Pulmonary cytochrome P450 in rats exposed to formaldehyde vapor.

The lungs of rats exposed to formaldehyde vapor, for 6 hr/day over 4 consecutive days, were examined for signs of injury and for changes in the level, or activity, of cytochrome P450. The animals were supplied with 10 ppm formaldehyde vapor generated, in two separate experiments, either from an aqueous solution of formaldehyde or from heated paraformaldehyde. All rats were exposed for 6 hr, on each of 4 consecutive days, and killed 1 day after the onset of the fourth period of exposure. The lung weights and gains in body weight of exposed animals were indistinguishable from those of their controls. Lungs from the formaldehyde-exposed animals did not show any signs of injury, even at the ultrastructural level. Bronchoalveolar lavage samples from exposed animals showed no increase in alkaline phosphatase or gamma-glutamyl transpeptidase activity. The total concentration of cytochrome P450 in the lungs of exposed animals was similar to that found in their controls. The P450 activity of pulmonary microsomes from exposed animals was not significantly different from that obtained with samples from the control animals. These results indicate that repeated exposure to 10 ppm formaldehyde vapor does not injure the deep lung of rats and has no effect on the level of lung P450 or on its activity against substrates for the most common pulmonary forms of this enzyme.

Allopurinol inhibition of neutrophilic alveolar response during hyperoxia.

Allopurinol is a potent xanthine oxidase inhibitor that has been administered to animals to protect tissues from oxidant injury. We hypothesized that allopurinol may protect against oxidant injury by inhibiting the inflammatory response. Male Sprague-Dawley rats were injected daily with vehicle or allopurinol and compared with noninjected controls. Animals were exposed to room air or 90% oxygen for 14 days. At the end of the exposure period, all animals were lavaged and bronchoalveolar lavage fluid (BALF) was examined for cell counts, lactate dehydrogenase (LDH), and protein. BALF neutrophils were significantly increased in oxygen-exposed noninjected controls (33 +/- 7 x 10(3)/mm3) and also in the vehicle-inoculated oxygen-exposed animals (43 +/- 6 x 10(3)/mm3). Allopurinol treatment resulted in a decrease in the neutrophilic alveolar response in oxygen-exposed animals (5.3 +/- 4 x 10(3)/mm3, P < 0.001). These data reveal that oxygen exposure produces a neutrophilic alveolar response that is attenuated by allopurinol treatment. BALF protein and LDH were significantly increased in all inoculated and noninoculated oxygen-exposed animals compared with air-exposed animals. Therefore, allopurinol decreases the neutrophilic alveolar response produced by a hyperoxic exposure in the rat but does not decrease lung injury as assessed by alveolar LDH and protein release.

Cathepsin L activity is increased in alveolar macrophages and bronchoalveolar lavage fluid of smokers.

Elastinolytic enzymes derived from alveolar macrophages (AM) are considered to play an important role in the development of emphysema associated with cigarette smoking. In this study, the enzyme activity and mRNA expression of cathepsin L were quantitated in AM and bronchoalveolar lavage (BAL) fluid obtained from current smokers and compared with those from nonsmokers. Activity was measured with the synthetic substrate Z-Phe-Arg-MCA combined with a novel cathepsin B inhibitor, CA-074. We found that the specific activity of cathepsin L was significantly elevated in BAL cells from smokers (7.1 +/- 0.7 mumol/mg protein/h, mean +/- SEM) compared with cells from nonsmokers (2.9 +/- 0.3) (p < 0.01). The expression of cathepsin L mRNA in BAL cells as determined by dot-blot analysis was also higher in BAL cells from smokers, which was comparable to the increase in the enzyme activity. About 5 to 6% of the specific activity of cathepsin L in BAL cell lysates was detected in unconcentrated BAL fluid; specific activity was also significantly higher in samples from smokers (0.38 +/- 0.04 mumol/mg protein/h) than from nonsmokers (0.14 +/- 0.02). In addition, procathepsin L (42 kD) and the mature form of cathepsin L (33 kD) were demonstrated in BAL fluid by immunoblot analyses. These data suggest that cigarette smoking induces mRNA expression and the synthesis of cathepsin L in AM and the release of procathepsin from AM into extracellular milieu. Furthermore, increased activity levels of cathepsin L in extracellular compartments may contribute to the proteolysis of elastin in the process of lung destruction associated with cigarette smoking.

Metabolism of bradykinin by peptidases in the lung.

