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Biomedical subjects

E Crimi

Publications and source records attributed to E Crimi.

At least 19 recordsLinked to original sources
PubMed2006

Cooperation between Myc and YY1 provides novel silencing transcriptional targets of alpha3beta1-integrin in tumour cells.

We show that human osteosarcoma cells (Saos-2) have downregulation of alpha3beta1-integrin compared to normal bone cells; this was further described in human osteosarcomas and in a primary murine sarcoma. The alpha3 gene was silenced in Saos-2 cells causing a low expression of alpha3beta1-integrin and reduction in collagen attachment with increasing migratory capacity. Chromatin immunoprecipitation assay performed on alpha3 promoter established that Myc and Yin Yang protein (YY1) cooperate in tandem to downregulate the alpha3 gene. This silencing mechanism involves the binding of Myc and YY1 to DNA and formation of complexes among Myc/Max, YY1, CREB-binding protein and deacetylation activity. The promoter containing deletions of E-boxes or YY1 cassettes failed to downregulate the transcription of a reporter gene as well as the inhibition of deacetylation activity. Overexpression of both Myc and YY1 was necessary to determine the alpha3-integrin promoter downregulation in normal osteoblasts. This downregulation of alpha3beta1-integrin can contribute to the acquisition of a more aggressive phenotype. YY1 regulated negatively the Myc activity through a direct interaction with the Myc/Max and deacetylase complexes. This represents a novel silencing mechanism with broad implications in the transcription machinery of tumours.

Animals↗
PubMed2002

Actions other than smooth muscle relaxation may play a role in the protective effects of formoterol on the allergen-induced late asthmatic reaction.

Long-acting beta(2)-adrenoceptor agonists attenuate the allergen-induced late asthmatic reaction. We evaluated whether other mechanisms in addition to airway smooth muscle relaxation may be implicated in this protective effect. The effects of formoterol (Foradil Aerolizer(TM), 24 microg dry powder) on the late asthmatic reaction were assessed by a randomised crossover factorial study in 24 patients with asthma. Four challenge/treatment combinations were tested: (A) saline/placebo, (B) saline/formoterol, (C) allergen/placebo, (D) allergen/formoterol. Formoterol and placebo were administered double blind after the last inhalation of the allergen or saline. FEV(1) was measured up to 32 h. The bronchodilator effect of formoterol was estimated as (B-A) and the overall protective effect as (D-C). The effect not due to bronchodilation was estimated as [(D-C)-(B-A)]/2. The bronchodilator effect of formoterol was statistically significant up to 5h (all P< or =0.015). Formoterol significantly attenuated the late asthmatic reaction between 3 and 32 h after allergen inhalation (all P< or =0.0012). The difference between this protective effect and the bronchodilator effect was statistically significant at 5 h and between 7 and 28 h after allergen inhalation (all P< or =0.035). Our results suggest that functional antagonism may not be the sole mechanism by which formoterol attenuates the allergen-induced late asthmatic reaction.

Adolescent↗
PubMed2002

In allergic asthma experimental exposure to allergens is associated with depletion of blood eosinophils overexpressing LFA-1.

BACKGROUND: In atopic individuals, exposure to allergens is followed by recruitment of blood eosinophils in the target tissue. We investigated whether allergen inhalation challenge could result in depletion of blood eosinophils overexpressing adhesion molecules involved in eosinophil migration. METHODS: Blood eosinophils were isolated from seven atopic asthmatic patients and seven control subjects and the "at baseline" expression of lymphocyte function-associated antigen-1 (LFA-1), macrophage antigen-1 (Mac-1) and very late antigen-4 (VLA-4) was assessed by monoclonal antibody staining and flow cytometry analysis. Asthmatic patients underwent allergen challenge and the expression of LFA-1, Mac-1 and VLA-4 by blood eosinophils was again evaluated 3 h and 24 h after allergen challenge. RESULTS: As compared to controls, eosinophils from atopics showed at baseline enhanced LFA-1 expression (P=0.0012), but similar Mac-1 or VLA-4 expression (P > 0.1, each comparison). In atopics, the percentage and absolute number of blood eosinophils were significantly decreased 3 h after allergen challenge (P=0.001 and P=0.022, respectively) but returned to similar values to prechallenge values after an additional 21 h (P > 0.1). Allergen challenge was also followed by a significant decrease in LFA-1 expression by eosinophils, at 3 h (P=0.002) and at 24 h (P=0.038), while no changes in Mac-1 and VLA-4 were observed. A significant correlation between postchallenge decrease in LFA-1 expression and in blood eosinophilia, both expressed as percentage (r=0.88; P < 0.01) or absolute number (r=0.87; P < 0.01) was demonstrated at 3 h (r=0.88; P < 0.01) but not at 24 h (r=0.64, P > 0.05 and r=0.11; P > 0.05, respectively). CONCLUSION: In allergic asthma, an early recruitment of blood eosinophils overexpressing LFA-1 occurs in the first hours after allergen challenge.

