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Study Objective: We hypothesized that the use of inhaled alkaloidal ("crack") cocaine could increase lung content of iron, either by inducing alveolar hemorrhage or by other mechanisms. Intrapulmonary accumulation of iron could promote chronic lung diseases in crack users. The goal of this study was to determine whether iron and ferritin content of alveolar macrophages or fluid recovered by BAL was increased in subjects using crack, compared with nonsmokers.Methods: BAL was performed in 31 volunteer subjects, including healthy nonsmokers (n = 7), subjects smoking crack alone (n = 7), as well as subjects smoking both crack and cigarettes (n = 7) or cigarettes alone (n = 10). Iron content of alveolar macrophages and BAL fluid was determined by a colorimetric method and ferritin content of alveolar macrophages, and BAL fluid was measured by a two-sided immunoradiometric method.Results: Alveolar macrophages recovered from crack users contained more iron than did alveolar macrophages from nonsmokers (25.4 +/- 2.9 nmol/10(6) vs 5.5 +/- 0.6 nmol/10(6) [mean +/- SE]; p < 0.01). There were similar increases in alveolar macrophage ferritin as well as BAL fluid iron and ferritin in crack users, compared with nonsmokers. BAL fluid ferritin concentrations in subjects smoking both crack and cigarettes were increased, compared with subjects smoking crack alone or cigarettes alone (p < 0.05).Conclusions: Use of crack increases intrapulmonary concentrations of iron and ferritin. Effects of crack on extracellular ferritin concentrations may be additive with effects of cigarette smoking. Although the mechanism(s) causing pulmonary iron accumulation were not identified by this study, it may be a result of occult alveolar hemorrhage or increased vascular permeability. The increase in lung iron burden in habitual crack users could promote chronic lung diseases in these subjects. [ABSTRACT FROM AUTHOR]

Alveolar macrophages (AMs) mobilize iron from the surface of iron-containing minerals such as asbestos and synthesize ferritin for intracellular iron storage or secretion. Although the synthesis of iron-free ferritin (apoferritin) provides antioxidant protection, the secretion of iron-containing ferritin by AMs could increase the availability of catalytic iron in the lungs. Cigarette smoking may promote the secretion of ferritin by AMs after iron acquisition from mineral sources, because smokers' AMs are iron loaded. The first objective of this study was to determine whether ferritin secretion/release by AMs after in vitro exposure to crocidolite asbestos is enhanced by cigarette smoking. The second objective was to assess whether exogenous ferritin-bound iron could enhance the toxicity of crocidolite to lung cells in vitro. AMs recovered from nonsmokers (n = 8) or smokers (n = 8) were exposed to crocidolite or titanium dioxide (TiO2)(1 x 10(6) AMs, 50 to 200 microg/mL) for up to 18 hours. AMs exposed to crocidolite but not TiO2 showed increased cell content of iron and ferritin and increased cell supernatant ferritin concentrations. Increases in iron and ferritin content were similar for AMs recovered from smokers and those recovered from nonsmokers; however, increases in supernatant ferritin were >7-fold greater for smokers' AMs than for nonsmokers' AMs (P < .001). Exposure of A549 cells, a lung cancer-derived cell line, to crocidolite (50 to 200 microg/mL, 18 hours) caused dose-dependent cell death as indicated by lactate dehydrogenase release. The addition of ferritin (> or = 500 mg/mL) but not apoferritin to culture media enhanced crocidolite-induced LDH release (P < .01). These findings suggest that cigarette smoking and crocidolite exposure have synergistic effects that promote ferritin release by AMs, which could catalyze oxidative injury to other alveolar cells.

The human lung accumulates iron with senescence. Smoking escalates the accumulation of iron, and we have demonstrated regional variability in the accumulation of iron in smokers' lungs. Iron has been reported to influence the production of a number of proinflammatory mediators, including human interleukin (IL)-1beta. We postulated that we could (1) demonstrate regional differences in the release of IL-1beta from human alveolar macrophages and (2) influence the production of IL-1beta in human macrophages by altering intracellular iron concentrations. To test these hypotheses, alveolar macrophages were obtained by independent lavage of the upper and lower lobes of healthy volunteers (both smokers and nonsmokers), after which the ability of each population to secrete IL-1beta was quantified, together with their ability to produce tumor necrosis factor-alpha, IL-6, and IL-8. Additionally, we established an in vitro model of "iron-loaded" cells of the human myelomonocytic cell line THP-1 in order to examine more directly the effect of iron and its chelation on the secretion of IL-1beta. We report here that an intracellular, chelatable pool of iron expands with exogenous iron-loading as well as with lipopolysaccharide (LPS) stimulation and appears to suppress transcription of IL-1beta, whereas shrinkage of this pool by early chelation augments transcription of IL-1beta beyond that induced by LPS alone. And finally, we demonstrate a regional relationship in the lung between excess alveolar iron and the production of human alveolar macrophage-derived IL-1beta, suggesting a partnership between iron and inflammation that may have clinical significance, especially in relation to lung diseases with a regional predominance.

