Alveolar macrophage/peripheral blood monocyte-derived factors modulate proliferation of primary lines of human lung fibroblasts.

Pulmonary fibrosis is characterized by an alteration in lung collagen synthesis and deposition, as well as by increased fibroblast proliferation. It is also characterized by an intermittent influx of immune and inflammatory cells in the lung. To investigate the nature of the target cell in this disorder, we established a series of primary lines of human adult lung fibroblasts and studied the effect of mediators released from activated normal human alveolar macrophages (AM) and peripheral blood monocytes (PBM) on the proliferation of both normal lung fibroblasts and fibroblasts established from lung tissue of patients with active fibrosis. Our data show that monocyte supernatants containing a 15-18 kD monokine from either AM or PBM inhibits growth of logarithmic phase proliferating lung fibroblasts in a dose-dependent manner. This effect can be entirely abrogated by treating the fibroblasts with indomethacin and is reconstituted by adding exogenous PGE2. A study of the kinetics of this interaction shows that exposure to monocyte supernatant for 30 min to 1 hr is sufficient to cause significant inhibition of fibroblast proliferation and that this effect can be halted, but not reversed, at any stage by incubation with indomethacin. We also show that fibroblasts derived from patients with pulmonary fibrosis are affected more quickly by exposure to the mediators, although the final extent of inhibition seen at each concentration of mediators is similar in normal and "fibrotic" fibroblasts. These studies indicate that activated AM or PBM release cytokines (including IL-1) which inhibit the growth of proliferating normal and fibrotic fibroblasts through activation of the intrinsic arachidonic acid pathway of this cell and also that this effect requires a continuous activation of this pathway to be fully expressed.

Acute response to bronchodilator. An imperfect guide for bronchodilator therapy in chronic airflow limitation.

We conducted a four-period cross-over randomized trial in which we found that patients with chronic airflow limitation demonstrated symptomatic improvement with both inhaled albuterol and oral theophylline. The response, however, was not uniform. We therefore tested the ability of acute change in forced expired volume in one second (FEV1) following inhaled beta agonist to predict long-term symptomatic response to albuterol and theophylline. We found that the reproducibility of acute change in FEV1 over three repetitions was poor (intraclass correlation 0.17). Furthermore, the mean improvement FEV1 following inhaled albuterol across the three repetitions did not relate closely to symptomatic response to either albuterol or theophylline. We conclude that acute response to inhaled beta agonist is not useful for identifying patients with chronic airflow limitation who are likely to benefit from bronchodilator treatment.

Aerosol fenoterol by intermittent positive pressure breathing in asthmatic patients.

Ten subjects with mild to moderately severe asthma participated in a study of the bronchodilator activity and incidence of side effects of fenoterol aerosol administered by intermittent positive pressure breathing (IPPB). The doses of fenoterol used in the Bird micronebulizer were 0, 0.25 mg, 0.5 mg, 1.0 mg, and 2.5 mg, and these were administered in a randomized, double-blind fashion. The bronchodilator response, assessed by the area under the FEV1 curve, showed mean (+/- SE) values of 1.44 +/- 0.53 1 hr for 0.25 mg of fenoterol to 1.66 +/- 0.56 1 hr for 2.5 mg of fenoterol (p greater than 0.05), longer (p less than 0.01) than the mean placebo response of 0.06 +/- 0.38 1 hr. A dose-dependent increase in tremor was observed for each of the doses of fenoterol. The 0.25-mg dose of fenoterol solution is an appropriate starting dose for the treatment of moderately severe asthma.

Response of asthmatic patients to fenoterol inhalation: a method of quantifying the airway bronchodilator dose.

