Concentrations of volume-regulatory hormones after acute exercise in physically conditioned males.

Plasma renin activity and plasma concentrations of atrial natriuretic peptide (ANP), arginine vasopressin (AVP) and aldosterone (Aldo) were determined in six physically conditioned male volunteers and five unconditioned volunteers who served as controls. All volunteers were subjected to acute exercise for 15 min or until exhaustion. In the conditioned volunteers, the plasma concentrations of all hormones did not change when compared with pre-exercise values measured immediately after and 60 min after exercise. Similarly, plasma renin activity (PRA) after exercise was unchanged when compared with pre-exercise levels. In contrast, the unconditioned volunteers showed elevation of the plasma concentrations of AVP, and Aldo. PRA also increased in the unconditioned volunteers, but plasma ANP concentrations were not significantly different from base-line pre-exercise levels. These data suggest a decrease in central volume with exercise in the unconditioned individuals, which probably does not occur in the conditioned individual because of adaptive mechanisms. The data also suggest that in the physically conditioned individual, significant atrial distention with resultant release of atrial natriuretic peptide does not occur, or alternatively, that significant atrial distention in these subjects fails to produce the expected release of atrial natriuretic peptide. In the unconditioned individual, the postulated decrease in effective central volume following exercise would not be expected to trigger any rise in ANP.

Effect of age on changes in flow rates and airway conductance after a deep breath.

The effects of aging on changes in maximal expiratory flow rates and specific airway conductance after a deep breath were evaluated in 64 normal subjects. Flow rates (Vp) on partial expiratory flow-volume curves (PEFV), initiated from 60-70% of the vital capacity (VC), were compared with those (Vc) on maximal flow-volume curves (MEFV), initiated from total lung capacity (TLC), at a lung volume corresponding to 25% of VC on the MEFV curves. Specific airway conductance was measured before (sGaw) and after a deep inspiration (sGawDI). Bronchodilation after inspiration to TLC was inferred by Vp/Vc less than 1 and sGaw/sGawDI less than 1. The mean Vp was less than Vc. However, the ratio Vp/Vc increased significantly with age (r = 0.75, P less than 0.001). Specific conductance also increased after a deep inspiration (sGaw less than sGawDI). The ratio sGaw/sGawDIj increased slightly but significantly with age (r = 0.28, P less than 0.02). Measurement of lung elastic recoil pressures before and after a deep breath in a subgroup of patients (n = 14) suggested that the age-related increase in Vp/Vc was secondary to a decrement in the ability of a deep breath to decrease the upstream airway resistance. These findings suggest that even though changes in airway size after a deep breath as measured by sGaw/sGawDI have minimal age dependence, aging diminishes expiratory flow rates of MEFV curves relative to PEFV curves because of a decrease in the ability of a deep breath to increase the size of the peripheral airways.

Long-term survival of a lung cancer patient treated with photodynamic therapy.

A 63-year-old male, status post-right pneumonectomy, presented with hemoptysis. Although chest X-ray and CAT scan film findings were negative, bronchoscopy with biopsy from the left mainstem bronchus demonstrated squamous cell carcinoma. Because of the inoperable location of the lesion, the patient was treated with photodynamic therapy (PDT) in February 1984. At present, the patient is cancer free more then 6 years after PDT.

Effects of thoracic gas compression on maximal and partial flow-volume maneuvers.

Airway hysteresis can be evaluated by comparing maximal (MEFV) and partial (PEFV) expiratory flow-volume curves. The maneuvers are often obtained from pulmonary function systems that are subject to gas-compression artifacts. Because gas-compression artifacts might differentially affect PEFV vs. MEFV curves, we simultaneously obtained MEFV and PEFV curves by use of a spirometer and a volume-displacement plethysmograph (a method not subject to gas-compression artifacts) in normal and asthmatic subjects. Plethysmographic flow rates exceeded spirometric flow rates on all MEFV and PEFV maneuvers. When maximal flow exceeded partial flow (or vice versa) in the plethysmograph, the same result was virtually always observed for spirometric measurements. Alveolar pressure (PA) was higher on MEFV than on PEFV maneuvers in asthmatic subjects; comparisons between PA (on PEFV and MEFV maneuvers) in normal subjects varied at different lung volumes. Ratios of Vmax on PEFV maneuvers to Vmax on MEFV maneuvers (Vmax-p/Vmax-c) obtained from a volume-displacement plethysmograph differ quantitatively from ratios determined in systems subject to gas-compression artifacts; qualitatively, however, failure to account for thoracic gas compression ordinarily will not influence the ability to identify airway hysteresis (or lack thereof) by use of Vmax-p-to-Vmax-c ratios.

