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Bronchoalveolar lavage was performed in 47 volunteers: 19 nonsmokers and 28 smokers. Total protein, albumin, immunoglobulins G and A, and carcinoembryonic antigen (CEA) were measured in the concentrated lavage effluent. Although a significant increase (p < 0.001) in the ratio of CEA to total protein recovered from the group of smokers was found, this increase primarily reflected the greater increase that occurred in a subgroup of 7 smokers. However, the increases in lavage CEA correlated weakly (p = 0.096) with smoking history in pack-years, and not at all with plasma CEA concentrations. Results regarding the number of cells recovered and immunoglobulin-to-albumin concentration ratios in these subjects were similar to those reported by others. Thus, CEA was increased in the lavage fluid of a subgroup of otherwise normal young smokers. It is possible that CEA might serve as a useful indicator of future airway disease in certain young smokers.

Although orally administered theophylline has been prescribed widely in patients with nonreversible airway obstruction, symptomatic benefit has not been established. To assess the effects of orally administered theophylline on dyspnea, we performed a randomized, double-bind, crossover, placebo-theophylline clinical trial in 12 ambulatory male patients with moderate to severe nonreversible airway obstruction. Dyspnea was rated using 2 clinical indexes based on 3 components affecting breathlessness: functional impairment, magnitude of task that evokes dyspnea, and the associated magnitude of effort. Dyspnea and physiologic parameters were measured on 4 occasions: at baseline, 4 wk after initial treatment, a second baseline after a 2-wk washout period, and 4 wk after the second medication. For the 12 patients, mean age (+/- SD) was 60 +/- 7 yr, forced expiratory volume in one second was 1.36 +/- 0.67 L (mean, 40% of predicted), and arterial oxygen tension was 71 +/- 10 mmHg. During the treatment phase, all patients had a therapeutic theophylline blood level (range, 12 to 19 micrograms/ml). Theophylline significantly decreased the components of functional impairment (p = 0.02) and magnitude of task (p = 0.02) relating to dyspnea, as well as the overall dyspnea rating (p = 0.01). There were no significant differences between placebo and theophylline therapy for spirometry, arterial blood gas tensions, and the 12-min walking distance. Thus, sustained-release theophylline significantly reduced dyspnea in these ambulatory patients with moderate to severe nonreversible airway obstruction without altering lung function, gas exchange, or exercise performance.

Although the human alveolar macrophage in tissue culture can secrete an elastolytic metalloenzyme that is not inactivated by alpha 1-antiprotease (AAP), levels of this proteolytic activity and its relationship to AAP in human lung lavage fluid ( HLF ) are unknown from previous studies. Therefore, we measured elastolytic activity in concentrated (20- to 30-fold) HLF from 15 smokers and 10 nonsmokers and related results to measurements of AAP in these fluids. Activity (mean +/- SEM) against a C elastin substrate (expressed as nanograms of porcine pancreatic elastase equivalents per milligram of lavage fluid protein) in smokers, 18.9 +/- 6.7, significantly exceeded (p = 0.05) levels present in nonsmokers, 4.4 +/- 1.8. With the synthetic elastin-like chromophore substrate succinyl-trialanine-nitroanilide ( SLAPN ), activity in individual samples was reduced 79% by EDTA, a metalloproteinase inhibitor, whereas activity was reduced by only 29% in the presence of PMSF, a serine proteinase inhibitor. In addition, using a pooled sample of HLF and C elastin substrate, 80% of activity against the elastin substrate was eliminated by EDTA, whereas 51% was eliminated by PMSF. The activity measured with C elastin substrate correlated inversely with antigenic AAP (r = -0.05, p = 0.01), but no correlations were found between this activity and HLF cell number, cell viability, differential count, or subject smoking history. The detection of activity with C elastin in HLF , with primarily a metalloenzyme inhibitor profile, in the presence of antigenically detectable AAP, may have pathogenetic relevance for emphysema in humans.

Nonchemotherapeutic drugs may also cause pulmonary parenchymal alterations. Mechanisms of pulmonary damage by these agents are diverse and may involve alterations of pulmonary homeostasis. Clinical features of noncytotoxic, drug-induced pulmonary disease are more heterogeneous than those associated with cytotoxic drugs, and several clinical syndromes are equally represented. Treatment and outcome vary with each individual drug and clinical presentation. In part 2, clinical and pathogenic aspects of noncytotoxic, drug-induced pulmonary disease are discussed.