We investigated the release of carboxypeptidase M (CPM), neutral endopeptidase 24.11 (enkephalinase, NEP), and angiotensin I converting enzyme (kininase II, ACE) and their contribution to bradykinin metabolism in the rat lung. The P3, membrane-enriched fraction of the homogenized lung was rich in all three peptidases. The activities of CPM and NEP were high in bronchoalveolar lavage fluid but lower in alveolar macrophages indicating that they originate from other cells present on the alveolar surface. In situ perfusion of rat lung with buffer that contained either deoxycholate or melittin or compound 48/80, produced lung edema. CPM, NEP, and ACE activities were recovered both in edema and perfusate fluid. The level of CPM and NEP was higher in edema fluid whereas, in contrast, more ACE activity was released into the perfusate. To evaluate the effect of peptidase inhibitors on changes in vascular permeability induced by bradykinin in the in situ perfused rat lung we measured the increase in lung weight as an index of increased vascular permeability or edema. Combined inhibition of either ACE plus NEP or ACE plus CPM augmented the effect of a subthreshold dose of bradykinin. Inhibitors of ACE, NEP, or CPM given alone and a combination of NEP plus CPM inhibitors did not enhance the bradykinin effect. Our results indicate that CPM, NEP, and ACE although present on different lung cells, synergistically modulate bradykinin effects. The different ratios of distribution of these enzymes in the perfusate and in edema fluid may not be due only to their presence on different pulmonary cells but also to their different anchoring mechanisms to plasma membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Neutrophil mediators, Pseudomonas, and pulmonary dysfunction in cystic fibrosis.

Proteolytic enzymes derived from inflammatory cells or Pseudomonas aeruginosa may destroy lung matrix in cystic fibrosis (CF). Antielastases appear to be overwhelmed by large amounts of free neutrophil elastase (NE) activity in lower respiratory tract secretions, and proteolytic or oxidant stress is thought to account for such deficiency. The purpose of this study was to measure NE and myeloperoxidase activity in bronchoalveolar lavage fluid (BAL) from patients with CF and to correlate levels of these mediators with the degree of airflow obstruction and density of P. aeruginosa in BAL. We measured NE activity in BAL fluid from 14 patients with respiratory exacerbations of CF. NE complexed with alpha 1-antiprotease in peripheral blood was measured in 13 of the 14 patients subjected to BAL and in 21 additional patients who did not undergo BAL. Because oxidants generated by myeloperoxidase may contribute to increased elastase activity via inactivation of alpha 1-antiprotease, myeloperoxidase activity in BAL was also measured. We found that elastase activity in BAL correlated significantly with the ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC ratio) (r = -0.80, p < 0.001) and FEV1 percent predicted (r = -0.62, p = 0.02). Myeloperoxidase activity also significantly correlated with airflow obstruction (FEV1/FVC ratio, r = -0.70, p = 0.005; FEV1 percent predicted, r = -0.52, p = 0.05). However, the degree of airflow obstruction, NE activity, myeloperoxidase activity, or total neutrophils in BAL did not correlate with the density of P. aeruginosa (CFU/ml) or total pathogen burden in BAL fluid.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary air-space enlargement induced by intratracheal instillment of hyaluronidase and concomitant exposure to 60% oxygen.

Although emphysema is generally characterized by damage to pulmonary elastic fibers, the causes of such injury appear to be complex and are not entirely explained by a singular imbalance between elastases and their inhibitors. Other factors could compromise elastic fiber integrity. To test the validity of this argument, hamsters were instilled intratracheally with a nonelastolytic enzyme, hyaluronidase (which reduces lung hexuronic acid content by 21% after 24 h), then exposed to an otherwise nontoxic concentration of oxygen (60%) for 4 days. Additional groups were given (1) hyaluronidase and room air, (2) saline and 60% oxygen, and (3) saline and room air. Treatment with both hyaluronidase and 60% oxygen resulted in a significant increase in air-space enlargement at 4 days (67.1 vs. 57.9 microns for saline/room air controls; p < .05), which was accompanied by only minimal inflammatory changes, as determined by both light microscopy and lavage cytology. Animals receiving either hyaluronidase or 60% oxygen alone showed no significant increases in air-space size compared to those given saline and exposed to room air. While the mechanisms responsible for these results are unclear, the marked increase in radiolabeling of lung elastin cross-links (desmosine and isodesmosine) in animals receiving both hyaluronidase and 60% oxygen (429 vs. 168 cpm/g dry lung for saline/room air controls; p < .05), as well as a significant decrease in total lung desmosine and isodesmosine (32.5 vs. 37.7 micrograms/lung for saline/room air controls; p < .05), suggests that elastic fiber damage is a potential factor. Moreover, only those animals receiving both hyaluronidase and 60% oxygen showed a significant rise in cell-free elastase activity in lavage fluids compared to saline/room air controls (83.3 vs. 48.3 ng; p < .05). On the basis of these findings, it is concluded that while elastic fiber damage may be a common pathway in emphysema, the factors that initiate the disease may be more varied than previously suspected and not always related to the balance between elastases and their inhibitors.