A radiotracer technique is described which enables direct measurement of the dose and distribution of inhaled aerosol bronchodilator in man. The mean (+/-SD) amounts of the B2-adrenergic agonist, fenoterol, administered to a group of 12 asthmatic subjects in a double-blind randomized fashion were: placebo, 0 microgram; low dose, 5.6 (+/-1.2) microgram; medium dose, 32.7 (+/-7.3) microgram; and high dose, 127.5 (+/-29.2) microgram, with a mean of 86.3% of the total subject dose being deposited in the lungs. The medium and high doses of fenoterol produced similar increases above baseline in forced expired volume in 1 sec (FEV1), maximum flow at 50% of vital capacity (V max 50), and maximum flow at 25% of vital capacity (V max 25). These increases were greater than those with placebo for the entire 4-hr study (p less than 0.01). The low dose of fenoterol was more effective than placebo in increasing FEV1, V max 50, and V max 25 above baseline values (p less than 0.05), but not for the entire 4-hr study. The high-dose fenoterol caused palpitations and tremor in 3 of the 12 subjects, and the medium-dose fenoterol caused palpitations in one of these subjects.

Selectivity of beta adrenoreceptor antagonist drugs assessed by histamine bronchial provocation.

In a double-blind, within-patient, randomized study, 12 mild asthmatics were given single oral doses of propranolol (80 mg), metoprolol (100 mg), timolol (10 mg), or placebo. Resting heart rate and forced expiratory volume in one sec (FEV1) were measured before and 90 min after treatment. Nonspecific bronchial reactivity was measured by inhaled histamine at 90 min. Following each active drug, resting heart rate changed to a similar extent and to a greater degree than after placebo (p less than 0.01). Changes in FEV1 were small and not different from those after placebo. In contrast, after each active drug, bronchial reactivity increased more than after placebo. The degree of reactivity with each active drug was similar but the differences from corresponding placebo values were significant (p less than 0.05). We conclude that, in mild asthmatics, nonspecific bronchial reactivity is a more sensitive index of airway effects than resting FEV1. Moreover, in the context of this study, since the beta-blockers were given in doses likely to induce equivalent cardiac beta-blockade, there is no evidence to suggest that any one of them is more "cardioselective" than the others.

Principles of aerosol therapy.

Aerosol therapy with a variety of drugs is superior to oral and, except perhaps in status asthmaticus, parenteral therapy. An understanding of aerosol physics and the physiologic characteristics relating to ventilation allows optimum aerosol delivery for maximum benefit in the majority of patients. In those patients who are unable to use metered-dose inhalers effectively, simple inhalation devices have been developed which assure breath-actuated aerosol delivery to the lower respiratory tract with minimal side effects.

Hemoptysis due to MDI therapy in a patient with permanent tracheostomy: treatment with mask AeroChamber.

Persistent minor hemoptysis resulted from extensive granulation tissue on the main carina and adjacent bronchi due to frequent spraying of metered-dose inhaler (MDI)-generated aerosol medications directly into a permanent tracheostomy. Salbutamol, containing oleic acid, was considered the most likely cause. After an AeroChamber equipped with an infant mask was interposed between the MDI and the tracheal stoma, hemoptysis and the pathologic changes gradually resolved.

Cerebral dye embolus: a complication of selective bronchography following transbronchial biopsy.

Cerebral embolization of an aqueous solution of propyliodone (Dionosil) occurred during selective bronchographic studies following a fiberoptic bronchoscopic procedure with transbronchial biopsy in a patient undergoing investigation of a pulmonary lesion. The embolization resulted in a grand mal seizure and transient neurologic deficits. This potential complication has not been previously reported. We suggest that selective bronchographic studies be avoided when the transbronchial biopsy is associated with endobronchial bleeding.

Thoracoscopy. A safe, accurate diagnostic procedure using the rigid thoracoscope and local anesthesia.

A thoracoscopic examination was performed in 41 patients under local anesthesia in the lateral decubitus position. Prior thoracocentesis (38 patients) and blind biopsy with an Abrams' needle (32 patients) had been nondiagnostic. The initial nine patients were examined with the flexible fiberoptic bronchoscope, yielding a diagnostic accuracy of 56 percent (five cases). This technique was discontinued when two patients had normal findings on biopsies, despite the visual observation of later diagnosed carcinoma. Subsequent thoracoscopic procedures were performed with a rigid 11-mm single-puncture thoracoscope (Storz), which was diagnostic in 28 (88 percent) of the remaining 32 patients. A hemothorax (400 ml) was the only potentially serious complication. Twelve patients were prospectively monitored during the thoracoscopic procedure for changes in cardiac rhythm and oxygen saturation. Sinus tachycardia was the only arrhythmia observed. The mean fall in oxygen saturation was 1.4 percent. We conclude that thoracoscopic examination with the rigid thoracoscope is diagnostically superior to the fiberoptic bronchoscope and is a safe procedure which can be performed under local anesthesia.

