A novel activity for substance P: stimulation of peroxisome proliferator-activated receptor-gamma protein expression in human monocytes and macrophages.

BACKGROUND AND PURPOSE: Substance P (SP) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) play important roles in different inflammatory conditions and are both expressed in human monocytes and macrophages. However, it is not known whether or not they interact. This study was undertaken to evaluate the effects of SP on PPAR-gamma protein expression in monocytes and macrophages (MDMs: monocyte-derived macrophages) from healthy smokers and non-smokers. EXPERIMENTAL APPROACH: PPAR-gamma protein was detected by western blot and quantified by calculating the ratio between PPAR-gamma and beta-actin protein expression. Constitutive tachykinin NK(1) receptor expression in monocytes and MDMs from healthy smokers and non-smokers was evaluated by western blot. Cytokine release was evaluated by ELISA. KEY RESULTS: In the concentration range 10(-10)-10(-6) M, SP stimulated PPAR-gamma protein expression in monocytes and MDMs, being more effective in cells from healthy smokers. Moreover, in these cells there was a constitutively increased expression of NK(1) receptors. SP-induced expression of the PPAR-gamma protein was receptor-mediated, as it was reproduced by the NK(1) selective agonist [Sar(9)Met(O(2))(11)]SP and reversed by the competitive NK(1) antagonist GR71251. SP-induced maximal effects were similar to those evoked by 15-deoxy-Delta(12,14)-prostaglandin J(2); an endogenous PPAR-gamma agonist, and were significantly reduced by a PPAR-gamma antagonist. NK(1) and PPAR-gamma agonists exerted opposite effects on TNF-alpha release from monocytes and MDMs. CONCLUSIONS AND IMPLICATIONS: Enhancement of PPAR-gamma protein expression represents a novel activity for SP, which could contribute to a range of chronic inflammatory disorders.

Oral nifedipine in chronic cor pulmonale secondary to severe chronic obstructive pulmonary disease (COPD).

Hemodynamic effects of orally-administered nifedipine were evaluated in 12 patients with pulmonary hypertension secondary to severe COPD after short-term (30 and 60 minutes) treatment and then again in eight of these 12 patients after long-term (average 55 days) treatment. Pulmonary vascular resistance (PVR) decreased from 426 +/- 52 to 294 +/- 28 dynes.s.cm-5 (p less than 0.001) after therapy with 20 mg sublingual nifedipine (at 60 minutes). Cardiac index (CI) increased from 3.7 +/- 0.2 to 4.6 +/- 0.3 L/min/m2 (p less than 0.001). There was a decrease in mean pulmonary artery pressure (MPAP) only in 4/12 patients after Nifedipine. There was no significant fall in PaO2, while PvO2 and oxygen delivery (CI X CaO2) increased significantly 60 minutes after administration of sublingual nifedipine. PVR decreased from 482 +/- 82 to 374 +/- 44 dynes.s.cm-5 (p less than 0.05) after long-term nifedipine therapy. The changes in PVR and CI 60 minutes after administration of nifedipine in the patients on long-term treatment were similar to those observed with the same doses of nifedipine before initiation of therapy. Despite beneficial hemodynamic effects in two of eight patients, there was progressive clinical worsening. The benefit of long-term administration of nifedipine is difficult to predict on the basis of short-term effects.

Efficacy and tolerability of nedocromil sodium versus placebo in chronic reversible obstructive airways disease.

In this 8-week, double-blind, comparative trial of nedocromil sodium (4 mg q.i.d.) versus placebo in 42 patients with chronic reversible obstructive airways disease, there was a trend in favor of nedocromil sodium compared to placebo in parameters assessed by patients (nocturnal symptom scores, evening PEFR values) and those assessed by clinicians (asthma severity scores) compared with baseline values. There was a statistically significant difference (p < 0.05) in favor of nedocromil sodium in the inhaled bronchodilator requirements in the last 2 weeks of treatment. Both patients' and clinicians' evaluation of the overall efficacy of treatment was significant in favor of nedocromil sodium (p < 0.01 and p < 0.05, respectively). The treatments were well tolerated by the majority of patients. From these data, it can be concluded that nedocromil sodium (4 mg q.i.d.) is of value in the preventive treatment of chronic reversible obstructive airways disease.

Severity scores in respiratory intensive care: APACHE II predicted mortality better than SAPS II.

