Patterns of lung disease in a "normal" smoking population: are emphysema and airflow obstruction found together?

STUDY OBJECTIVES: We determined whether emphysema demonstrated on high-resolution CT (HRCT) scanning in apparently well smokers is associated with airflow obstruction. INTERVENTIONS: Lung function testing and limited HRCT scanning. DESIGN: Lung function measurements and scans were analyzed independently of each other. We used analysis of covariance to compare FEV(1) and maximum expiratory flow at 50% of vital capacity (MEF(50)) values after suitable corrections, between subjects with and without parenchymal damage (emphysema and/or reduced carbon monoxide transfer coefficient [KCO]), and to compare indexes of parenchymal damage between subjects with and without airflow obstruction. SETTING: Radiology and lung function departments of a district general hospital. PARTICIPANTS: Eighty current cigarette smokers and 20 lifetime nonsmoking control subjects (aged 35 to 65 years) who volunteered following publicity in local media. In all subjects, FEV(1) was > 1.5 L; no subjects were known to have lung disease. MEASUREMENTS AND RESULTS: FEV(1) and MEF(50) were measured spirometrically; static lung volumes were measured by helium dilution and body plethysmography; KCO was measured by a single-breath technique. HRCT scans were analyzed for emphysema by two radiologists. Of smokers, 25% had HRCT emphysema, generally mild; 16.3% and 25% had reduced FEV(1) and MEF(50), respectively; 12.5% had reduced KCO. Smokers with airflow obstruction were not more likely to have parenchymal damage. Smokers with parenchymal damage did not have reduced airway function. Nonsmokers generally had normal airways and parenchyma. CONCLUSIONS: "Normal" smokers with lung damage had either airflow obstruction or parenchymal damage, but not generally both.

Bronchial responsiveness to beta-adrenergic stimulation and enhanced beta-blockade in asthma.

OBJECTIVE: Beta-adrenergic blocking drugs have no effect on the airways of normal subjects but in asthma even small doses may cause severe deterioration. A seemingly obvious explanation for this abnormal sensitivity is that asthmatic airways, but not normal airways, are tonically dilated by the sympatho-adrenal system. However, studies suggest that sympatho-adrenal activity is normal in asthma, as is bronchial sensitivity to beta-agonists. The present study re-examines bronchial beta-adrenergic sensitivity in asthma and also measures antagonism produced in normal and asthmatic bronchi by a beta-blocking drug. METHODOLOGY: The threshold bronchodilator doses of inhaled isoprenaline (dose required for a 35% increase in specific airway conductance 'PD35') was measured in 11 normal and 14 asthmatic adults on two separate occasions. After administering propranolol (inhaled or intravenously) PD35 was remeasured. RESULTS: Sensitivity to isoprenaline was greater in symptomatic asthmatics (PD35 = 0.003 micromol) than in asymptomatic asthmatics (PD35 = 0.021 micromol) and in non-asthmatics (PD35 = 0.123 micromol; P < 0.001 in each case). Symptomatic asthmatics also showed 66-fold more antagonism than non-asthmatics when they were given propranolol by inhalation (P < 0.001) and sixfold more with intravenous propranolol (P = 0.005). CONCLUSIONS: The increased sensitivity of asthmatics to inhaled isoprenaline suggests that they may also be more sensitive to their endogenous adrenaline, which may thus dilate and stabilize their airways. Taken with enhanced antagonism by propranolol, this provides insight into the aggravation of asthma by beta-blocking drugs.

Purification and N-terminal amino acid sequence of sheep neutrophil cathepsin G and elastase.

Sheep cathepsin G (CG) and neutrophil elastase (NE) were isolated from a crude leukocyte membrane preparation by elastin-Sepharose 4B and CM-Sepharose 4B chromatography, followed by native preparative PAGE. The N-termini of CG and NE were sequenced to 24 and 20 residues, showing 96 and 85% identity with human CG and NE, respectively. During SDS-PAGE, sheep CG and NE migrated parallel to human CG and NE and have apparent molecular masses of 28 and 26 kDa, respectively. Following incubation of sheep CG and NE with human alpha(1)-antichymotrypsin and alpha(1)-proteinase inhibitor, complexes with apparent molecular masses of 89 and 81 kDa respectively were observed by SDS-PAGE. Polyclonal antibodies to human CG and NE cross-reacted with purified sheep CG and NE, respectively. These results indicate that sheep neutrophils contain CG and elastase that are analogous to human CG and NE in terms of molecular mass, reactivity with endogenous inhibitors, immunocross-reactivity, and N-terminal sequence.