Management of asthma and chronic airflow limitation. Are methylxanthines obsolete?

After almost 50 years as first-line drugs in the management of asthma and COPD, methylxanthines have been largely superceded by inhaled adrenoceptor agonist and anticholinergic bronchodilators which are more potent and far less toxic. Accumulating evidence indicates that intravenous theophylline contributes side effects, but is rarely of benefit in acute exacerbations of asthma or COPD. In the maintenance therapy of asthma, first-line therapy is dose-optimized inhaled steroids, reducing the need for bronchodilators. Inhaled adrenoceptor agonists are second line medications, anticholinergic aerosols third line, and theophylline, if needed at all, may fulfill a minor systemic steroid-sparing function in severe asthmatics on maximum doses of the inhaled medications. In the maintenance therapy of some patients with COPD, theophylline sometimes may be useful but these responders should be identified by objectively establishing therapeutic benefit. Since many patients have side effects from the methylxanthines, while their therapeutic benefit over and above dose-optimized inhaled therapy is marginal, their continued almost routine use in the management of reversible airflow obstruction is hard to justify, although this class of drugs may be useful in selected patients in whom both subjective and objective benefit can be demonstrated. In COPD, theophylline may improve exercise capacity in some patients by still incompletely understood mechanisms probably unrelated to bronchodilation.

Are active and passive smoking harmful? Determining causation.

Assessing the evidence regarding any causal question involves examining the strength of the studies conducted and applying a series of "diagnostic tests" for causation. We have reviewed the strength of the evidence incriminating smoking as a cause of lung cancer, and passive smoking as a cause of respiratory illness and decreased pulmonary function in children. There are eight prospective studies of smoking and lung cancer which have consistently shown a strong relationship. These studies have confirmed the temporality of the association and demonstrated a dose-response gradient. The studies addressing the effects of passive smoking in children are considerably weaker. Although they are consistent in suggesting increased infections for children less than one year of age, neither increased risk nor a dose-response gradient is consistently found in older children and the effect size, when present, is small. The rules for assessing causation applied here can be used to integrate new information concerning the health hazards of smoking.

Dose-effect relationship of the beta-agonists fenoterol and salbutamol in patients with asthma.

QUESTION: What is the relative per microgram potency and side effect profile of the beta-agonists salbutamol and fenoterol? METHOD: The relative bronchodilator (delta FEV1, V25, V50) potency and side effect profile (delta tremor, heart rate, breathlessness, BP) of nebulized salbutamol and fenoterol were evaluated by means of a randomized, double-blind, crossover, cumulative (50 to 2,500 micrograms) dose-response study. Both beta-agonists were administered to 12 patients with stable asthma over age 18 years with baseline FEV1 between 35 to 70 percent predicted. RESULTS: (1) Salbutamol and fenoterol both provided significant bronchodilatation compared with baseline. (2) There was no dose-effect difference between the two beta-agonists with respect to bronchodilator response. (3) Overall there was no significant difference between the side effect profiles of the two beta-agonists, although at the highest dose of fenoterol, there was marginally greater tremor when measured by accelerometry. (4) There was no difference in the vital signs or subjective patient evaluations of tremor, palpitations, or breathlessness as estimated by a visual analogue scale. (5) No significant adverse reactions occurred. SUMMARY AND CONCLUSION: Equivalent bronchodilatation and similar side effect profiles were measured in a group of patients with stable asthma after treatment with nebulized salbutamol or fenoterol in the dose range 50 to 1,250 micrograms (cumulative, 2,500 micrograms). This indicates that both beta-agonists have similar per microgram potency and side effect profiles. Observed clinical differences in response or side effects associated with fenoterol metered-dose inhaler administration may be a result of its higher dose per puff metered-dose inhaler formulation.