BACKGROUND: In recent years several scoring systems have been developed to describe the severity of illness, to establish the individual prognosis, and to group adult ICU patients by predicted risk of mortality. In addition, these scores can be used to measure and/or compare the quality of care in different ICUs. We compared the mortality predictions of the Acute Physiology and Chronic Health Evaluation (APACHE II) score and a new Simplified Acute Physiology Score (SAPS II) in patients with respiratory disease who require intensive care. PATIENTS & METHODS: We prospectively studied all 306 admissions from January 1, 1992 through December 31, 1994. McNemar and Hosmer-Lemeshow tests, and receiver operating characteristic (ROC) curves were used to describe and analyze our data. RESULTS: The average APACHE II score was 17.5 (SD 6.0), corresponding to a mean predicted death rate of 24.9% (SD 17.2%) as compared to an observed overall RICU mortality rate of 21.6%. The average SAPS II score was 39.1 (SD 11.1) corresponding to a mean predicted death rate of 26.0% (SD 18.4%). The ratio between the actual and predicted hospital mortality was 86% for APACHE II and 83% for SAPS II. Survivors had a significantly lower predicted risk of death than nonsurvivors (p < 0.0001) with both indices, and a higher Glasgow coma scale score (p < 0.0001). The ROC-curve analysis suggested the superior predictive ability of APACHE II in our patients. Area under the APACHE II ROC curve was 80.88% (standard error [SE] 2.89%), significantly larger (p < 0.01) than that found for SAPS II (73.52%, SE 3.61%). CONCLUSIONS: The APACHE II score was a good predictor of hospital outcome and better than SAPS II in our population.

[Evaluation of the therapeutic effects of broncaspin in chronic bronchopneumopathies]. / Valutazione degli effetti terapeutici del "Broncaspin" nei broncopneumopatici cronici.

A controlled single-blind clinical trial was made with Broncaspin, on original synthetic molecule obtained by condensing acetylsalicylic acid and guaiacol, in a comparison of its local and general tolerance, and antipyretic, antiexudative and balsamic properties with those of dimethylaminophenazone guaiacolglycolate, a well-known preparation, in two randomly composed groups of 15 patients with chronic obstructive bronchial and lung diseases, using 1,2 g Broncaspin suppositories and the commercial form of the other product twice a day for 14 consecutive days. Therapeutic assessment was based on the symptomatological, spirometric and blood gas data.

External negative pressure ventilation techniques.

External ventilation was introduced at the beginning of the century to treat acute and chronic respiratory failure. Long-term negative pressure ventilation (NPV) has proved useful in patients with respiratory failure, secondary to a restrictive impairment of neuromusculoskeletal origin. Although NPV may be successfully used in acute-on-chronic respiratory failure in patients with chronic airflow obstruction (CAO), its use in the long-term management of this type of patient seems much less promising. The various types of ventilators, iron lung, pneumo-wrap and cuirass are discussed. All these prostheses, except for the pneumo-wrap, are connected to a pump able to generate negative and positive pressure. NPV must be a controlled ventilation, because an effective trigger is not yet available. The most important feature of the ventilator must be the ability to vary the ventilatory pattern to adapt the machine drive to the patient drive. The goal of NPV is not only to normalize gas exchange, but also to restore an effective spontaneous ventilation. This kind of ventilation has no negative effects on haemodynamics, because it does not vary physiological gradients of transthoracic pressure. However, due to lack of coordination between the respirator and the pharyngeal muscles of the patient, obstructive apnoeas may occur during NPV in sleeping patients.

[Efficacy and safety of the use of levodropropizine in patients with chronic interstitial lung diseases]. / Efficacia e sicurezza di impiego di levodropropizina in pazienti affetti da pneumopatie interstiziali croniche.

Efficacy and tolerability of an antitussive drug, levodropropizine, in 21 adult patients with interstitial lung disorders was evaluated in this study. Levodropropizine dosage was 60 mg t.i.d. for four days of therapy. The authors evaluated the effectiveness of the antitussive therapy and, on the other hand, the tolerability of levodropropizine in these patients, monitoring PaO2, PaCO2 and pH values. The changes in cough frequency (34.1 +/- 5.6 20.4 +/- 5.4 mean +/- d.s. before and after treatment) and the overall efficacy judgment as reported by the doctor indicate a decrease in cough as confirmed by the significance of Kruskal-Wallis test (p less than 0.05). Furthermore the tolerability has been excellent, because the PaO2, PaCo2 ad pH values before and after treatment were unchanged (PaO2 mmHg: basal 71 +/- 16.6, after treatment 73.8 +/- 14.2; PaCO2 mmHg: basal 36.6 +/- 5, after treatment 36.6 +/- 4.6; pH basal 7.4 +/- 0.03, after treatment 7.4 +/- 0.02).