Adolescent↗
PubMed2002

Pain control during diagnostic and/or therapeutic procedures in children.

Children's fear of pain in illness has been greatly underestimated. In cancer disease, pain characterizes most of the diagnostic and long-term therapeutic procedures. Children's psycho-emotional processing during illness has been recently recognized as characterized by loss of control, anger, and fear, to which pain adds fear of death jeopardizing the sense of survival. Illness and pain provoke a traumatic condition affecting psycho-emotional maturation. The aim of the pharmacologic and psychologic support is to help children better cope with pain and prevent the healed child having traumatic effects in his/her future personality structure and behavior. To assure the best pain control, support has to be offered right from the first intrusive procedure in order to avoid anticipatory anxiety. Respiration, relaxation, visualization, desensibilization through the "switch technique" and the "magic glove", distraction and involvement, muscular relaxation all have the common aim of focusing the child's mind and attention away from body perception of pain connected to the procedure. Different medical methods are utilized depending on the child's age and the level of consciousness required for the procedure. Local anaesthesia and conscious sedation are used. Children are particularly sensitive in this critical condition and need as serene and comfortable an environment as possible. Relief of pain and suffering in cancer treatments that cause further discomfort to the patient is a fundamental ethics in the treatment of clinical neoplasias.

Anesthesia↗
PubMed2001

Allergic inflammation and airway smooth muscle function.

It is widely accepted that airway smooth muscle (ASM) contraction plays a key role in asthmatic attacks. Whether abnormalities of contractility or autonomic regulation exist in the asthmatic ASM is still debated. Studies based on isometric contraction failed to show differences in the force-generation capability between asthmatic and normal ASM. Recent studies in vitro have shown that sensitized ASM: (1) shortens more and more rapidly than normal ASM; and (2) develops a myogenic response to stretching. The increased velocity of shortening may compromise in vivo the ability of tidal cycling to reduce airway tone, which would result in an enhanced response to bronchoconstrictor stimuli. The myogenic response may result in a sustained bronchospasm after a deep inhalation, a maneuver that in normal individuals causes bronchodilatation. Although there is no evidence that neural or humoral abnormalities in the autonomic regulation of ASM tone are central to the pathogenesis of bronchial asthma, recent data suggest that ASM receptor dysfunction may develop secondary to airway allergic response. It has been shown that exposure of passively sensitized human bronchi to allergens in vitro causes M2- and beta2-receptor dysfunction. Impairment of pre-junctional M2-autoreceptors may result in an enhancement of neurally mediated bronchoconstrictor responses, whereas beta2-receptor dysfunction may reduce the sensitivity to bronchodilator treatment. Airway inflammation, which is a characteristic feature of bronchial asthma, may alter both the contractile properties and the autonomic regulation of ASM. These changes may contribute to the severity of asthma, as they may cause an, imbalance between factors favoring and opposing airway narrowing.

Asthma↗
PubMed2001

Differential role of CD80 and CD86 on alveolar macrophages in the presentation of allergen to T lymphocytes in asthma.