Lipopolysaccharide-induced expression of prostaglandin H synthase-2 in alveolar macrophages is inhibited by dexamethasone but not by aspirin.

Alveolar macrophages cultured with lipopolysaccharide release markedly increased amounts of prostanoids upon subsequent stimulation, an effect that is due to induction of prostaglandin H synthase-2 (J. Biol. Chem., (1992), 267, 14545-14550, and Biochem. Biophys. Res. Comm., (1992), 187, 1123-1127). The effects of dexamethasone and aspirin on this enhanced formation of thromboxane by stimulated lipopolysaccharide-primed alveolar macrophages were investigated. Under conditions of maximum inhibition, dexamethasone and aspirin decreased the formation of thromboxane by approximately 50% and 80%, respectively. Expression of lipopolysaccharide-induced prostaglandin H synthase-2 in dexamethasone-treated macrophages was similarly inhibited by about 50%, as determined by Northern blot and immunoprecipitation. In contrast, levels of lipopolysaccharide-induced prostaglandin H synthase-2 mRNA and protein were not reduced in aspirin-treated macrophages. We conclude that inhibition of prostaglandin H synthase-2 expression represents a mechanism by which dexamethasone, but not aspirin, may inhibit prostanoid formation by alveolar macrophages.

Antigen-mediated pulmonary eosinophilia in immunoglobulin G1-sensitized guinea pigs: eosinophil peroxidase as a simple specific marker for detecting eosinophils in bronchoalveolar lavage fluid.

Eosinophil peroxidase (EPO) has been used previously to detect the number of eosinophils in the peritoneal exudate and bone marrow of mice. The present study was undertaken to determine 1) whether EPO activity may provide a measure of a change in eosinophils in bronchoalveolar lavage fluid (BALF) of guinea pigs, 2) whether immunoglobulin (Ig)G1 could play a role in pulmonary eosinophilia and 3) effects of pharmacological agents on the EPO response in an IgG1 passively sensitized animal model. The activity of EPO was assessed by the ability of cell lysates (0.1% Triton-100 treatment) to oxidize 1 mM o-phenylenediamine in the presence of 1 mM H2O2 for 5 min at 22 degrees C. The enzyme activity was found to be eosinophil dependent, inhibited by the EPO inhibitor 3-amino-1,2,4-triazole (IC50 = approximately 0.1 mM) and relatively resistant to heat treatment (no loss of activity after 2-hr preincubation at 56 degrees C). To determine antigen-dependent eosinophil and EPO responses, guinea pigs were passively sensitized i.p. with 0.5 mg/kg of an affinity-purified antiovalbumin (OA) IgG1. Two to 3 days later, the sensitized animals were injected with pyrilamine (5 mg/kg, i.p.) before OA aerosol challenge. Aerosolized OA (0.1%) caused a significant increase in both eosinophil number and EPO activity in BALF of sensitized guinea pigs at 18 to 24 hr post-challenge. At a given concentration of aerosolized OA, the enzyme activity increased as a function of the antibody dose and time post-OA challenge.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchoalveolar lavage and the study of proteinases and antiproteinases in the pathogenesis of chronic obstructive lung disease.

Bronchoalveolar lavage has been used for 15 yrs to investigate the role of proteinases and antiproteinases in the pathogenesis of emphysema, but the results are confused by numerous technical factors, many of which may prove insurmountable. Even if the problems can be overcome, the technique will probably not prove sensitive enough to provide a true insight into the pathogenesis of emphysema in man. Nevertheless, the studies with this technique have provided important information and methodologies that have advanced our scientific, if not pathological, knowledge. Perhaps further applications of the knowledge obtained, to cellular and genetic studies, will eventually establish the true mechanisms involved in determining whether a smoker remains "healthy" or develops disabling disease. Lavage may have played a major role in the study of emphysema, if for no other reasons than to establish the fact that the pathogenesis of the disease is far from clear.

[Enkephalinase activity in the guinea pig model of asthma].

