Effect of nedocromil on bronchospasm induced by inhalation of substance P in asthmatic subjects

Several studies have demonstrated that neuropeptides are present in peptidergic fibres of bronchial tissue. The aim of the present study was to evaluate in vivo the effect of nedocromil sodium (2 x 2 mg) on bronchospasm induced by inhalation of substance P. Six moderate asthmatic patients, mean age 25.17 years, were studied. Airway response was measured as FEV1 and the dose of substance P (using a dose range of 23-736 nmol) producing a 20% decrease in FEV1 (PD20) was calculated from the individual semilogarithmic dose-response curves. Patients were studied on 3 separate days in a randomized, double-blind manner. On the first day a baseline PD20 value was determined. On subsequent days substance P challenge was performed after pretreatment (20 min before challenge) with either placebo or nedocromil sodium. Student's paired t-test and Wilcoxon's test were used for statistical analysis. The results of this study demonstrated that inhalation of substance P causes a dose-dependent bronchoconstriction and that the bronchoconstriction induced by substance P can be prevented by pre-treatment with nedocromil sodium.     

Changes in neurokinin A (NKA) airway responsiveness with inhaled frusemide in asthma

BACKGROUND: Inhaled frusemide exerts a protective effect against bronchoconstriction induced by several indirect stimuli in asthma which could be due to interference of airway nerves. A randomised, double blind, placebo controlled study was performed to investigate the effect of the potent loop diuretic, frusemide, administered by inhalation on the bronchoconstrictor response to neurokinin A (NKA) and histamine in 11 asthmatic subjects. METHODS: Subjects attended the laboratory on four separate occasions to receive nebulised frusemide (40 mg) or matched placebo 10 minutes prior to bronchial challenge with NKA and histamine in a randomised, double blind order. Changes in airway calibre were followed as forced expiratory volume in one second (FEV1) and responsiveness to the agonists was expressed as the provocative concentration causing a 20% fall in FEV1 from baseline (PC20). RESULTS: Compared with placebo, inhaled frusemide reduced the airway responsiveness to NKA in all the subjects studied, the geometric mean (range) values for PC20NKA increasing significantly (p < 0.001) from 130.3 (35.8-378.8) to 419.9 (126.5-1000) micrograms/ml after placebo and frusemide, respectively. Moreover, a small but significant change in airway responsiveness to histamine was recorded after frusemide, their geometric mean (range) PC20 values being 0.58 (0.12-3.80) and 1.04 (0.28-4.33) mg/ml after placebo and frusemide, respectively. CONCLUSIONS: The decrease in airway responsiveness to NKA after administration of frusemide by inhalation suggests that this drug may interfere with the activation of neurotransmission in human asthma.




     

Intranasal steroid reduces exhaled bronchial cysteinyl leukotrienes in allergic patients

BACKGROUND: Allergic rhinitis (AR) precedes and is often associated with bronchial asthma. Indeed, local and systemic inflammations in both conditions are very similar. Cysteinyl-leukotrienes (cys-LTs) are generated during early- and late-phase allergic reactions and induce smooth-muscle contraction, microvascular leakage, and mucous hypersecretion. Cys-LTs are detected in exhaled breath condensate (EBC) of asthmatics and regardless of bronchial symptoms, they are also found in EBC of rhinitic patients. OBJECTIVE: To evaluate cys-LTs in EBC of allergic patients and to assess the activity of nasal fluticasone propionate (FP) on EBC cys-LTs levels. METHODS: Cys-LTs coefficient of variation (CV) was evaluated from different EBC in 5 healthy volunteers. Cys-LTs levels from EBCs in 13 healthy controls and 56 allergic rhinitic (n=31) and rhinitic/asthmatic (n=25) patients were also evaluated at baseline. Subsequently patients were randomized to receive either FP 100 microg/day per nostril or placebo for 2 weeks and then re-evaluated for EBC cys-LTs. RESULTS: The CV was 14.12%. EBC cys-LTs in allergic patients were significantly higher than in healthy subjects (70.9 vs. 20.6 pg/mL (median), P<0.05), while it did not differ between asthmatic/rhinitic and purely rhinitic patients. Treatment significantly reduced cys-LTs (from 93.6 to 19.9 pg/mL, P<0.001). This effect was evident both in asthmatic/rhinitic and in rhinitic patients. CONCLUSION: Treatment of AR with FP significantly reduces the levels of cys-LTs, major noninvasive markers of lower airway inflammation, suggesting that upper and lower airway inflammation is present and should be thus treated as a whole in subjects with AR with and without asthma.     