Effect of aerobic exercise on mouth-to-cecum transit time.

To examine the premise that exercise reduces the gastrointestinal transit time, we evaluated the effect of walking 4.5 km in an hour on mouth-to-cecum transit time. Twenty-three healthy volunteers, 9 men and 14 women, with an age range of 19-28 yr, were studied. After an overnight fast, the subjects ingested 10 g of lactulose in 150 ml of water while breath hydrogen concentrations were analyzed at 15-min intervals. On separate days, in random sequence, subjects either sat in a chair or walked on a treadmill for 60 min. Mean transit time was 55 +/- 8 min when resting and 89 +/- 4 min when exercising (p less than 0.001). In conclusion, light aerobic exercise prolonged the mouth-to-cecum transit time. On the basis of this observation, exercise as a causative factor in runner's diarrhea and its value in the management of chronic constipation may be questioned.

Beta-endorphin/beta-lipotropin release and gonadotropin secretion after acute exercise in physically conditioned males.

beta-endorphin (beta-EP) and beta-lipotropin (beta-LPH) concentrations were measured in the basal state and after acute exercise for 15 min or until exhaustion in 6 physically conditioned male volunteers. Serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and prolactin were also measured in the basal state. In addition, the concentrations of the gonadotropins (LH and FSH) were determined after exercise and the gonadotropin response to gonadotropin releasing hormone was assessed before and after exercise. The data show that acute exercise stimulates the release of both beta-EP and beta-LPH which return to base-line levels within 60 min after exercise. This is in contrast to our previously described results in physically unconditioned male volunteers in whom only beta-LPH release was noted after exercise. Serum LH concentrations declined after exercise reaching nadir values between 60 to 150 min after exercise. As we previously reported in physically unconditioned male volunteers, serum FSH concentrations did not change with exercise and the gonadotropin response to LRH stimulation was uninfluenced by exercise. Serum testosterone and prolactin concentration were within the normal range for healthy adult males. We speculate that the difference in beta-EP release with exercise in physically conditioned and unconditioned males represents a difference in processing of the opioid precursor molecule (pro-opiomelanocortin, POMC) in the two groups.

The MVV/FEV1 ratio in normal and asthmatic subjects.

We compared the ratio of maximal voluntary ventilation/forced expiratory volume in one second (MVV/FEV1) in normal individuals and asthmatic subjects. Our hypothesis was that MVV/FEV1 would be lower in asthmatic subjects. We also compared MVV/FEV1 results with the effects of deep inspiration (DI) on bronchomotor tone and with methacholine responsiveness. In normal subjects, MVV/FEV1 was higher than that in asthmatic subjects. Specific conductance (SGaw) increased after a single DI or an MVV maneuver in normal individuals. An MVV maneuver caused SGaw to decrease in asthmatic subjects. In asthmatic subjects, there was a significant correlation between MVV/FEV1 ratio and magnitude of decrease in SGaw after an MVV maneuver. Results of methacholine testing indicated that asthmatic subjects with low MVV/FEV1 ratios were more responsive to methacholine than those whose MVV/FEV1 ratios were within normal range. We conclude that MVV/FEV1 ratios are abnormally low in many asthmatic subjects and that low MVV/FEV1 ratios may indicate increased bronchial responsiveness to methacholine.

Physiologic characteristics of malignant unilateral main-stem bronchial obstruction. Diagnosis and Nd-YAG laser treatment.