Laser resection of a pedunculated tracheal adenoma.

We report a case of tracheal adenoma presenting as hemoptysis and reversible airflow obstruction in an ex-smoker. A questionable defect in the tracheal air shadow on a posteroanterior chest radiograph was shown on CT to be a pedunculated, mid-tracheal tumor. Two-stage bronchoscopic laser resection resulted in an apparently normal tracheal mucosa. Results of postresection spirometry were normal.

A controlled trial of ambroxol in chronic bronchitis.

Ambroxol is a mucolytic agent which is widely used in chronic bronchitis in Europe. We conducted a double-blind randomized controlled trial of ambroxol vs matched placebo in 90 patients with chronic bronchitis and difficulty clearing secretions. It was concluded that there was no advantage to taking ambroxol.

Clinical evaluation of a simple demand inhalation MDI aerosol delivery device.

Inhalation of medication is the preferred method for treating reversible airway obstruction; however, difficulties in the use of pressurized canisters frequently lead to suboptimal results. The Aerochamber (Monoghan Medical Corp) is a portable breath-actuated device that attaches to a metered-dose inhaler (MDI) and is designed to overcome many of the problems of aerosol delivery encountered by some patients. The attachment of this breath-actuated device to an MDI reduced pharyngeal deposition of aerosol 14-fold, but delivery of aerosol to intrapulmonary airways in normal subjects and patients with bronchitis remained unchanged. In a group of nine patients with stable asthma, inhalation of a bronchodilator aerosol using the breath-actuated device (Aerochamber) achieved effective bronchodilation similar to an optimally administered MDI. Advantages of the breath-actuated device (Aerochamber) include (1) aerosol delivery of medication whether or not the discharge of aerosol is synchronized with inhalation, (2) effective therapeutic response compared with optimally administered MDI; (3) greatly reduced deposition of aerosol in the upper airways, which might be expected to reduce adverse effects of steroids; and (4) universal application to all bronchodilator and steroid MDIs.

Efficiency of bronchodilator aerosol delivery to the lungs from the metered dose inhaler in mechanically ventilated patients. A study comparing four different actuator devices.

STUDY OBJECTIVE: To compare aerosol delivery to the lungs in ventilated patients from two devices with holding chamber and two devices without holding chamber. DESIGN: A controlled clinical trial with randomization to one of four delivery devices. SETTING: An academic university-affiliated Canadian ICU. PATIENTS: Forty-eight patients undergoing mechanically assisted ventilation for a variety of clinical reasons and each judged to require inhaled bronchodilator therapy by the attending physician. INTERVENTIONS: Patients received 4 puffs of fenoterol labeled with technetium 99m pertechnetate delivered by metered-dose inhaler via 1 of the following: A, a 167-ml chamber device; B, a 700-ml chamber device; C, a nonchamber device (A, B, and C, all in the ventilator inspiratory line); and D, a nonchamber device on the end of the endotracheal tube. MEASUREMENTS AND RESULTS: One-minute images of the thorax were made by a portable gamma camera at the bedside. Deposition of radioactivity in the lungs (uncorrected for tissue absorption and calculated as a percentage of the radioactivity delivered from 4 puffs) was 5.53 +/- 0.72 (mean +/- 1 SEM), 6.33 +/- 1.16, 1.67 +/- 0.43, and 3.89 +/- 0.52 percent for devices A, B, C, and D, respectively (p = 0.004). Subgroup analysis showed a statistically significant difference in delivery between devices A and C and between devices B and C only. CONCLUSION: There were statistically significant differences between delivery from both chamber devices and the inline nonchamber device, but not between delivery from other devices. Further work will be necessary to determine the effect of device position in the ventilator circuit on aerosol delivery.

Ciliary function, cell viability, and in vitro effect of ribavirin on nasal epithelial cells in acute rhinorrhea.