Evaluation of the activity of the carbocysteine-sobrerol combination on mucus spinnability

Among the rheological properties of bronchial mucus, "spinnability", i.e. the ability to form threads under the effect of traction, should be regarded as the most closely related to the mucociliary transport function. In the present study the "spinnability" parameter was included in the functional tests aimed at evaluating the efficacy of the carbocysteine-sobrerol combination in 16 patients suffering from chronic abstructive lung disease with bronchial hypersection. Treatment was administered for ten days under double-blind conditions compared with a placebo. The results obtained showed the tested combination to be able to favourably affect all the most important rheological parameters of mucus, including spinnability, leading to a rapid disappearance of signs and symptoms and to the improvement of the most important respiratory function indexes.     

Impact of intranasal budesonide on immune inflammatory responses and epithelial remodeling in chronic upper airway inflammation

BACKGROUND: Histologic and immunohistologic features of nasal polyps (NP) are similar to those observed in asthma, thus suggesting a similar immunopathology. OBJECTIVE: The primary objective of this study was to further understand the anti-inflammatory and immunoregulatory effects of locally delivered corticosteroids. To this end, the effect of intranasal budesonide on the expression of specific cytokines, lymphocyte subsets, and epithelial remodeling in this model of airway tissue inflammation were studied. METHODS: We used immunohistochemical techniques to examine nasal mucosae (NM) from healthy individuals and nasal polyp (NP) tissues from patients with nasal polyposis obtained before and after intranasal budesonide treatment. RESULTS: First, the density of CD8(+) cells was markedly increased in NP tissues after intranasal budesonide treatment from 16.1 +/- 8.4 (M +/- SEM) per mm(2) to 39.9 +/- 24.1. Second, the density of cells immunoreactive for IL-4, IL-5, IFN-gamma, IL-12, and TGF-beta in NP was significantly greater than in control NM tissues. The density of IL-4(+) and IL-5(+) cells in NP tissues significantly decreased after budesonide treatment from 40 +/- 12 to 17.8 +/- 8 and from 19.3 +/- 11 to 10.4 +/- 7, respectively. In contrast, the density of IFN-gamma(+) and IL-12(+) cells remained unchanged. In addition, we found that the density of TGF-beta(+) cells significantly increased after intranasal budesonide from 18 +/- 5 to 41 +/- 9. Third, damage to the entire length of the NP epithelium was quantified using a grading system. The epithelium of untreated NP was substantially damaged; remarkable epithelial restitution with no apparent changes in stromal collagen deposition was observed after intranasal budesonide treatment. CONCLUSIONS: These findings demonstrate that intranasal budesonide induced an increase in CD8 population and a selective regulatory effect on tissue cytokine expression. Furthermore, intranasal budesonide promoted epithelial remodeling. We hypothesize that these immunoregulatory and remodeling effects elicited by steroids might be, at least in part, mediated by the induction of TGF-beta.     

Influence of asthmatic and rhinitic symptomatology duration on bronchial responsiveness to histamine

Our Study aimed to investigate the influence of the time in years elapsed from the onset of symptoms on bronchial nonspecific responsiveness in rhinitic and asthmatic patients. The study was performed on 83 asthmatic patients and on 46 patients with allergic rhinopathy. The beginning of the symptoms and years of asthmatic or rhinitic history were particularly investigated. A histamine challenge was performed. The dose of histamine producing at 20% change in FEV1 (forced expiratory volume in one second) was calculated from the individual semilogarithmic dose-response curve (PD20). Bronchial responsiveness to histamine showed wide variability in subjects of two groups, and an overlap of the distribution curves was observed between asthmatic and rhinitic patients. A significant relationship (p less than 0.01) between the years elapsed from the onset of symptoms and bronchial responsiveness to histamine was observed in each group of patients. We noticed that the number of the years passed heightened the bronchial responsiveness to histamine in both groups of patients.     

Bradykinin differentiates human lung fibroblasts to a myofibroblast phenotype via the B2 receptor

BACKGROUND: The identification of factors mediating the transition of lung fibroblasts into myofibroblasts is considered fundamental in the comprehension of abnormal reparative processes. Bradykinin, a mediator known for its proinflammatory action, is able to induce cytokine production and contractility in fibroblast cultures. OBJECTIVES: In this study the ability of bradykinin to drive fibroblast into a myofibroblast phenotype at the cellular and molecular level was evaluated. METHODS: alpha-Smooth muscle actin (alpha-SMA) expression and TGF-beta in bradykinin stimulated fibroblasts were tested by means of flow cytometry, Western blot, and RT-PCR. Cell proliferation and collagen production were evaluated by the colorimetric methylthiazol tetrazolium assay and sirius red assay, respectively. Which bradykinin receptor mediates the expression of alpha-SMA was evaluated using selective B1 and B2 blocking agents. Furthermore, the effect of bradykinin on extracellular signal-regulated kinase 1/2 phosphorylation was explored. RESULTS: Bradykinin caused in lung fibroblasts a significant increase in alpha-SMA at the cellular and molecular level. The B2 receptor was held responsible for this effect because a specific receptor antagonist had entirely blocked this effect. Bradykinin was able to induce fibroblast proliferation and collagen production. Bradykinin significantly activated mitogen-activated protein kinase pathway by phosphorylating extracellular signal-regulated kinase 1/2, whereas PD98059, a specific inhibitor, was able to block myofibroblast induction. Although bradykinin induced an increase of TGF-beta on fibroblasts, the blockage of this cytokine did not alter alpha-SMA expression. CONCLUSION: The data support the hypothesis that bradykinin may be involved in bronchial remodeling and lung fibrosis beyond its well recognized proinflammatory activity, also suggesting a new potential therapeutic strategy to control altered reparatory processes.     