Endogenous cortisol and lung damage in a predominantly smoking population.

We examined the association of endogenous corticosteroid status with lung structure and function in a cross-sectional and longitudinal study in response to a recent finding of a relationship between plasma cortisol and rate of annual decline in airway function. We recruited 74 cigarette-smoking and 20 never-smoking volunteers 35 to 65 yr of age after publicity in local media. Exclusion criteria were FEV1 < 1.5 L or a history of airway disease. We performed spirometry and a high resolution CT lung scan and measured CO transfer, serum cortisol, and 24-h urinary cortisol excretion. There were no differences in serum or urinary cortisol between those with and those without low FEV1, low KCO, or high resolution CT (HRCT) emphysema, except that urinary cortisol was 19% higher in subjects with HRCT emphysema (p = 0.05). Log urinary cortisol/body weight was negatively correlated with KCO (p = 0.000) and KCO was lower in the highest tertile of urinary cortisol (p = 0.001). Subjects were restudied after 520 +/- 69 d. Changes in FEV1 and KCO showed no significant correlations with serum or urinary cortisol. We conclude that airway function does not relate to serum or urinary cortisol, but there may be a relationship between cortisol excretion and emphysema.

Cigarette smoke inhalation and lung damage in smoking volunteers.

Cigarette smoking is the dominant risk factor for chronic obstructive pulmonary disease (COPD) but only 10-15% of smokers develop the condition. Risk does not relate closely to cumulative cigarette consumption, perhaps because smokers vary in the degree and depth of smoke inhalation. This study examined the role of smoke inhalation in the development of COPD. Eighty current smokers and 20 lifetime nonsmoking volunteers (aged 35-65 yrs) were recruited. Lung function variables were measured and high-resolution computed tomography (HRCT) scans performed. Smoke inhalation was assessed by CO boost (the increment of expired carbon monoxide 5 min after smoking a cigarette) and serum cotinine. Mean CO boost was 6.3 parts per million (ppm) in smokers with low CO transfer coefficients (KCO) and 2.9 ppm in those with normal KCO (p=0.006); 7.2 ppm in smokers with both HRCT-defined emphysema and a low KCO and 2.6 ppm in those with neither abnormality (p=0.002); 4.5 ppm in smokers with HRCT-defined emphysema alone and 2.8 ppm in those without (p=0.08). Mean serum cotinine was 328 ng x mL(-1) in smokers with chronic productive cough and 243 ng x mL(-1) in those without (p=0.005). Lifetime nonsmokers had normal HRCT scans, lung function and serum cotinine. Emphysema is associated with high alveolar smoke exposure as measured by CO boost. Productive coughing is associated with high nicotine uptake, probably from airway smoke particle deposition.

Purification and characterization of a novel Kazal-type serine proteinase inhibitor of neutrophil elastase from sheep lung.

A Kazal-type elastase inhibitor was purified by trichloroacetic acid precipitation of sheep lung lavage fluid followed by chymotrypsin affinity and gel-filtration chromatography of the supernatant. Sheep lung elastase inhibitor (SLEI) is glycosylated. Laser desorption mass spectrometry indicated that SLEI has a molecular mass of 16.8-17.3 kDa. Partial protein sequence of SLEI and of a peptide derived from SLEI showed 31-52% and 51-66% homology at the N-terminus and at the inhibitory site respectively with Kazal-type double-headed proteinase inhibitors (bikazins). SLEI inhibited human leukocyte elastase and porcine pancreatic elastase but not human cathepsin G. It was inactivated by chloramine-T and reactivated when incubated with methionine sulfoxide peptide reductase and dithiothreitol, indicating the presence of a methionine at the active site. The concentration of SLEI in bronchoalveolar lavage fluid (BALF) and lung lymph was 0.28 microM (0.23-0.49); 0.24 microM (0.20-0.31) (median, (range), n = 5), respectively and was undetectable in plasma (< 0.03 microM) suggesting that SLEI is produced in the lung. The median molar ratios of SLEI to alpha1-proteinase inhibitor in BALF and lung lymph were 3.2 to 1 and 0.017 to 1, respectively. These results indicate that SLEI probably makes an important contribution to antielastase defence in epithelial lining liquid.