To evaluate the effects of severe, unilateral main-stem malignant bronchial obstruction on airway dynamics, we obtained maximal expiratory flow-volume (MEFV) curves in 11 patients 59 +/- 18 yr of age (mean +/- 1 SD), three with and eight without underlying emphysema, before and after laser therapy (10 patients) or lung resection (one patient). Mean main-stem bronchial diameters before and after treatment were 1.1 +/- 1.3 and 9.0 +/- 0.8 mm, respectively (p less than 0.05). In the three patients with underlying emphysema, MEFV curves showed a diffuse intrathoracic obstructive pattern before and after treatment; in the other eight patients, MEFV curves demonstrated an apparently restrictive pattern, with associated airflow obstruction in four, reversible after laser treatment in three of these four. After treatment, all patients exhibited an increase in FVC with a roughly parallel shift of the MEFV curve and little change in the slope of the descending limb of the MEFV curve: FVC improved from 54 +/- 16 to 86 +/- 13% predicted in patients without emphysema and from 54 +/- 16 to 77 +/- 8% predicted in patients with emphysema, whereas the slope of the descending limb of the MEFV curve between 45 and 55% of FVC changed minimally from 2.0 +/- 0.6 to 1.8 +/- 0.5 s-1 in patients without emphysema and from 0.8 +/- 0.3 to 0.8 +/- 0.1 s-1 in patients with emphysema.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnosis and Nd-YAG laser treatment of unsuspected malignant tracheal obstruction.

Thirteen adult patients underwent palliative Nd-YAG laser treatment for relief of severe dyspnea due to malignant endotracheal obstruction. Three of the 13 patients had underlying chronic airflow obstruction (CAO) due to diffuse obstructive pulmonary disease. Despite dyspnea, cough, wheezing, stridor and/or hemoptysis, the diagnosis was delayed because of a normal chest roentgenogram in eight patients and nondiagnostic pulmonary function studies (including maximal expiratory and inspiratory flow-volume loops) in all three patients with CAO and in four of ten patients without CAO. The location of the tumor was extrathoracic in two patients, including one with CAO; intrathoracic in seven patients, including two with CAO; and combined extra- and intrathoracic in four. Tracheal diameter increased from 3.5 +/- 1.0 mm before, and to 9.8 +/- 2.0 mm after single or multiple laser treatments. Increased patency of the trachea after laser surgery was associated with improvement in expiratory and/or inspiratory flow rates and with symptomatic relief in all patients which persisted for 14.1 +/- 8.7 months (range four to 48 months). These results indicate that severe symptomatic narrowing of the extra- and/or intrathoracic trachea to a diameter of 2 to 5 mm may not be detected by conventional chest radiography or even by sensitive physiologic tests, especially in patients with underlying CAO. The resultant delay in diagnosis defers possible relief of disabling symptoms with palliative therapy, including Nd-YAG laser photocoagulation.

How much theophylline is enough?

Theophylline not only is a bronchodilator but also has other effects (inhibition of mediator release, enhancement of mucociliary clearance, enhancement of diaphragmatic contractility) that are potentially beneficial to asthmatic patients. Recent studies suggest that theophylline pharmacodynamics vary among asthmatic patients. However, on average, most of the total bronchodilatory response occurs at serum theophylline concentrations of 0 to 10 mg/liter. Additional (but less) bronchodilatation occurs at serum theophylline levels between 10 and 20 mg/liter. Pharmacodynamic relationships are not well established for other therapeutic effects of theophylline, such as attenuation of pharmacologically induced bronchoconstriction. An important feature of oral controlled-release theophylline therapy is timing of drug administration. Because airway reactivity increases and airway caliber decreases at night, it has been suggested that the greatest benefit is derived from theophylline when peak serum concentration is reached during the night or the early morning.

Effect of dimethylthiourea on plasma paraquat concentration.