Enkephalinase exists in airway epithelial cells, smooth muscle, and submucosa near glands, and cleaves tachykinins to inactive metabolites, thereby reducing there effects. To study the role of enkephalinase in asthmatic response, we measured its activity in guinea pig model of asthma. When compared with the control values, the enkephalinase activity was reduced during in immediate asthmatic response (IAR) and late asthmatic response (LAR). Compared with the control values (100%), each value was 79.7%, 73.4% in the trachea and 74.3%, 55.7% in the lung respectively. Tracheal muscle preparation taken from the control, IAR, and LAR groups were made and mounted in oxygenated modified Krebs-Ringer solution. The response was monitored by isometric transducer. Concentration response curves to NKA with or without phosphoramidon were obtained. The contractile responses of the LAR groups were enhanced in potency and efficiency. Phosphoramidon potentiated the NKA induced contraction of control and the IAR groups but was less potent in enhancing the contractile response in the LAR group, showing less enkephalinase activity in the LAR. These results suggest that the enkephalinase plays an important role in LAR. In LAR, the enkephalinase activity may be inhibited and the responsiveness of the smooth muscle to some bronchoconstrictor, such as tachykinins, may be increased.

Modulation of pulmonary immune defense mechanisms by sulfuric acid: effects on macrophage-derived tumor necrosis factor and superoxide.

There is considerable interest in the potential health effects resulting from inhalation of acidic aerosols. However, except for well documented irritant effects and acid-induced changes in lung clearance function, other potential health effects have not been well defined. This study was designed to provide further insight regarding the relationship of sulfuric acid aerosol to the pathogenesis of respiratory disease by describing the effects of inhaled acid on the release and/or activity of biologically active mediators critical for maintaining pulmonary immunocompetence and resistance against infectious diseases. Results of this study demonstrated that a single inhalation exposure of rabbits to environmentally relevant and higher concentrations of sulfuric acid depresses the release/activity of lipopolysaccharide-stimulated tumor necrosis factor-alpha and also reduces the ability of pulmonary macrophages to produce superoxide anion radical in response to opsonised zymosan. These findings should be considered when evaluating the health risks associated with sulfuric acid exposure.

Dose-dependent pulmonary effects of inhaled endotoxin in guinea pigs.

As a cell wall component of gram-negative bacteria, endotoxin is thought to play a significant role in the respiratory effects of inhaled organic dusts which are microbially contaminated. Assessment of occupational survey data and clinical studies suggests that few measureable, acute functional changes occur below 30-50 ng/m3 endotoxin (as sampled in airborne dust with a vertical elutriator). Little information is available on the inflammatory effects of inhaled endotoxin at these low concentrations. The present study examined the dose-response relationship between inhaled endotoxin and functional, biochemical, and histological endpoints in the lungs of guinea pigs. Animals were exposed to 0.03 to 50.5 micrograms/m3 aerosolized endotoxin or the vehicle water for 4 hr. At 2 hr into exposure, significant decreases in specific airway conductance were observed only in animals exposed to 9.6 and 50.5 micrograms/m3 endotoxin (17.3 +/- 1.2 and 35.5 +/- 0.5% decreases from baseline values, respectively (mean +/- SE)). Total cell count and lactate dehydrogenase levels in bronchoalveolar lavage fluid were significantly elevated at 24 hr after exposure in all endotoxin-exposed groups except the lowest dose, 0.03 micrograms/m3 (P < 0.05). Polymorphonuclear leukocyte influx into the alveolar region was also dependent on the concentration of inhaled endotoxin. Thus, LDH activity, a biochemical marker of cell injury, and total cell counts and polymorphonuclear leukocytes, markers of inflammation, were more sensitive indices of adverse pulmonary effects from inhaled endotoxin than a functional measurement. These results suggest that subtle inflammatory changes may occur at airborne endotoxin concentrations which may produce no acute respiratory symptoms.

Disodium cromoglycate in the treatment of bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) has become the most common form of chronic lung disease in the neonate. Recently, we have experienced a severe case of BPD and examined the effect of disodium cromoglycate (DSCG) on BPD. The gestational age and birthweight of the patient were 27 weeks and 1,000 g, respectively. Although RDS subsided after surfactant replacement therapy, the arterial-alveolar oxygen tension ratio (a/APO2) gradually decreased and FiO2 increased with age, respectively, and pure oxygen supplementation was eventually required after 67 days of life. The DSCG treatment was commenced at 80 days of life. After 6 days of the inhalation therapy, a/APO2 gradually increased. After 10 days of the treatment, the baby was extubated. While the baby was intubated, intratracheal lavage fluid samples were obtained. Eosinophilic cationic protein (ECP) and polymorphonuclear (PMN) elastase concentrations were determined. ECP and PMN elastase concentrations of intratracheal lavage fluids gradually decreased with the DSCG treatment. These results may indicate that DSCG has led to an improvement of pulmonary function and facilitated weaning from mechanical ventilation in an infant with BPD.

