseline value 24 h after the hyperbaric-chamber test (1776 x 2.4 microg) and after the SCUBA test (1500 x 2.67 microg). No significant change in FEV1 was observed after the tests in both groups. CONCLUSION: SCUBA diving is associated with development of early airway hyperresponsiveness to MCh in atopic subjects.

Adult↗

PubMed2002

Beclomethasone rapidly ablates allergen-induced beta 2-adrenoceptor pathway dysfunction in human isolated bronchi.

Bronchial rings from nonatopic humans were passively sensitized with serum from allergic subjects. Allergen challenge significantly reduced the relaxant effect of salbutamol on carbachol-induced contractions, suggesting beta(2)-adrenoceptor (beta(2)-AR) pathway dysfunction. Incubation of challenged rings for 3 h with 3 x 10(-6) M beclomethasone dipropionate (BDP) restored the relaxant effect, suggesting reversal of beta(2)-AR pathway dysfunction. Incubation with the G(s)alpha protein-stimulating cholera toxin attenuated contractile responses to carbachol significantly less in challenged than in unchallenged rings. Treatment of challenged rings with BDP resulted in an inhibitory effect of cholera toxin that was similar to the effect in unchallenged rings. G(s)alpha protein expression was not significantly altered by BDP, suggesting that the activity of G(s)alpha protein was increased. Relaxation of challenged rings by forskolin was not significantly affected by BDP, suggesting that beta(2)-AR pathway dysfunction was proximal to the adenylyl cyclase. In conclusion, short-term (3-h) treatment with BDP after allergen challenge ablated beta(2)-AR pathway dysfunction by increasing the activity of the G(s)alpha protein in human isolated bronchi.

Adenylyl Cyclases↗

PubMed2002

Deep breaths, methacholine, and airway narrowing in healthy and mild asthmatic subjects.

Deep breaths taken before inhalation of methacholine attenuate the decrease in forced expiratory volume in 1 s and forced vital capacity in healthy but not in asthmatic subjects. We investigated whether this difference also exists by using measurements not preceded by full inflation, i.e., airway conductance, functional residual capacity, as well as flow and residual volume from partial forced expiration. We found that five deep breaths preceding a single dose of methacholine 1) transiently attenuated the decrements in forced expiratory volume in 1 s and forced vital capacity in healthy (n = 8) but not in mild asthmatic (n = 10) subjects and 2) increased the areas under the curve of changes in parameters not preceded by a full inflation over 40 min, during which further deep breaths were prohibited, without significant difference between healthy (n = 6) and mild asthmatic (n = 16) subjects. In conclusion, a series of deep breaths preceding methacholine inhalation significantly enhances bronchoconstrictor response similarly in mild asthmatic and healthy subjects but facilitates bronchodilatation on further full inflation in the latter.

Adult↗

PubMed2002

Exercise-induced bronchodilation in natural and induced asthma: effects on ventilatory response and performance.

We studied whether bronchodilatation occurs with exercise during the late asthmatic reaction (LAR) to allergen (group 1, n = 13) or natural asthma (NA; group 2, n = 8) and whether this is sufficient to preserve maximum ventilation (VE(max)), oxygen consumption (VO(2 max)), and exercise performance (W(max)). In group 1, partial forced expiratory flow at 30% of resting forced vital capacity increased during exercise, both at control and LAR. W(max) was slightly reduced at LAR, whereas VE(max), tidal volume, breathing frequency, and VO(2 max) were preserved. Functional residual capacity and end-inspiratory lung volume were significantly larger at LAR than at control. In group 2, partial forced expiratory flow at 30% of resting forced vital capacity increased greatly with exercise during NA but did not attain control values after appropriate therapy. Compared with control, W(max) was slightly less during NA, whereas VO(2 max) and VE(max) were similar. Functional residual capacity, but not end-inspiratory lung volume at maximum load, was significantly greater than at control, whereas tidal volume decreased and breathing frequency increased. In conclusion, remarkable exercise bronchodilation occurs during either LAR or NA and allows VE(max) and VO(2 max) to be preserved with small changes in breathing pattern and a slight reduction in W(max).

Adult↗