In the asthmatic lung the altered expression of costimulatory molecules (CD80, CD86) by alveolar macrophages contributes to T lymphocyte activation and expansion. We hypothesized that CD80 and CD86 on alveolar macrophages could differentially support allergic inflammation in adult asthma. Here we studied 11 subjects with mild allergic asthma and 11 atopic non-asthmatics as controls. Dermatophagoides-specific T cell lines were derived from peripheral blood from each subject. Bronchoalveolar lavage with evaluation of lung inflammatory cells was performed in all individuals at baseline and 24 h after allergen challenge. The expression of CD80 and CD86 costimulatory molecules by alveolar macrophages was studied and, in parallel, the efficiency of antigen presentation was measured in terms of IL-4 and IL-5 production by allergen-stimulated autologous T cells. We found that in asthmatic subjects (i) the percent of CD80+, but not CD86+ alveolar macrophages was increased at baseline and did not change following allergen challenge; (ii) CD86, but not CD80, membrane expression was up-regulated following allergen challenge; (iii) both CD80 and CD86 were required to support Th2 cytokine production by allergen-specific T cells, with a prevalent role of CD86 after allergen challenge. Our data indicate that alveolar macrophages deliver costimulatory signals via CD80 and CD86, which support the production of Th2 cytokines by allergen-specific T cells. They also indicate that CD86 in vivo is up-regulated in the 24 h following allergen exposure and that this modulation is functionally relevant.

Adult↗
PubMed2001

Extracellular cyclic ADP-ribose potentiates ACh-induced contraction in bovine tracheal smooth muscle.

Cyclic ADP-ribose (cADPR), a universal calcium releaser, is generated from NAD(+) by an ADP-ribosyl cyclase and is degraded to ADP-ribose by a cADPR hydrolase. In mammals, both activities are expressed as ectoenzymes by the transmembrane glycoprotein CD38. CD38 was identified in both epithelial cells and smooth myocytes isolated from bovine trachea. Intact tracheal smooth myocytes (TSMs) responded to extracellular cADPR (100 microM) with an increase in intracellular calcium concentration ([Ca(2+)](i)) both at baseline and after acetylcholine (ACh) stimulation. The nonhydrolyzable analog 3-deaza-cADPR (10 nM) elicited the same effects as cADPR, whereas the cADPR antagonist 8-NH(2)-cADPR (10 microM) inhibited both basal and ACh-stimulated [Ca(2+)](i) levels. Extracellular cADPR or 3-deaza-cADPR caused a significant increase of ACh-induced contraction in tracheal smooth muscle strips, whereas 8-NH(2)-cADPR decreased it. Tracheal mucosa strips, by releasing NAD(+), enhanced [Ca(2+)](i) in isolated TSMs, and this increase was abrogated by either NAD(+)-ase or 8-NH(2)-cADPR. These data suggest the existence of a paracrine mechanism whereby mucosa-released extracellular NAD(+) plays a hormonelike function and cADPR behaves as second messenger regulating calcium-related contractility in TSMs.

ADP-ribosyl Cyclase↗
PubMed2001

Inflammatory and mechanical factors of allergen-induced bronchoconstriction in mild asthma and rhinitis.

We studied whether different bronchial responses to allergen in asthma and rhinitis are associated with different bronchial inflammation and remodeling or airway mechanics. Nine subjects with mild asthma and eight with rhinitis alone underwent methacholine and allergen inhalation challenges. The latter was preceded and followed by bronchoalveolar lavage and bronchial biopsy. The response to methacholine was positive in all asthmatic but in only two rhinitic subjects. The response to allergen was positive in all asthmatic and most, i.e., five, rhinitic subjects. No significant differences between groups were found in airway inflammatory cells or basement membrane thickness either at baseline or after allergen. The ability of deep inhalation to dilate methacholine-constricted airways was greater in rhinitis than in asthma, but it was progressively reduced in rhinitis during allergen challenge. We conclude that 1) rhinitic subjects may develop similar airway inflammation and remodeling as the asthmatic subjects do and 2) the difference in bronchial response to allergen between asthma and rhinitis is associated with different airway mechanics.

Adult↗
PubMed2001

On the functional consequences of bronchial basement membrane thickening.