Tobacco smoke affects expression of peroxisome proliferator-activated receptor-gamma in monocyte/macrophages of patients with coronary heart disease.

BACKGROUND AND PURPOSE: Tobacco smoke represents a relevant risk factor for coronary heart disease (CHD). Although peroxisome proliferator-activated receptor (PPAR)gamma activation reduces inflammation and atherosclerosis, expression of PPARgamma in cells and its modulation by smoking are poorly investigated. We previously reported that monocyte/macrophages from healthy smokers exhibited an enhanced constitutive expression of PPARgamma. Here, we evaluated PPARgamma expression and basal cytokine release in monocytes and monocyte-derived macrophages (MDMs) from 85 CHD patients, classified by their smoking habit (smokers, non-smokers and ex-smokers), and assessed the role of PPARgamma ligands in this context. EXPERIMENTAL APPROACH: PPARgamma protein was detected by Western blot and semi-quantified by PPARgamma/beta-actin ratio; cytokine release was measured by elisa and nuclear factor-kappaB (NF-kappaB) translocation by electrophoretic mobility shift assays. KEY RESULTS: As compared to the other groups, MDMs from smoker CHD patients exhibited a reduced PPARgamma/beta-actin ratio and an increased spontaneous release of tumour necrosis factor-alpha (TNF-alpha) and interleukin-6, but with no major variations in monocytes. In cells from selected CHD patients, rosiglitazone inhibited TNF-alpha release and NF-kappaB translocation induced by phorbol-12-myristate 13-acetate. The selective PPARgamma antagonist GW9662 reversed these effects, with some variations related to smoking habit. CONCLUSIONS AND IMPLICATIONS: In CHD patients, exposure to tobacco smoke profoundly affected PPARgamma expression, and this was related to levels of secretion of pro-inflammatory cytokines. MDMs from CHD smokers showed the lowest PPARgamma expression and released more inflammatory cytokines. Moreover, rosiglitazone's ability to inhibit cytokine release and its reversal by GW9662 clearly indicated PPARgamma involvement in these changes in CHD patients.

Pulmonary vascular responsiveness at rest and during exercise in idiopathic pulmonary fibrosis: effects of oxygen and nifedipine.

To detect whether pulmonary vascular responsiveness is a factor which can aggravate the pulmonary hypertension induced by irreversible pulmonary fibrosis, we examined the acute hemodynamic effects of low-flow oxygen and of nifedipine both at rest and during exercise in 8 patients with idiopathic pulmonary fibrosis (IPF). During exercise, the increments in pulmonary artery pressure, pulmonary vascular resistance (PVR), and right ventricular stroke work index relative to resting values were blunted by both treatments. During exercise, both systemic vascular resistance and PVR decreased more significantly after nifedipine than on oxygen (p less than 0.001). At exercise, nifedipine administration induced a greater increment in oxygen delivery (CaO2 X CI) than that produced by oxygen breathing (p less than 0.01). Our results in patients with IPF seem to confirm that active vasoconstriction of pulmonary vessels may contribute to the pulmonary hypertension during exercise. The evaluation of reversibility of pulmonary hypertension by nifedipine in IPF deserves further long-term studies.

Inhibition of fog-induced bronchoconstriction by nedocromil sodium and sodium cromoglycate in intrinsic asthma: a double-blind, placebo-controlled study.

The efficacy of pretreatment with two doses of nedocromil sodium (4 and 8 mg) and sodium cromoglycate 12 mg were compared with placebo in inhibiting the bronchoconstriction induced by inhalation of ultrasonically nebulized distilled water ('fog') in 10 subjects with intrinsic asthma. Each fog challenge consisted of three inhalations of 30, 60 and 120 s duration, respectively, given at 4-min intervals, and the bronchoconstrictor response was assessed as the postchallenge percentage fall in FEV1 from baseline. Statistically significant drug effects (p less than 0.05) were observed after 120 s of fog challenge: both nedocromil sodium 4 and 8 mg and sodium cromoglycate were significantly more effective than placebo in inhibiting fog-induced bronchoconstriction; in addition, nedocromil sodium 4 mg proved statistically significantly more effective than sodium cromoglycate.

Inhibition of exercise-induced asthma by oral procaterol, a new beta 2-adrenergic drug.

8 asthmatics were studied for 2 consecutive days in order to assess the preventive effect of a new oral beta 2-sympathomimetic, procaterol hydrochloride, against exercise-induced asthma. Statistical analysis of the resulting data showed that this preparation, unlike other oral beta 2-sympathomimetics, affords good protection against exercise-induced asthma.

Prevention of non-specific bronchial hyperreactivity. Dose-dependent effect of sodium cromoglycate metered dose aerosol.