We compared the elastase and lysozyme activities of cells obtained by bronchoalveolar lavage from normal smokers and nonsmokers. After total and differential cell counts were obtained for the initial lavage cell population, we determined the enzyme activities of the total lavage cell population, the culture vessel's adherent alveolar macrophage cell fraction, and the cell culture supernatant medium. Our data indicated that macrophages, particularly from smokers, synthesized a calcium-dependent activity against a synthetic elastase substrate, succinyl-trialanine-p-nitroanilide. This activity was enhanced in smokers and was distinct from the polymorphonuclear leukocyte elastase as measured with this synthetic substrate. Measurements using insoluble elastin labeled with 3H demonstrated that smokers' macrophages also contained a serine-proteinase activity whose inhibitor profile resembled that of polymorphonuclear leukocyte elastase. Finally, macrophages from smokers secreted 5 times more lysozyme and contained more lactate dehydrogenase activity than did nonsmokers' macrophages. We suggest that pulmonary macrophages take up the polymorphonuclear leukocyte elastase and contain a synthetic substrate, "elastase". The biologic significance of this elastase activity is unclear. The enhanced lysozyme secretion by smokers' alveolar macrophages indicated increased biosynthetic activity by these cells.

Although bronchoalveolar lavage (BAL) has been used as a research tool for over a decade, the technique of lavage has varied markedly between laboratories. For example, lavage instillate volumes from 50 to 300 ml have been used, and yet the influence of the variable of total lavage volume on subsequent protein recovery is uncertain. We performed sequential BAL (50 ml/aliquot; total volume, 300 ml) of the right middle lobe of 14 normal volunteers and separately processed and analyzed recovered aliquots for the absolute and relative concentrations of several protein substances. These proteins include free secretory component and secretory IgA, which emanate from airway secretions, and IgG, which is thought to transude from more distal alveolar sites. Analysis of these data showed a marked decrease in the absolute concentration of all proteins measured in serial aliquots. Analysis of protein ratios in sequential aliquots, however, revealed no significant change from the first to the fifth recovered aliquot. Finally, we analyzed the influence of the size of the first recovered aliquot on absolute and relative concentrations of proteins. Here there seemed to be a trend indicating preferential recovery of airway proteins in smaller aliquots. This was significant for the ratio of free secretory component to albumin (p less than 0.05). We conclude that lung proteins are efficiently and homogeneously sampled with 100 ml of lavage instillate. Larger volumes will add more protein but not alter protein ratios. Lavage with smaller volumes may preferentially sample airway proteins.

With a radionuclide technique, left ventricular ejection fraction and stroke volume index were measured in the basal state and after the stress of a methoxamine-induced increase in afterload in 10 men with severe chronic obstructive pulmonary disease. The resting mean left ventricular ejection fraction was normal in all 10 patients. After an acute increase in resistance to left ventricular ejection with methoxamine, the left ventricular ejection fraction and the stroke volume index did not decrease significantly, even in the presence of cor pulmonale in 5 patients. Mean pulmonary capillary wedge pressure was normal before, and did not change significantly after, methoxamine infusion. The data suggest that latent left ventricular dysfunction is not present in this group of patients with severe chronic obstructive pulmonary disease.

This study was designed to determine whether alterations in systemic oxygen transport induced by the use of vasodilators for pulmonary hypertension would simultaneously affect oxygen uptake in patients with chronic obstructive pulmonary disease (COPD). Six stable patients with moderate to severe COPD were studied during resting conditions, nitroprusside infusion, a second control period, and after administration of hydralazine. Systemic oxygen transport fell with nitroprusside infusion (523 +/- 94 to 418 +/- 78 ml/min/m2, p less than 0.05). With this there was a fall in oxygen uptake (135 +/- 11 to 119 +/- 12 ml/min/m2, p less than 0.05), but only a minimal increase in oxygen extraction. In contrast, systemic oxygen transport was augmented in all patients when hydralazine was administered (444 +/- 121 to 840 +/- 157 ml/min/m2, p less than 0.05). There was also a net increase in oxygen uptake in these patients (122 +/- 19 to 148 +/- 21 ml/min/m2, p less than 0.05). We postulate that these clinically stable patients have a resting oxygen uptake that may become dependent on systemic oxygen transport whenever the latter decreases. This phenomenon has been described previously only in patients with adult respiratory distress syndrome, and it is important to consider when designing studies of pharmacologic therapy for COPD complicated by pulmonary hypertension.