In a previous study, administration of the hydroxyl radical scavenger, dimethylthiourea (DMTU), and paraquat was associated with higher mortality in rats than was paraquat alone. In the present study, the possibility was evaluated that administration of DMTU increased plasma paraquat levels. Plasma paraquat concentrations were measured in Sprague-Dawley rats 1, 2, 4, 8 and 24 h after intraperitoneal (i.p.) injection of 29 mg paraquat cation/kg body wt. Another group of rats was treated identically except that they received i.p. injections of DMTU before injections of paraquat. Administration of DMTU was associated with increased plasma paraquat concentration (P less than 0.01). Pharmacokinetic analyses indicated that, compared to rats receiving paraquat alone, rats given paraquat and DMTU showed: (1) greater area under the paraquat concentration time-curve; (2) lower total body paraquat clearance; and (3) smaller apparent volume of distribution. Plasma biochemical studies indicated that paraquat caused hyperglycemia as well as an early reduction (compared to controls) in hepatic enzymes. We conclude that: (1) DMTU administration is associated with increased plasma paraquat concentrations; and (2) impaired synthesis or inhibition of release of hepatic proteins may be an early effect of paraquat.

Adverse effects of (15S)-15-methyl-prostaglandin E1 in normal and paraquat-exposed rats.

Single, daily injections of approximately 1 mg/kg of (15S)-15-methyl-PGE1 (mPGE1), a PGE1 analog, have been reported to inhibit inflammation and to prolong survival in several animal models of local and systemic inflammation. We examined the effect of this dose of mPGE1 on paraquat toxicity in rats. A significant increase in early mortality was identified in mPGE1-treated rats as early as 3 hr following injection of paraquat and appeared associated with increased respiratory effort. Rats given mPGE1 without paraquat also appeared to increase respiratory effort but did not die. Rats killed at 3 hr following injections demonstrated increased lung weights in both paraquat-injected and control animals receiving mPGE1. Although a neutrophilia was identified in these animals, no significant increase in lung lavage neutrophils or albumin was identified. These data suggest that large intermittent doses of a PGE1 analog may adversely affect the respiratory system of normal and injured animals, and will accelerate mortality following exposure to potentially lethal doses of paraquat.

Effect of chestwall removal on expiratory flow in dogs.

We studied the effect of chestwall removal on Flow-Volume (F-V) curves in anesthetized dogs, by applying suction at the airway opening. Pressure and volume ranges utilized were comparable to those by others in the past for studies of expiratory flow in canine models. It was found: 1) Expiratory flow became nil at residual volume (RV) in the intact animal. On the contrary, flow after chestwall removal continued below RV, until the lung reached its minimal volume (Vmin) which averaged 11 +/- 6% TLC or 50% RV. 2) At high lung volumes, flow, particularly peak flow of F-V curves, was greater before than after chestwall removal. Thus the chestwall has a bimodal effect on flow. At low lung volumes, particularly below RV, the chestwall inhibits expiratory flow, and chestwall removal always results in flow increase, such that the lung can empty until all airways are collapsed, down to a volume of about 50% RV. On the contrary, the chestwall facilitates expiratory flow at high lung volumes, particularly at peak flow. The bimodality of chestwall effect on expiratory flow is consistent with the well known directional reversal of chestwall elastic recoil as volume changes, being nil at chestwall resting volume (Vcwr), and directing inwards (thus helping expiration) above Vcwr, or outwards (thus inhibiting expiration) below this volume (12). In a hypothetical situation of no chestwall resistance, chestwall effect on flow would be nil at Vcwr. In our experimentation, we found that the volume where the chestwall had no effect on expiratory flow averaged 71% TLC, clearly higher than Vcwr (49% TLC). We attribute the difference to the chestwall resistance.

Effect of lung inhomogeneity on partial flow-volume manoeuvres.