Effects of smoking and clinical status on lung function in human immunodeficiency virus (HIV)-seropositive subjects.

Lung function was measured at 3-month intervals for up to 1 yr in a group of Caucasian HIV-seropositive subjects. The objective was to document any deterioration in lung function and seek correlations between such deterioration and smoking history and Centers for Disease Control (CDC) status. Ninety-nine subjects were studied at enrollment; 43 were followed-up (mean duration 9 +/- 3 months). Ninety-five of the 99 enrolled subjects remained free of HIV-related respiratory disease and were included in the analysis. At enrollment, carbon monoxide diffusing capacity (TLCO) was significantly lower than predicted in non-smokers, smokers and ex-smokers (88, 77 and 88%, respectively, P < 0.001). The TLCO measurements in the smoking group were significantly lower than those of the life-long non-smoking subjects (P < 0.01). Residual volume (RV) was significantly higher than predicted in smokers (111%, P = 0.02). During follow-up, all three groups demonstrated significant declines in TLCO (7%, P = 0.01; 9%, P = 0.005; 13%, P < 0.001, respectively), and increases in RV (9%, P = 0.03; 13.5%, P = 0.02, 22%, P = 0.02, respectively). At enrollment, significantly lower than predicted values of TLCO were observed in groups stratified by CDC criteria: in asymptomatic HIV-seropositive subjects (CDC 11) 89%, P = 0.01; persistent generalized lymphadenopathy (PGL) 84%; AIDS-related complex (ARC) 81%; and in non-pulmonary AIDS (IV C1) 69%, P = 0.0001, respectively. Residual volume was significantly higher than predicted in CDC II (114%, P = 0.05). During follow-up, TLCO fell in groups PGL and ARC by 7 and 9%, respectively, while RV increased in groups CDC II, PGL and ARC by 17, 15 and 8%, respectively. Only the TLCO decline in PGL showed any linkage to clinical deterioration. This study demonstrates deficits at enrollment, and a continuing decline of TLCO and increase in RV in HIV-seropositive subjects without overt lung disease.

Enhanced muscarinic receptor blockade with atropine in the asthmatic tracheobronchial tree. Evidence for increased drug delivery.

We measured the competitive antagonistic effect of atropine in bronchi of 8 normal and 15 asthmatic subjects. Classic pharmacologic theory states that the degree of competitive antagonism depends only upon (1) antagonist concentration at the receptor and (2) receptor affinity. Delivery and affinity also influence agonist responsiveness, but measurement of bronchial antagonism allows study of these factors in isolation. Bronchial responsiveness to methacholine was measured as the cumulative dose required to produce a 35% fall in specific airway conductance (PD35). On different days three measurements of control PD35 were made on each subject. On 2 days PD35 was measured after inhalation of 0.14 mg atropine and, on another day, after intravenous injection of 0.32 mg atropine. The antagonist effect of atropine was measured as dose ratio - 1 (DR - 1), where DR = PD35 after atropine/control PD35. Geometric mean DR - 1 with inhaled atropine in asthmatic subjects (11.7) was 6.3 times that of normal subjects (1.9) (p less than 0.001), and DR - 1 with intravenous atropine in asthmatic subjects (8.0) was 5.6 times that of normal subjects (1.4) (p less than 0.001). In conclusion, there is enhanced muscarinic blockade from inhaled and intravenously administered atropine in asthmatic bronchi. We suggest that this is due to increased access of the drug to bronchial muscarinic receptors.

Measurement of lung tissue mass in interstitial lung disease.