Determination of human neutrophil elastase in bronchoalveolar lavage fluid: homogeneous immunoactivation versus heterogeneous enzyme immunoassay.

Elastase mass concentrations of bronchoalveolar lavage fluid were determined by a homogeneous immunoactivation and a heterogeneous enzyme immunoassay. There was an excellent correlation between both assay systems (y = 1.0376 . x + 1.311; r = 0.9901; n = 43) indicating the suitability of the immunoactivation method for the determination of elastase concentrations in bronchoalveolar lavage fluid as a matrix. Furthermore, dilution of bronchoalveolar lavage fluid samples did not influence the elastase recovery of either assay system.

Localization and health effects of lanthanum chloride instilled intratracheally into rats.

Lanthanum (La) is one of the rare earths used in diverse high technology fields for which sufficient data for assessing its health effects have been lacking. The biological effects and metabolic behaviors of La were studied by instilling lanthanum chloride intratracheally into male Wistar rats. The distribution of La among tissues revealed that the metal remains mostly in the lung with a biological half-time of 244 days. The subcellular localization by transmission electron microscopy with an X-ray microanalyzer indicated that La localizes in macrophages as high electron-dense granular inclusions in lysosomes and on the cell surface and basement membranes of type I pneumocytes among lung cells. The pulmonary health effects were examined by biological indices of the bronchoalveolar lavage fluid (BALF) and lung tissue. The acute toxicity estimated by lactate dehydrogenase activity in BALF was comparable to those of yttrium and copper that had been determined under the same protocol. Microscopic examination of the lung indicated a characteristic increase in the number of eosinophils.

Dynamic balance changes between elastase and antiprotease in the early stages after smoke inhalation injury.

Following the use of a rabbit smoke inhalation injury model established in this institute, there were marked reductions in elastase activities in neutrophils and alveolar macrophages; rapid increases in elastase activity in broncho-alveolar lavage fluid (BALF); reductions of serum trypsin inhibitory capacity; a decrease of Pao2 and an increase of PaCO2, and marked increases of lung water volume. Significant correlations were found between the increased extravascular lung water content and the rising elastase activity in BALF. It seems probable that the imbalance between elastase and antiprotease played an important role in the development of acute lung injury after smoke inhalation.

[Superoxide dismutase activity in the broncho-alveolar lavage fluid in late asthmatic response model in guinea pigs].

In order to investigate the mechanism of the late asthmatic responses (LAR), LAR model in guinea pigs was made by inhalation of a large quantity of egg albumin antigen. Serial changes of inflammatory cells and superoxide dismutase activities in broncho-alveolar lavage fluids obtained from these animals were observed. In this model, increase in inflammatory cells, such as neutrophils, was observed in the broncho-alveolar lavage fluid during the late asthmatic responses of the attack and superoxide dismutase activity increased in the broncho-alveolar lavage fluid in parallel with the increase in inflammatory cells. These results suggest that change in superoxide dismutase activity in the broncho-alveolar lavage fluid may be involved in the onset of the late asthmatic responses.

Pulmonary cellular effects in rats following aerosol exposures to ultrafine Kevlar aramid fibrils: evidence for biodegradability of inhaled fibrils.