Reticular basement membrane (RBM) thickness and airway responses to inhaled methacholine (MCh) were studied in perennial allergic asthma (n = 11), perennial allergic rhinitis (n = 8), seasonal allergic rhinitis (n = 5), and chronic obstructive pulmonary disease (COPD, n = 9). RBM was significantly thicker in asthma (10.1 +/- 3.7 microm) and perennial rhinitis (11.2 +/- 4.2 microm) than in seasonal rhinitis (4.7 +/- 0.7 microm) and COPD (5.2 +/- 0.7 microm). The dose (geometric mean) of MCh causing a 20% decrease of 1-s forced expiratory volume (FEV(1)) was significantly higher in perennial rhinitis (1,073 microg) than in asthma (106 microg). In COPD, the slope of the linear regression of all values of forced vital capacity plotted against FEV(1) during the challenge was higher, and the intercept less, than in other groups, suggesting enhanced airway closure. In asthma, RBM thickness was positively correlated (r = 0.77) with the dose (geometric mean) of MCh causing a 20% decrease of FEV(1) and negatively correlated (r = -0.73) with the forced vital capacity vs. FEV(1) slope. We conclude that 1) RBM thickening is not unique to bronchial asthma, and 2) when present, it may protect against airway narrowing and air trapping. These findings support the opinion that RBM thickening represents an additional load on airway smooth muscle.

Adult↗
PubMed2000

G(s) protein dysfunction in allergen-challenged human isolated passively sensitized bronchi.

We studied the intracellular mechanisms of allergen-induced beta(2)-adrenoceptor dysfunction in human isolated passively sensitized bronchi. Sensitization was obtained by overnight incubation of bronchial rings with serum containing a high specific IgE level to Dermatophagoides but a low total IgE level. Allergen challenge was done by incubation with a Dermatophagoides mix. The G(s) protein stimulant cholera toxin (2 microg/ml) displaced the carbachol (CCh) concentration-response curves of control and sensitized but not of challenged rings to the right. Cholera toxin (10 microg/ml) displaced the concentration-response curves to CCh of control, sensitized, and challenged rings to the right, but this effect was less in challenged rings. The effects of the G(i) protein inhibitor pertussis toxin (250 ng/ml or 1 microg/ml) on salbutamol concentration-relaxation curves did not differ significantly between challenged and sensitized rings. The adenylyl cyclase activator forskolin and the Ca(2+)-activated K(+)-channel opener NS-1619 relaxed CCh-contracted bronchial rings without significant differences between control, sensitized, and challenged rings. Neither G(i) nor G(s) alpha-subunit expression differed between control, sensitized, and challenged tissues. We conclude that G(s) protein dysfunction may be a mechanism of allergen-induced beta(2)-adrenoceptor dysfunction in human isolated passively sensitized bronchi.

Adenylyl Cyclases↗
PubMed1999

Increased expression of the CD80 accessory molecule by alveolar macrophages in asthmatic subjects and its functional involvement in allergen presentation to autologous TH2 lymphocytes.

BACKGROUND: Alveolar macrophages (AMs) are more efficient antigen-presenting cells in allergic individuals than in nonatopic subjects. OBJECTIVE: We studied whether this difference may be correlated to increased expression of membrane costimulatory molecules, such as the B7 molecules (CD80 and CD86). METHODS: Eleven subjects with allergic asthma sensitized to Dermatophagoides pteronyssinus and 5 healthy nonatopic volunteers underwent bronchoalveolar lavage, and the costimulatory molecule expression on AMs was evaluated. Peripheral blood T cells, either freshly isolated or as established D pteronyssinus -specific cell lines, were cultured with autologous monocytes or AMs as antigen-presenting cells. In vitro allergen-induced proliferation and cytokine production were evaluated in the presence of B7-blocking reagents. RESULTS: Allergic individuals had a significantly higher proportion of AMs expressing the CD80 molecule than control subjects (28.5% +/- 14.8% vs 1.4% +/- 1.2%; P <.001), whereas no difference was observed in CD86 expression (2.0% +/- 2.3% vs 1.1% +/- 0.6; P >.1). In a large proportion of the asthmatic subjects we studied, AMs were presenting soluble antigens (tetanus toxoid and streptolysin-O) to freshly isolated T cells more efficiently than AMs from nonatopic control subjects. Finally, both T-cell proliferation and cytokine production of D pteronyssinus- specific established T-cell lines were inhibited by a CD80-blocking antibody in a dose-dependent manner. CONCLUSION: Costimulation by means of CD80 expressed by AMs is probably involved in the amplification of the allergen-specific T-lymphocyte response in the airways of asthmatic subjects.