A gamma camera and 99m Technetium were used to obtain transmission and emission scans of the thorax in order to estimate transthoracic tissue thickness, and volumes of blood and interstitial tissue in each pixel of the gamma camera image. This technique has been applied to six patients with stage 2/3 pulmonary sarcoidosis and eight with cryptogenic fibrosing alveolitis and age and sex-matched control groups without lung disease. In both conditions transthoracic tissue thickness was significantly increased: mean values (SD) were 14.6 (1.8) cm in cryptogenic fibrosing alveolitis and 12.3 (2.2) cm in stage 2/3 sarcoidosis. This was partially accounted for by an increase in the interstitial fluid compartment. Blood volume was unaffected. Measurement of transthoracic tissue thickness involves minimal radiation exposure and may be of value in monitoring these diseases; measurement of interstitial fluid volume may give information on disease activity.

Airway obstruction and bronchial hyperresponsiveness in left ventricular failure and mitral stenosis.

Small and large airways narrow in LVF and the term cardiac asthma is often used. However, current usage of this term is inconsistent and its meaning is therefore ambiguous. The term is better avoided despite several emerging similarities with bronchial asthma. Airway narrowing may be precipitated by acute elevation of pulmonary or bronchial vascular pressures. This appears to be mainly due to reflex bronchoconstriction. The afferents of this reflex are C-fibers with their endings in the lung parenchyma, bronchi, and pulmonary blood vessels and RAR in the larger airways, and they run in the vagus nerves, as do the efferent bronchoconstrictor fibers. Chronic elevation of pulmonary vascular pressures, as in mitral stenosis, are also associated with airway narrowing. Pulmonary edema (in the absence of vascular hypertension) also causes reflex bronchoconstriction. Bronchial responsiveness to bronchoconstrictor drugs is increased in LVF, partly, at least, due to reflex mechanisms. Bronchial mucosal swelling may also contribute. Narrowing by nonreflex mechanisms definitely occurs and there is direct evidence that decreased lung volume caused by pulmonary edema may cause this. There is little evidence for bronchial narrowing due to the mechanical effect of peribronchial edema, or by swelling of the bronchial mucosa. However, edema foam may terminally cause grave obstruction. Patients with LVF are commonly treated with bronchodilator drugs, but the basis for this approach needs further clarification.

Use of an impedance meter for measuring airways responsiveness to histamine.

We compared spirometry (FEV1) and airway impedance (z) in the assessment of airway responsiveness to histamine. Airway impedance was measured by the oscillator technique during quiet breathing; both measurements were made twice after each increment of histamine during the challenge. Percentage change in impedance was related to percentage change in FEV1 according to: -delta z = 1.09-2.66 (delta FEV1), r = -0.73, p less than 0.01, ie, impedance increased on average 2.7 times as much as FEV1 fell. The cut-off point for the standard test is the histamine concentration giving a 20 percent fall of FEV1 (PC20(FEV1)). The corresponding cut-off value chosen for impedance was a 30 percent increase (PC30(z)). (PC30(z)) = 0.74 (PC20(FEV1))-0.48, rs = 0.88, where rs is the Spearman rank correlation coefficient. Thus, impedance is a more sensitive index than FEV1 because a smaller dose of histamine gave a diagnostic result. Impedance is a practical alternative to FEV1, being less arduous for the patient and requiring little cooperation.

Estimation of lung oedema in humans by transmission-emission scintigraphy with 99Tcm.

UNLABELLED: We have used a combination of transmission and emission gamma camera techniques to scan the thorax in the anteroposterior plane in 21 patients with partially treated cardiogenic pulmonary oedema and have compared their results with those from 20 age-matched normal subjects who were scanned previously. For transmission scanning, an external 99Tcm flood source was used; for emission scanning we labelled sequentially the vascular compartment with 99Tcm autologous erythrocytes and the interstitium with 99Tcm diethylenetriaminepentaacetic acid (99Tcm-DTPA). From the transmission scans we derived the transthoracic tissue thickness (Tt) and from the emission scans, after correction for attenuation, the regional blood and interstitial volumes. In the lower zone of the right lung, mean (S.D.) Tt in normal subjects was 10.9 (S.D. 3.1) cm and in subjects with lung oedema was 12.5 (S.D. 3.1) cm (P = 0.07). There was a weak correlation between Tt and a radiographic numerical score of oedema severity (r = 0.47, P less than 0.05). In eight subjects with lung oedema, lung tissue thickness (T1) was estimated (by subtraction from Tt of radiographically estimated chest wall thickness). The T1 correlated closely with the radiographic score (r = 0.78, P less than 0.01). There was no significant change in blood or interstitial volumes in oedema. IN CONCLUSION: (1) transmission scanning gives an indication of oedema severity if an allowance is made for chest wall thickness; (2) 99Tcm-DTPA fails to equilibrate fully with oedema liquid during an equilibration period of 5 min.