Previous chronic inhalation studies have shown that high concentrations of Kevlar fibrils produced fibrosis and cystic keratinizing tumors in rats following 2-year inhalation exposures. The current studies were undertaken to evaluate mechanisms and to assess the toxicity of inhaled Kevlar fibrils relative to other reference materials. Rats were exposed to ultrafine Kevlar fibers (fibrils) for 3 or 5 days at concentrations ranging from 600-1300 fibers/cc (gravimetric concentrations ranging from 2-13 mg/m3). A complete characterization of the fiber aerosol and dose was carried out. These measurements included gravimetric concentrations, mass median aerodynamic diameter, fiber number, and count median lengths and diameters of the aerosol. Following exposures, cells and fluids from groups of sham- and fiber-exposed animals were recovered by bronchoalveolar lavage (BAL). Alkaline phosphatase, lactate dehydrogenase (LDH), protein, and N-acetyl glucosaminidase (NAG) values were measured in BAL fluids at several time points postexposure. Alveolar macrophages were cultured and studied for morphology, chemotaxis, and phagocytosis by scanning electron microscopy. The lungs of additional exposed animals were processed for deposition, cell labeling, retained dose, and lung clearance studies, as well as fiber dimensions (from digested lung tissue), histopathology, and transmission electron microscopy. Five-day exposures to Kevlar fibrils elicited a transient granulocytic inflammatory response with concomitant increases in BAL fluid levels of alkaline phosphatase, NAG, LDH, and protein. Unlike the data from silica and asbestos exposures where inflammation persisted, biochemical parameters returned to control levels at time intervals between 1 week and 1 month postexposure. Macrophage function in Kevlar-exposed alveolar macrophages was not significantly different from sham controls at any time period. Cell labeling studies were carried out immediately after exposure, as well as 1 week and 1 month postexposure. Increased pulmonary cell labeling was measured in terminal bronchiolar cells immediately after exposure but returned to control values 1 week later. Fiber clearance studies demonstrated a transient increase in the numbers of retained fibers at 1 week postexposure, with rapid clearance of fibers thereafter. The transient increase in the number of fibers could be due to transverse cleaving of the fibers, since the average lengths of retained fibers continued to decrease over time. In this regard, a progressive decrease in the mean lengths and diameters of inhaled fibers was measured over a 6-month postexposure period.(ABSTRACT TRUNCATED AT 400 WORDS)

Towards an understanding of the mode of action of Bacillus Calmette-Guérin-therapy in bladder cancer treatment, especially with regard to the role of fibronectin.

The interaction between Bacillus Calmette-Guérin (BCG) and the host was investigated after repeated intravesicular BCG-therapy for superficial bladder cancer. Studies were performed on (a) the local reaction in the bladder, (b) the systemic reaction, and (c) short and long term interactions in both the bladder and the serum/plasma. The analytes measured included anti-BCG IgA and IgG, fibronectin, lactoferrin, elastase-alpha 1-proteinase inhibitor, myeloperoxidase and alpha 2-proteinase inhibitor. All analytes, with the exception of alpha 2-proteinase inhibitor, were measured in both serum/plasma and urine. An additional group of 94 patients undergoing bronchoalveolar lavage was used for comparison with other diseases affecting mucous membranes. In vitro studies on human bladder in culture were also carried out to study the relationship between BCG, elastase and fibronectin. The results revealed a normal defence reaction, in which IgA and IgG antibodies specific to BCG were produced by the host. Maximal concentrations of all analytes in urine were found about 4 h after BCG instillation. Immunoglobulins, soluble fibronectin, and granulocyte markers all appeared in urine after instillation and all showed a similar time course. The in vitro study showed the synergistic effect of elastase and BCG in stimulating the host defence reaction. The relationship between BCG and fibronectin can be seen as fortuitous but not indicative of the efficacy of BCG-therapy in patients with superficial bladder cancer.

Erythromycin reduces neutrophils and neutrophil-derived elastolytic-like activity in the lower respiratory tract of bronchiolitis patients.

Diffuse panbronchiolitis (DPB) is a disease of adults characterized by chronic inflammation of the respiratory bronchioles and the infiltration of chronic inflammatory cells. The clinical efficacy of erythromycin therapy has been demonstrated in DPB patients, but the mechanism of action of this drug is unknown. We investigated the localization of neutrophils in lung biopsy specimens, as well as the cell population and elastolytic-like and chemotactic activity of bronchoalveolar lavage (BAL) fluid, before and after treatment with erythromycin or ampicillin in 11 DPB patients (six biopsy-proven and five clinically diagnosed) and one follicular bronchiolitis patient. These bronchiolitis patients had a high percentage of neutrophil and a high neutrophil-derived elastolytic-like activity in BAL fluid compared with chronic bronchitis patients and normal control subjects. The number of neutrophils and the neutrophil-derived elastolytic-like activity in BAL fluid decreased significantly after treatment with erythromycin along with a significant improvement in pulmonary function studies, although there was no significant change in the chemotactic activity of BAL fluid. No significant reduction in BAL fluid neutrophilia was found in the ampicillin-treated patients. These results suggest an important role for the neutrophil in the pathogenesis or development of bronchiolitis, and also suggest that erythromycin may be useful for the treatment of bronchiolitis through its direct action upon host phagocytic cells.