Adolescent↗
PubMed1999

Value of immunoglobulin E density in predicting nasal and bronchial response to inhaled allergens in rhinitic and asthmatic subjects with multiple sensitizations.

BACKGROUND: In atopic subjects with multiple sensitizations to inhalant allergens the relationship between the specific serum immunoglobulin (Ig) E and the in vivo response to each allergen is not well established. OBJECTIVE: To investigate the relationship between the specific serum IgE expressed as amount (kU/L) or density (specific IgE/total IgE percentage) with the in vivo response to inhaled allergens in rhinitic and asthmatic subjects with multiple sensitization. METHODS: By means of Reverse Enzyme AllergoSorbent Test (REAST) the absolute values and the density of specific IgE for each sensitizing allergen was determined. Rhinitics (n = 12) underwent nasal and asthmatics (n = 11) bronchial allergen challenges with the two to three sensitizing allergens for a total of 33 nasal and 32 bronchial challenges. Correlations and degree of concordance between specific serum IgE and results of challenges were calculated. RESULTS: IgE density significantly correlated with nasal challenge score (rs = 0.72, P < 0.001), bronchial challenge score (rs = 0.56, P < 0.001) and late asthmatic response (rp = 0.53, P < 0.005). Among subjects with three sensitizations, comparison of values of IgE density with the results of challenges showed significant concordance in graduation (chi2 = 11.3, P < 0.005). CONCLUSIONS: In subjects with multiple sensitizations, the nasal and bronchial response to the different sensitizing allergens may be predicted, at least in part, by the IgE density. A satisfactory agreement between graduation of the IgE density to the different allergens and the in vivo response to the same allergens has been found within subject.

Administration, Inhalation↗
PubMed1999

Effect of methacholine challenge on cellular composition of sputum induction.

BACKGROUND: Induced sputum and methacholine inhalation challenge are routinely used for the assessment of airway inflammation and airway hyperresponsiveness, respectively. This study investigates whether a methacholine challenge performed one hour before sputum induction alters the cellular and biochemical constituents of sputum. METHODS: Sixteen stable asthmatic patients with lung function within the normal range underwent two sputum inductions within one week. One hour before one of the sputum inductions a methacholine challenge was performed. RESULTS: There were no significant differences in total cell count, macrophages, neutrophils, eosinophils, lymphocytes, epithelial cells, ECP, and albumin between the two challenges. The repeatability of cell counts was good for all cells, ECP and albumin, but poor for total cells. CONCLUSIONS: In patients with stable asthma a methacholine challenge carried out one hour before sputum induction does not significantly alter the cellular and biochemical constituents of sputum.

Adolescent↗
PubMed1999

Airway responsiveness to methacholine: effects of deep inhalations and airway inflammation.

We determined the dose-response curves to inhaled methacholine (MCh) in 16 asthmatic and 8 healthy subjects with prohibition of deep inhalations (DIs) and with 5 DIs taken after each MCh dose. Flow was measured on partial expiratory flow-volume curves at an absolute lung volume (plethysmographically determined) equal to 25% of control forced vital capacity (FVC). Airway inflammation was assessed in asthmatic subjects by analysis of induced sputum. Even when DIs were prohibited, the dose of MCh causing a 50% decrease in forced partial flow at 25% of control FVC (PD(50)MCh) was lower in asthmatic than in healthy subjects (P < 0.0001). In healthy but not in asthmatic subjects, repeated DIs significantly decreased the maximum response to MCh [from 90 +/- 4 to 62 +/- 8 (SD) % of control, P < 0.001], increased PD(50)MCh (P < 0.005), without affecting the dose causing 50% of maximal response. In asthmatic subjects, neither PD(50)MCh when DIs were prohibited nor changes in PD(50)MCh induced by DIs were significantly correlated with inflammatory cell numbers or percentages in sputum. We conclude that 1) even when DIs are prohibited, the responsiveness to MCh is greater in asthmatic than in healthy subjects; 2) repeated DIs reduce airway responsiveness in healthy but not in asthmatic subjects; and 3) neither airway hyperresponsiveness nor the inability of DIs to relax constricted airways in asthmatic subjects is related to the presence of inflammatory cells in the airways.

Administration, Inhalation↗
PubMed1998

Selective differences in the expression of the homing receptors of helper lymphocyte subsets.