We evaluated the accuracy of the CO2 rebreathing method (CO2rb) for measuring cardiac output at rest and during steady-state exercise in 15 patients (mean +/- SD age, 59.7 +/- 7.5 yr) with obstructive airway disease. At rest, there was a significant correlation between direct Fick and CO2rb methods using measured arterial PCO2 (r = 0.70; p = 0.002), but not with using end-tidal PCO2 (r = 0.38; p = NS). During exercise, there was greater correlation with CO2rb using arterial PCO2 (r = 0.79; p = 0.001) than using end-tidal PCO2 (r = 0.63; p = 0.007) compared with the direct Fick determination. Correlation between the CO2rb and direct Fick methods was greater with moderate air-flow obstruction (n = 6) than with severe airway disease (n = 9), and the CO2rb method was more accurate during exercise than at rest. The CO2rb method using either end-tidal or arterial PCO2 underestimated the direct Fick measurement in 13 of 15 patients at rest, which may reflect inadequate equilibration between alveolar and oxygenated mixed venous PCO2. However, no consistent error was observed during exercise when higher CO2 production and an increased venoarterial PCO2 difference would diminish potential inaccuracies. We concluded that the CO2rb technique is an acceptable method for measuring cardiac output during exercise in patients with moderate and severe obstructive airway disease as long as arterial PCO2 is directly measured rather than estimated from end-tidal PCO2.

Cigarette smoking is known to be an important etiologic factor in several lung diseases; however, the number of smokers who develop these diseases represents a small segment of the smoking population. It is possible that evidence of inhalation-induced injury to bronchial epithelial cells of smokers will be reflected in the proteinaceous products of these cells, thereby identifying a high-risk subgroup. We have tested this hypothesis by analysis of 2 proteins, free secretory component (FSC) and the keratins, in lavage fluids obtained from 4 groups of subjects: 30 normal nonsmokers, 15 asymptomatic smokers, 22 symptomatic smokers, and 40 carcinoma patients. Among symptomatic smokers, FSC relative to total protein (FSC/TP) was depressed compared with that in nonsmokers and asymptomatic smokers. The keratins were detected only in symptomatic smokers and correlated with pack/years of smoking history (p = 0.017). Carcinoma patients had depressed FSC/TP and detectable keratin (33 of 38 patients studied). Lung sections from carcinoma patients studied immunohistochemically revealed an apparent inverse relationship between tissue FSC and keratins. This inverse relationship was borne out by analysis of these proteins in the lavage fluid of cancer patients (r = -0.4, p = 0.04). Thus, in cancer patients, immunohistochemical evidence of airway injury correlates with bronchial lavage levels of mucosal epithelial cell proteins. It is possible that smokers with altered levels of these proteins may be the ones at increased risk of smoking-associated lung disease.

A combined hemodynamic and radionuclide approach was used to evaluate right ventricular performance during upright exercise in 12 male patients with chronic obstructive pulmonary disease. To assess the influence of intrathoracic pressure on hemodynamic parameters, pleural pressure was measured using an esophageal balloon. Mean age was 58.5 +/- 6.7 yr (+/- SD), and all had dyspnea on physical exertion. For the group, forced expiratory volume in one second (FEV1) was 1.04 +/- 0.40 L and arterial oxygen-tension (PaO2) was 77 +/- 11 mmHg. During steady-state, upright exercise on the bicycle ergometer at 58% of maximal oxygen consumption (VO2 max): (1) mean pulmonary artery pressure (Ppa) and pulmonary vascular resistance index (PVRI) increased significantly; (2) right ventricular ejection fraction (RVEF) failed to augment appropriately (less than 5% increase); and (3) right ventricular end-diastolic volume index (RVEDVI) increased significantly, whereas right ventricular end-systolic volume index (RVESVI) did not change. A diminished pulmonary vascular bed, the change in PaO2, and possibly increased alveolar pressure appeared to contribute to the increased load placed on the right ventricle. Both RVEDVI and RVESVI were significantly correlated with Ppa at rest and during exercise. In 2 of the 12 patients, stroke volume index and left ventricular end-diastolic volume index showed minimal change with exercise. VO2max was correlated with the FEV1 (r = 0.75; p = 0.01) as well as resting (r = -0.60; p = 0.02) and exercise (r = -0.61; p = 0.02) PVRI. These results suggest that exercise performance may be limited by right ventricular dysfunction in addition to respiratory impairment in some patients with chronic airway disease.