Isolation and characterization of sheep alpha 1-proteinase inhibitor.

Sheep plasma proteinase inhibitor, analogous to human alpha 1-proteinase inhibitor (alpha 1 PI), was isolated to homogeneity. Purification was achieved by using (NH4)2SO4 precipitation, concanavalin A-Sepharose chromatography, Mono Q ion-exchange chromatography and PAGE. Sheep alpha 1 PI had an Mr of 56,000, inhibited human leucocyte elastase, pig pancreatic elastase and bovine trypsin on a 1:1 molar basis and had a plasma concentration of 1.6 +/- 0.21 g/l (mean +/- S.D.). Amino acid/carbohydrate composition (15% glycosylated) was similar to that of human alpha 1 PI (16% glycosylated); N-terminal analysis to 31 residues revealed 48-52% identity between the human and sheep proteins. Sheep alpha 1 PI was susceptible to oxidative inactivation by chloramine-T. Re-activation with the use of methionine sulphoxide peptide reductase and dithiothreitol indicated the presence of a methionine residue at the active site. These results establish that sheep alpha 1 PI has functional and structural characteristics close to those of human alpha 1 PI.

Thoracic tissue thickness measured by transmission scintigraphy with 99Tcm.

A flood source containing 25 mCi of technetium-99m (99Tcm) was used to measure thoracic tissue thickness (Tt) in 20 healthy subjects, 14 patients with cardiogenic pulmonary oedema, 8 patients with biopsy proven cryptogenic fibrosing alveolitis (CFA) and 10 subjects with radiographic evidence of severe, widespread emphysema. Unattenuated counts from the flood source were acquired first, and then with the subject seated between the flood source and the gamma camera, a second scan of transmitted counts was acquired. Assuming a constant linear attenuation coefficient of 0.135 cm-1, we calculated Tt per pixel of the gamma camera image, thus creating a profile of Tt throughout the length of the thorax. In normal subjects mean (S.D.) Tt at the base of the right lung was 10.8 (2.4) cm. In patients with pulmonary oedema, CFA and emphysema, mean (S.D.) values for Tt, in cm, were 12.9 (2.7) p less than 0.05, 14.4 (1.9) p less than 0.001 and 6.0 (1.1) p less than 0.0001 respectively. This simple, quick and inexpensive technique could be used to give regional measurements of Tt.

The influence of aerosol retention and pattern of deposition on bronchial responsiveness to atropine and methacholine in humans.

We have examined the influence of total intrapulmonary deposition and its pattern on the bronchial response to aerosolized methacholine and atropine in 10 normal and 12 asthmatic subjects. On Day 1 we performed a dose-response challenge to methacholine and defined responsiveness as the provocative dose (PD35) needed to cause a 35% decrease in specific airway conductance (SGaw). On Day 2 we repeated methacholine challenge after premedication with aerosolized atropine, and we defined the response to atropine as dose ratio-1 (DR-1) where DR = PD35 after atropine/PD35 without atropine. On Day 3 we imaged intrapulmonary aerosol deposition by mixing 99mtechnetium with methacholine aerosol and scanning the thorax with a gamma camera during the development of bronchoconstriction. Total pulmonary aerosol deposition varied considerably between individuals (1.2 to 23.6% of nebulized dose) but there was no difference between normal and asthmatic subjects, and no correlation between deposition and baseline SGaw or PD35; there was a significant positive correlation between deposition and DR-1. Deposition of aerosol in central lung zones was inversely related to SGaw and correlated positively with DR-1; there was no significant relationship with PD35. Total intrapulmonary aerosol deposition and its pattern partially determine bronchial responsiveness to atropine, but we have not demonstrated any significant effect on responsiveness to methacholine.