Effector functions are acquired by mature CD4 T lymphocytes in an exquisitely antigen-specific and antigen-dependent fashion. T cell receptor recognition of the processed antigen presented on the major histocompatibility complex molecule by antigen-presenting cells dictates the specificity of the T cell clones that will be expanded. A complex array of further coreceptor and lymphokine-mediated interactions determines whether activation or inhibition will follow and which effector phenotype will be acquired by the lymphocytes. On the basis of a first antigen encounter, CD4 T cells are functionally defined as naive or memory/effector cells. In memory/effector T cells, the pattern of cytokine production permits further classification as Th1 or Th2 cells. Th1 cells mainly produce IFN-gamma, whereas Th2 cells mainly produce IL-4. The functional properties of these cell subsets derive from the biological activities of these (and the related) lymphokines they produce. An established body of data supports the view that the migration of T lymphocytes is distinctively different in naive and memory/effector T cells. Both CD4 and CD8 memory/effector T cells selectively migrate into nonlymphoid organs, such as the skin, the gut, and the lung through the peripheral extravascular route, whereas naive T cells migrate through the high endothelial venules and enter lymphoid tissues, such as lymph nodes, Peyers' patches, and tonsils. Furthermore, the acquisition of a Th1 or Th2 profile further implies the coordinated expression of a relatively selective array of receptors capable of rerouting them differentially. These events have a dramatic effect on the outcome of an immune response and determine whether it will be protective or not. New therapeutic strategies can be envisaged that interfere with the key molecular processes taking place during these coordinated differentiation events.

Animals↗
PubMed1998

Airway eosinophilic inflammation and bronchial hyperresponsiveness after allergen inhalation challenge in asthma.

Allergen exposure in atopic asthmatic patients is associated with recruitment and activation of eosinophils in the airways. Once activated, eosinophils release toxic products, including the eosinophil cationic protein (ECP), able to damage bronchial structures and to increase bronchial hyperresponsiveness. With this background, the present study was designed to evaluate whether ECP levels in bronchoalveolar lavage (BAL) fluid could reflect, better than BAL eosinophil counts, the cellular activation that follows allergen exposure in atopic asthmatics. Twenty-two atopic patients attended the laboratory on two separate days. On the 1st day, they underwent methacholine (MCh) inhalation challenge to detect the degree of nonspecific bronchial hyperresponsiveness. On the 2nd day, they underwent fiberoptic bronchoscopy and BAL, at baseline or 4-6 h after allergen inhalation challenge. In this latter patient group, MCh challenge was repeated 3-5 h after allergen challenge, 1 h before fiberoptic bronchoscopy. The analysis of the mean baseline FEV1 values and the degree of bronchial reactivity to MCh (MCh Pd20) on the 1st study day did not demonstrate differences between the two patient groups (p > 0.1, each comparison). In addition, in the allergen-challenged group, MCh Pd20 was decreased significantly after allergen challenge (151.4 micrograms/ml and 67.6 micrograms/ml, respectively, before and after challenge; p < 0.05). Evaluation of the different BAL cell types demonstrated that the proportions of eosinophils and epithelial cells were increased significantly in the allergen-challenged group compared with the group evaluated at baseline (p < 0.01 and p < 0.05, respectively). Moreover, ECP levels, corrected by the correspondent albumin levels (ECP/Alb), were higher in the allergen-challenged group compared with the group evaluated at baseline (p < 0.05). In addition, although a positive correlation was demonstrated between BAL eosinophil percentages and ECP/Alb values (r = 0.72, p < 0.05) in the group evaluated at baseline, no links were found between these parameters in the allergen-challenged group (p > 0.1). However, in this latter group, a weak positive correlation was demonstrated between eosinophil percentages and delta Mch, i.e., the increased non-specific bronchial reactivity, which is observed after allergen challenge (r = 0.55; p < 0.05). Thus, in stable asthmatic patients an ongoing activation of eosinophils parallels their migration, but this eosinophilic inflammation is not strictly related to bronchial reactivity to Mch. By contrast, after allergen inhalation challenge, eosinophil recruitment and activation seem to follow different temporal kinetics, and eosinophilic inflammation may be partially associated with the degree of airway hyperresponsiveness.

Adolescent↗