The purpose of this study was to examine the relationship between immunoglobulin production and immunoglobulin levels in bronchoalveolar lavage (BAL) fluid and serum of normal subjects and patients with sarcoidosis. Eleven normal volunteers and 17 patients were studied. In normal subjects, no important relationship existed between the number of immunoglobulin-secreting cells and immunoglobulin levels in BAL or serum. By contrast, in patients with sarcoidosis, a highly significant correlation existed between the number of IgG secreting cells and IgG/alb% in BAL (p = 0.008) and between the number of IgG secreting cells in BAL and serum IgG mg/ml (p = 0.002). Similar associations did not exist for IgA and IgM. These data demonstrate for the first time the relationship between immunoglobulin production and immunoglobulin levels in normal persons, and convincingly show that immunoglobulin production at sites of disease activity is responsible for hypergammaglobulinemia in BAL and serum of patients with sarcoidosis.

Previous in vitro studies have suggested that bacterial adherence to buccal squamous epithelial cells may be a mechanism involved in postoperative colonization of the oropharynx. However, the relationship between bacterial binding to oral epithelial and ciliated respiratory cells is unknown. To investigate bacterial binding to other cells in the human respiratory tract, we measured adherence of Pseudomonas seruginosa to ciliated cells (from nose and trachea) and compared this to squamous cells (from buccal mucosa), Cell samples were collected from 16 noncolonized individuals undergoing either elective surgery or volunteer bronchoscopy. Adherence (mean +/- SEM) to tracheal cells (4.6 +/- 0.8 bacteria per cell) and to nasal cells (4.7 +/- 0.6 bacteria per cell) was similar. These values significantly (p less than 0.001) exceeded buccal cell adherence (0.9 +/- 0.2 bacteria per cell). Because cells from ciliated surfaces bind more bacteria than cells from squamous surfaces, bacterial adherence at these respiratory sites may involve different mechanisms. The enhanced bacterial attachment to ciliated cells may assume pathogenic importance when mucociliary function is impaired.

Numerous pharmacologic agents used in the treatment of cancer have been linked to pulmonary toxic side effects. Mechanisms of damage by these drugs include direct pulmonary toxicity and indirect effects through enhancement of inflammatory reactions. Risk factors for development of pulmonary damage have been elucidated for some agents but they remain unclear for others. Clinical features are similar for most categories of cytotoxic agents, and the most common associated clinical syndrome is chronic pneumonitis/fibrosis. Treatment and outcome vary with each particular agent. In Part 1 of this review, clinical aspects and pathogenic mechanisms of cytotoxic drug-induced pulmonary disease are discussed.

A variety of central nervous system (CNS) insults may be complicated by the acute development of pulmonary edema. This occurrence has been termed neurogenic pulmonary edema (NPE), and experimental models have clearly shown that CNS insults may cause pulmonary edema. Unfortunately, the pathophysiologic aspects of this response are not clearly understood. Basing an approach to the development of pulmonary edema on Starling's equation leads to the conclusion that NPE is caused by changes in pulmonary endothelial permeability and/or microvascular pressures. It was previously suggested (the "blast theory") that CNS insults caused acute systemic arterial and pulmonary venous spasm and increased venous return, which would result in a severe pulmonary vascular hydrostatic insult and a secondary permeability defect. Although such hydrostatic derangements may explain certain cases of NPE, recent clinical and experimental studies have indicated that CNS disorders may cause a permeability defect without a vascular insult. The mediating factor for a permeability defect is not clear. The implications of these findings are that NPE may be caused by either permeability abnormalities or hydrostatic insults, may present clinically in a variety of ways, and may require different approaches to treatment. Our understanding of the CNS sites that might mediate NPE is not sophisticated enough, at present, to define the neural mechanisms involved in the pathogenesis of NPE.