We evaluated the effects of inhomogeneous lung emptying on the relationship of partial to maximal complete expiratory flow by obtaining pre- and post-metaproterenol maximal (MEFV) and partial flow-volume curves in normal subjects and asthmatics. Partial curves were initiated between 65-70% of vital capacity after inspiration from functional residual capacity (PEFV curve) or after deflation from total lung capacity (PEFVDI curve). Since PEFVDI curves were initiated at lower lung volumes than MEFV manoeuvres (but with a similar volume history), non-homogeneous emptying should cause higher flow on PEFVDI than on MEFV manoeuvres. Expiratory flow (Vmax) was highest on MEFV manoeuvres in normals and PEFV curves in asthmatics. Pre- and post-metaproterenol Vmax was very similar on MEFV and PEFVDI manoeuvres in both groups, although Vmax(MEFV) slightly but significantly exceeded Vmax(PEFVDI) in normals and the reverse was true in asthmatics. Lung elastic recoil did not differ significantly on MEFV and PEFVDI manoeuvres in either group. We conclude that asthmatics demonstrate inhomogeneous emptying. However, because flow-volume curves are relatively insensitive to sequences of lung emptying, inhomogeneous emptying during forced expiration only has minor effects on the relationship of partial to maximal expiratory flow.

Epidermal growth factor receptor expression in human lung carcinomas defined by a monoclonal antibody.

Acetone-fixed frozen tissue sections from 56 cases of human lung carcinoma were tested for reactivity by an indirect immunoperoxidase technique with a monoclonal antibody (MAb 528) specific for the external domain of the epidermal growth factor receptor (EGFR). MAb 528 reacted with all epidermoid (22/22) and large-cell (4/4) lung carcinomas evaluated. The antibody was also positive with a subset of lung adenocarcinomas (13/21) and did not react with small-cell lung cancers (SCLCs) (0/9). MAb 528 also stained normal bronchial epithelium identified within the tumor sections of 5 cases. Thus EGFR was expressed by all epidermoid and large-cell lung carcinomas examined, a subset of lung adenocarcinomas, and normal bronchial epithelium. EGFR expression was not identified in any of the SCLCs tested. These data imply that immunohistochemical detection of EGFR expression may find future application in distinguishing epidermoid, large-cell, and some adenocarcinomas of the lung from SCLCs.

Pulmonary physiology in the postoperative period.

After upper abdominal or thoracic surgery, loss of lung volume, manifested most importantly by reduced FRC, and abnormal gas exchange, manifested by postoperative reduction in PaO2, are the rule rather than the exception. These physiologic alterations in lung function occur in the absence of superimposed complications such as pneumonia and/or lobar atelectasis; the usual physiologic alterations do, in fact, predispose to pulmonary complications (approximate 20 per cent incidence) which, when present, further compromise lung function. The mechanisms of postoperative impairment in lung function are multiple, interactive, and at the present, incompletely understood. An attempt to summarize the more important causes of impaired postoperative lung function is shown in Figure 6.

Evaluation of a metered-dose aerosol delivery system using partial flow-volume curves.

In 12 normal subjects, FEV1, FVC, peak expiratory flow rate, and flow at 25% of FVC on maximal (MEFV) and partial (PEFV) expiratory flow volume maneuvers were measured before and after inhalation of 2.6 mg of metaproterenol from a metered-dose inhaler (MDI) or from an MDI-holding chamber (MDI-HC) delivery system. The 2 delivery systems were studied on separate days using a randomized crossover design. Premetaproterenol pulmonary function results were very similar on both days. However, on the MDI-HC day, significantly greater bronchodilatation was observed; this was only detectable on PEFV maneuvers. Compared with those on the MDI day, postmetaproterenol PEFV rates on the MDI-HC day were approximately 11% higher (p less than 0.02); premetaproterenol to postmetaproterenol increments in PEFV rates were also larger on the MDI-HC day (p less than 0.05). These results can be explained by the phenomenon of airway hysteresis. The deep breath taken prior to performance of the FVC maneuver reduced bronchomotor tone in almost all subjects, thereby limiting the magnitude of possible change from inhaled bronchodilator. Partial flow-volume curves were not preceded by deep inspiration and were more sensitive in detecting bronchodilatation.

Relationships between minute ventilation, oxygen uptake, and time during incremental exercise.