Measurement of lung tissue mass in Pneumocystis carinii pneumonia.

Transmission-emission scanning of the thorax with a flood source of technetium-99m (99mTc), autologous 99mTc labelled red blood cells, and diethylenetriaminepenta-acetic acid (99mTc DTPA) allows measurement of thoracic tissue thickness and blood and interstitial volume per pixel of the gamma camera image. Volume of blood or interstitium per pixel divided by pixel area gives the thoracic tissue thickness for these two compartments. A measure of lung tissue thickness may be obtained by subtracting chest wall thickness as measured on a lateral chest radiograph. As part of the evaluation of this technique 13 patients were scanned before treatment for proved or presumed pneumocystis pneumonia and their results were compared with those of 12 normal young men, approximately matched for age. In the patients with pneumocystis pneumonia lung tissue thickness at the base of the right lung averaged 3.4 cm (71%) more than that in the normal subjects, and interstitial thickness was 1.2 cm (150%) more than in the normal subjects. After treatment 10 of the patients with pneumocystis pneumonia were scanned again. Lung tissue thickness remained greater than the control value by 1.2 cm and interstitial tissue thickness by 0.5 cm. Blood thickness remained unchanged. Lung tissue and interstitial tissue thickness was correlated with a numerical score of the changes in the chest radiograph. The changes in the properties of the lung tissue compartments in the patients presumably reflect the mural and intra-alveolar inflammation found in pneumocystis pneumonia. Transmission scanning alone measures the increase of lung tissue thickness as well as transmission-emission scanning. It may be of value in monitoring the progress of this condition during treatment.

Long term survival after treatment of disseminated T cell lymphoma presenting with tracheal obstruction in a patient with coeliac disease.

A 46 year old man with coeliac disease and upper airway obstruction was thought to have undifferentiated carcinoma of the trachea. Subsequent immunohistological examination showed that the neoplasm was a T cell lymphoma. He had combination chemotherapy and is alive and well seven years after diagnosis.

Influence of airway calibre on the intrapulmonary dose and distribution of inhaled aerosol in normal and asthmatic subjects.

We investigated the relationship between airway calibre and the dose and distribution of inhaled aerosol in ten normal and six asthmatic subjects. Subjects inhaled saline aerosol containing 99mTcO4 delivered from a nebulizer connected to a dosimeter, and the lung fields were scanned with a gamma-camera. Right lung dose (RLD) was calculated as percentage of total dose. Intrapulmonary distribution was measured as penetration index (PI) (peripheral zone counts/central zone counts). Asthmatics had a significantly lower PI than normal subjects and there was a linear relationship between PI and baseline specific airway conductance (sGaw, p less than 0.001), and forced expiratory volume in one second (FEV1, p less than 0.05). After bronchodilatation with salbutamol (delta sGaw 101 +/- 31%, mean +/- SEM), PI increased from 0.73 +/- 0.11 to 1.09 +/- 0.15 (p less than 0.05); after bronchoconstriction with methacholine (delta sGaw 62.6 +/- 2.9%), PI decreased from 1.42 +/- 0.24 to 1.06 +/- 0.22 (p less than 0.05). Changes of PI were correlated with changes in sGaw and FEV1 (n = 20, p less than 0.001) but changes of RLD and changes in airway calibre were not. The distribution of inhaled aerosol, but not the dose, is largely dependent on airway calibre. The differences in PI between normal and asthmatic subjects may at best be explained by the differences in central airway calibre.

Morning-evening changes in airway responsiveness to methacholine in normal and asthmatic subjects: analysis using partial flow-volume curves.

In eight normal and eight asthmatic subjects airway responsiveness to methacholine was measured by means of partial flow-volume loops at 0800 and 1800 hours on the same day. Airway responsiveness was lower in the evening in both normal and asthmatic subjects.