The protective effect of different doses of sodium cromoglycate (4 mg, 12 mg and 20 mg) given as pressurized aerosol on fog-induced bronchoconstriction were investigated in three different groups of asthmatic patients. Premedication with the active drug was compared versus absence of premedication. The authors discuss their results by a statistical analysis of the FEV1 variations. Sodium cromoglycate effectively prevents fog-induced bronchoconstriction with a clear dose-dependent effect.

Pulmonary vascular reactivity and hemorheology in patients with chronic cor pulmonale: responses to pentoxifylline at rest and during exercise.

This study was carried out in order to evaluate changes in pulmonary vascular reactivity and in hemorheology induced by pentoxifylline infusion (100 mg) at rest and during standardized exercise in patients with chronic cor pulmonale secondary to chronic obstructive pulmonary disease. The administration of pentoxifylline at rest was associated with reduction in mean pulmonary artery pressure (p less than 0.01), pulmonary vascular resistance (p less than 0.01) and right ventricular stroke work index (p less than 0.02). Standard exercise performed after pentoxifylline infusion was also associated with significant reduction in mean pulmonary artery pressure and pulmonary vascular resistance. Rheologic tests showed less evident changes. Our data suggest that pentoxifylline significantly improves pulmonary hemodynamics at rest and partly reverses its changes, after exercise, in patients with chronic obstructive pulmonary disease.

Evaluation of the addition of cromolyn sodium to bronchodilator maintenance therapy in the long-term management of asthma.

Three hundred ninety-seven patients, aged 5 to 63 years, took part in a year-long international multicenter, double-blind, placebo-controlled trial. The patients, whose asthma was considered not adequately controlled, were divided into two groups according to their principal medication at entry (group A, oral and/or inhaled beta 2-bronchodilators; group B, methylxanthines, with or without beta 2-agonists) and randomly allocated to additional treatment with cromolyn sodium (metered-dose inhaler, 2 mg, four times a day, or capsules, 20 mg, four times a day) or matching placebo. A 2-month baseline preceded 10 to 12 months of treatment. After 4 to 8 weeks of treatment, patients were encouraged to reduce bronchodilator usage. Patients used diary cards to record asthma severity, sleep difficulty, morning and evening peak expiratory flow rates, days of disruption of normal activity, use of test treatments, and concomitant medication. Significant differences favoring cromolyn sodium (p less than 0.05 and better) were observed for most of the treatment period in respect to (1) asthma severity, (2) morning and evening peak expiratory flow rates, and (3) days of disruption of normal activity. Patients receiving cromolyn sodium experienced fewer exacerbations and tended to use less concomitant medication than patients receiving placebo. Patients' opinions of treatment significantly favored cromolyn sodium. These results demonstrate the value of the addition of cromolyn sodium to existing therapy in the long-term management of asthma and endorse its use as a first-line treatment.

Idiopathic pulmonary fibrosis: can cell mediated immunity markers predict clinical outcome?

Most of the cells found in lung parenchyma in patients with idiopathic pulmonary fibrosis are activated T lymphocytes and macrophages. The serum levels of three markers of cell mediated immunity were measured in 20 patients with idiopathic pulmonary fibrosis, in 20 normal subjects and in 12 patients with sarcoidosis to evaluate their clinical and prognostic significance in idiopathic pulmonary fibrosis. The three markers were: soluble CD8 (from activated suppressor-cytotoxic lymphocytes), soluble interleukin (IL)-2 receptors (from activated T cells and macrophages), and neopterin (from activated macrophages). Patients with idiopathic pulmonary fibrosis had higher levels of all three markers than the control subjects. Soluble IL-2 receptor and neopterin tended to be lower (though not significantly) in patients with idiopathic pulmonary fibrosis than in those with sarcoidosis, whereas soluble CD8 was similar in the two groups of patients. No correlation was found between soluble IL-2 receptors or soluble CD8 and the clinical, radiological, and physiological measures of disease activity or with clinical outcome (after a mean follow up of 23 months). Tumour necrosis factor levels were also determined. Only 30% of patients with idiopathic pulmonary fibrosis or sarcoidosis had detectable circulating tumour necrosis factor; these patients had a lower percentage of bronchoalveolar lavage fluid neutrophils in their lavage fluid. Tumour necrosis factor levels did not correlate with clinical measures of severity or outcome. Thus our data support the hypothesis that cell mediated alveolitis occurs in idiopathic pulmonary fibrosis. They do not, however, provide evidence to support the use of these markers of cell mediated immunity to monitor the clinical course in these patients.