It has recently been reported that blood and muscle lactate increased exponentially during incremental exercise, casting some doubt upon the concept of 'anaerobic threshold'. To gain further insight into this controversy, we examined the relationships between minute ventilation (VE), time and oxygen uptake (VO2) in normal subjects during incremental exercise. During exercise, the relationship of VE to either time of exercise or to VO2 appeared curvilinear; VE was reliably described as an exponential function (y = axb + c) of both time of exercise (r2 = 0.96) and VO2 (r2 = 0.92). We also compared variables from 30-second incremental tests with variables obtained from quasi-steady-state incremental tests using cycle and treadmill ergometry. With the exception of heart rate, variables measured at maximum exercise were similar during short-duration and quasi-steady-state incremental tests. These data support the ideas that: there is no abrupt change in metabolism and oxygen availability during progressive exercise, and results of rapid incremental and quasi-steady-state exercise tests are generally comparable in normal individuals.

A novel monoclonal antibody-defined antigen which distinguishes human non-small cell from small cell lung carcinomas.

Spleen cells from BALB/c mice hyperimmunized with the human epidermoid lung carcinoma cell line T222 were fused with NS-1 mouse myeloma cells to produce monoclonal antibodies to human lung cancer antigens. Hybridoma culture supernatants were tested by an enzyme-linked immunosorbent assay for reactivity against a panel of human lung tumor cell lines. Supernatant from hybridoma EA1 (immunoglobulin G1) displayed strong reactivity with four of four non-small cell lung carcinomas but did not react with three of three small cell lung carcinoma (SCLC) cell lines. This hybridoma was cloned by limiting dilution and utilized to generate ascites antibody for subsequent immunohistochemical and antigen characterization studies. Evaluation of fresh frozen tumor tissue sections by immunoperoxidase staining methods revealed EA1 reactivity with the vast majority of non-SCLCs tested (21 of 21 epidermoid, 17 of 18 adenocarcinomas, four of four large cell, two of two bronchioloalveolar) and no reactivity with nine of nine small cell lung carcinomas. EA1 also stained bronchial epithelium and other benign and malignant epithelial tissues. The EA1 antigen was determined to have a molecular weight of 75,000 by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis of human non-SCLC tumor extracts. These data imply that EA1 recognizes a novel antigen expressed by non-SCLCs and other epithelial tissues. The absence of EA1 reactivity with SCLCs suggests that this monoclonal antibody may find future application in distinguishing non-SCLC from SCLC and prove useful in furthering our understanding of the histogenesis of lung carcinomas.

Time dependence of airways and lung parenchymal recoil hysteresis.

Hysteresis of airways and lung parenchymal recoil was examined in normal subjects by measuring specific conductance (sGaw) and lung elastic recoil (Pst,L) before and 5, 10, 15, and 30 s after deep inspiration (DI). Routine lung function tests were normal before and after inhaled metaproterenol. sGaw increased significantly for 10 s after DI. Also, sGaw(DI) was greater than sGaw in 11 of 12, 8 of 12, 7 of 12, and 6 of 12 subjects at 5, 10, 15, and 30 s, respectively, after DI. The response of sGaw to DI and metaproterenol correlated significantly with each other (r = 0.82, P less than 0.001). However, after metaproterenol, sGaw(DI) did not exceed sGaw. Pst,L decreased significantly for 15 s after DI, with the lowest measured Pst,L(DI) values occurring 5 s after DI (P less than 0.01-0.001). Both sGaw(DI) and Pst,L(DI) values returned to base line (preinspiration) in a time-dependent exponential manner, with time constants of 9.2 +/- 4.9 and 11.3 +/- 6.1 s, respectively; these time constants were not significantly different from each other. We conclude that airways hysteresis is the predominant finding in normal subjects (even without prior pharmacological bronchoconstriction) before but not after metaproterenol; Pst,L decreases after DI and, in normal individuals, returns to base line in a time-dependent manner; and the time-dependent behavior of airways and lung parenchymal hysteresis have opposite (and unequal) effects on airway caliber.