Nasal epithelial (NE) cells were collected from the nasopharynx of 25 individuals with symptomatic colds and 27 healthy volunteers (controls), and ciliary beat frequency (CBF) was assessed by microscopy employing video motion analysis techniques. Baseline CBF was statistically significantly elevated in the group with colds compared to the control group (14.6 +/- 1.5 Hz [mean +/- SD] vs 13.8 +/- 0.9 Hz; p = 0.02). After four days of incubation in culture, there was a significant decrease in the CBF in both groups, with a change from baseline of 1.9 Hz for the cold group, compared to 1.0 Hz for the control group (p = 0.0001). The in vitro addition of ribavirin at 500 micrograms/ml to NE cells from individuals with colds preserved the viability of the cells and maintained the CBF at baseline values. Twenty-four (96 percent) of 25 ribavirin-treated specimens from the cold group survived for four days in culture, compared with 17 (68 percent) of 25 untreated cold specimens. In addition, the ribavirin-treated cells had a mean CBF of 14.2 +/- 1.3 Hz, compared with 12.7 +/- 1.9 Hz for the untreated cell samples (p = 0.0005). Ribavirin had no effect on NE cells from the control group. These results suggest that ribavirin in a concentration of 500 micrograms/ml may have some benefit in the treatment of acute rhinorrhea.

The preferential deposition of inhaled isoproterenol and propranolol in asthmatic patients.

This study describes the use of central and diffuse airway deposition patterns of isoproterenol and radiotracer aerosol alone, and in the presence of centrally deposited propranolol and radiotracer aerosol, to investigate the distribution of beta 2 adrenoreceptors in six asthmatic patients. The central deposition technique was only partially successful. No definite beta 2 receptor distribution pattern could be interpreted from the airway function responses. It was noted that 3-10 micrograms of isoproterenol in the airways was able to produce 50 percent of the maximum possible flow rate response. Centrally deposited propranolol was an effective antagonist of isoproterenol.

The dyskinetic cilia syndrome. Ciliary motility in immotile cilia syndrome.

Ciliary motility was studied in three patients with Kartagener syndrome who had previously been found to have absent nasal and pulmonary mucociliary transport and missing dynein arms in nasal cilia. A video system was used to record movement of cilia obtained by nasal brushings for analysis of wave form and beat frequency. Two patterns of abnormal ciliary beat were observed; an oscillating and a rotating type of motion. There was no evidence of planar coordination of metachronicity. This abnormal motion was present in up to 40 percent of cells and the remainder were totally immotile. Thus, in Kartagener syndrome many ciliated cells are motile, but the motion is abnormal. We suggest that "immotile cilia syndrome" is a misnomer, and recommended it be renamed "dyskinetic cilia syndrome."

A randomized controlled trial on the effect of inhaled corticosteroids on airways inflammation in adult cigarette smokers.

STUDY OBJECTIVE: To determine whether inhaled corticosteroid treatment can reduce airways inflammation in adult cigarette smokers. DESIGN: This was a randomized, placebo-controlled, double-blinded clinical trial. SETTING: The subjects were recruited from the community by advertising. PARTICIPANTS: Seventy-one adults with a > or = 5 pack-year history who were current smokers, had a normal FEV1, and produced sputum daily. INTERVENTION: Sixty subjects were randomized to receive four puffs of placebo or beclomethasone dipropionate ([BDP]; total dosage, 1,000 microg/d) using a metered-dose aerosol inhaler with a valved holding chamber (AeroChamber; Trudell Medical; London, Ontario, Canada) for 28 days. MEASUREMENTS AND RESULTS: Eleven subjects were not randomized because of poor compliance. The primary outcome was fractional airway neutrophilia, as assessed by a differential cell count of sputum. Additional outcome measures were spirometry, measurement of airway responsiveness by methacholine challenge, and lung epithelial permeability measured by the clearance of radiolabeled diethylenetriamine pentaacetic acid. There were no significant differences between the two groups in any outcome measurement after 4 weeks of treatment. CONCLUSIONS: With normal spirometry, we found no benefit of treatment with inhaled BDP, 1,000 microg/d, on noninvasive measures of airways inflammation in adult smokers. This indicates that cigarette smoke-induced inflammation in its early stages (before a demonstrable airflow obstruction) is not steroid sensitive. This may occur because the site of involvement is not accessible to inhaled medications or because the inflammatory process is resistant to moderate doses of inhaled corticosteroids.