Effect of vasoactive intestinal peptide (VIP) on propranolol-induced bronchoconstriction

There is now considerable evidence in favor of vasoactive intestinal peptide (VIP) as a neurotransmitter of nonadrenergic noncholinergic nerves in the airways. The purpose of our study was to evaluate the influence of inhaled VIP on bronchomotor tone after a beta-adrenergic- and cholinergic-receptor blockage. The study was performed in six patients with asthma in 4 days. On the first day, a propranolol provocative dose producing a 20% change in FEV1 (PD20) was determined from the individual semilogarithmic dose-response curve. On the other days, the propranolol challenge was performed after inhalation of ipratropium bromide (40 micrograms), VIP (70 micrograms), and both drugs in randomized double-blind order. Statistical analysis was performed by two-way analysis of variance. The results demonstrated that mean propranolol PD20 was 0.14 mg (geometric mean + SD = 1.22). Ipratropium bromide administration, like VIP administration, significantly raised the PD20 value. The administration of both drugs elicited a further remarkable increase of mean propranolol PD20. The results demonstrated that inhaled VIP influences bronchomotor tone and that this effect is independent of the cholinergic blockage.     

Antiinflammatory-antioxidant treatment with a methane sulfonanilide in allergen-induced asthma.

Two groups of six asthmatic patients with biphasic bronchospastic response to inhaled Dermatophagoides pteronyssinus allergen extract were studied in a double-blind fashion. Early and late asthmatic reactions to allergen inhalation challenge were determined before and at the end of a 2-week treatment period with nimesulide (100 mg bid orally), a sulfonanilide with antioxidant properties, or placebo. Bronchial responsiveness to methacholine was evaluated 24 hours before and after allergen inhalation challenges. The dose of allergen causing EAR (15% decrease in FEV1) and the severity of LAR (maximum FEV1 fall) were similar before and at the end of the treatment period in both groups. In patients treated with nimesulide, bronchial responsiveness to methacholine was significantly increased after allergen inhalation challenge both before and at the end of the treatment period. These results do not support the hypothesis that the production of oxygen-free radicals plays a significant role in the development of bronchial hyperresponsiveness and late phase reaction to allergen in asthma.     

Elevated serum uric acid is associated with a greater inflammatory response and with short- and long-term mortality in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention

Background and aimsDespite elevated serum uric acid (eSUA) has been identified as independent risk factor for cardiovascular diseases, its prognostic value in the setting of ST-segment elevation myocardial infarction (STEMI) is still controversial. Although the mechanisms of this possible relationship are unsettled it has been suggested that eSUA could trigger the inflammatory response. This study sought to investigate the association between eSUA with short- and long-term mortality and with inflammatory response in patients with STEMI treated with primary percutaneous coronary intervention (pPCI).Methods and resultsBlood samples were collected on admission and at 24 and 48 h after pPCI: the inflammatory biomarkers C-reactive protein (CRP), neutrophil count and neutrophil to lymphocytes ratio (NLR) were considered. Baseline eSUA was defined as ≥6.8 mg/dl. Cumulative 30-days and 1-year mortalities were estimated using the Kaplan-Meyer analysis. Multivariable analyses were performed by Cox proportional hazard models.In the 2369 patients with STEMI considered, 30-day mortality was 5.8% among patients with eSUA and 2% among patient with normal SUA level (p < 0.001); 1-year mortality was 8.5% vs 4%, respectively (p < 0.001). At multivariable analyses eSUA was an independent predictor of 30-day mortality (HR 1.196, 95%CI 1.006–1.321, p = 0.042) and 1-year mortality (HR 1.178, 95%CI 1.052–1.320, p = 0.005). eSUA patients presented higher values in on admission CRP (p < 0.001) and in neutrophil count and NLR at 24 h (respectively, p = 0.020 and p < 0.001) and at 48 h (p = 0.018 and p < 0.001) compared to patients with normal SUA levels.ConclusionsElevated serum uric acid is associated with higher short- and long-term mortality and with a greater inflammatory response after reperfusion in patients with STEMI treated with primary PCI.