Reactive oxygen species may contribute to airway injury in patients with cystic fibrosis (CF) and iron catalyzes oxidant injury by promoting generation of highly reactive hydroxyl radicals. Iron in the lower respiratory tract may be free, ferritin bound (from which iron can be reductively mobilized), or transferrin bound (which generally prevents iron mobilization). Ferritin is composed of subunits that are heavy (H) or light (L), and H-rich ferritins have additional biologic effects including inhibition of lymphocyte proliferation and cell growth. To assess concentrations of iron and iron-binding proteins in the lower respiratory tract of patients with CF, we measured iron (ferrozine), L-ferritin, H-ferritin, and transferrin (enzyme-linked immunosorbent assay [ELISA]) in bronchoalveolar lavage (BAL) fluid recovered from stable patients with CF (n = 8), healthy nonsmokers (NS; n = 8), or heavy cigarette smokers (HS; n = 8). Iron was detected in BAL fluid from patients with CF and HS, but not NS, with higher iron concentrations in patients with CF (42.0 +/- 11.6 microgram/dl) than in HS (9.9 +/- 2.6 microgram/dl, p < 0.05). Ferritin was present in all BAL fluids, with higher total ferritin (L + H) in patients with CF (647 +/- 84 ng/ml) than in HS (181 +/- 25 ng/ml, p < 0.005) or NS (9 +/- 3 ng/ml, p < 0.0005). Ferritin recovered from HS and NS lungs was < 2% H type, whereas ferritin in CF lungs was > 40% H-type ferritin. Transferrin concentrations in BAL fluid were not different in any group. Tumor necrosis factor (TNF)-alpha was present only in BAL samples from patients with CF. To assess whether TNF-alpha contributed to H-ferritin accumulation in CF lungs, we treated lung epithelial cells (A549) with iron alone (FeSO(4), 10-40 microM) or with iron and TNF-alpha (5-20 ng/ml). Iron-treated A549 cells synthesized almost entirely L-ferritin whereas exposure to TNF-alpha with iron caused a dose-dependent increase in accumulation of H-type ferritin. These findings suggest that oxidant injury could be promoted in lungs of patients with cystic fibrosis by iron mobilized from extracellular ferritin and, in addition, that TNF-alpha-promoted accumulation of H-type ferritin may impair local immune function and cell growth.

Extracellular iron, which is predominantly bound by transferrin, is present in low concentrations within alveolar structures, and concentrations are increased in various pulmonary disorders. Iron accumulation by cells can promote oxidative injury. However, the synthesis of ferritin stimulated by metal exposure for intracellular iron storage is normally protective. The cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta may alter iron metabolism by alveolar cells. In this study, we assessed the effects of TNF-alpha and IL-1beta on iron metabolism with a cell line with properties of type 2 alveolar epithelial cells (A549) exposed to non-transferrin-bound (NTBI; FeSO(4)) or transferrin-bound (TBI) iron. In addition, we assessed the cytotoxicity of these exposures by measuring the cell accumulation of malondialdehyde (MDA), a product of lipid peroxidation, and cell death (MTT assay and lactate dehydrogenase release). A549 cells treated with NTBI or TBI in concentrations up to 40 microM accumulated iron and synthesized predominantly L-type ferritin without accumulation of MDA or cell death. Treatment of A549 cells with TNF-alpha (20 ng) or IL-1beta (20 ng) decreased cell transferrin-receptor expression and induced synthesis of H-type ferritin. TNF-alpha and IL-1beta decreased the uptake of TBI; however, the uptake of NTBI was increased. Both cytokines enhanced total ferritin synthesis (H plus L types) in response to iron treatments due to enhanced synthesis of H-type ferritin. Coexposure to TNF-alpha and NTBI, but not to TBI, induced MDA accumulation and greater cytotoxicity (MTT and lactate dehydrogenase release) than TNF-alpha alone. These findings indicate that TNF-alpha and IL-1beta modulate iron uptake by A549 cells, with differing effects on TBI and NTBI, as well as on H-ferritin synthesis. Enhanced iron uptake induced by TNF-alpha and NTBI was also associated with increased cytotoxicity to A549 cells.

The development of pulmonary disease as a result of cancer therapy is an increasingly recognized clinical problem. Chemotherapeutic drugs can induce an acute pneumonitis, pulmonary edema, and pulmonary fibrosis, as well as a variety of other pulmonary diseases in cancer patients.

Study Objectives: BAL induces alveolar inflammation, but its effects on intrapulmonary cytokines and the mechanisms causing inflammation are uncertain. The objectives of this study were: (1) to characterize cytokine response in the lungs to BAL, and (2) to determine whether endotoxin is introduced into the lungs during BAL, which could promote BAL-induced inflammation., Design and Methods: We performed two BAL procedures in healthy volunteers separated by 4 (n=6), 24 (n=5), or 72 h (n=3). The initial BAL was performed in the right middle lobe (RML) and the second BAL was performed in the same location and the lingula. Concentrations of interleukin-8 (IL-8), interleukin-1 (IL-1beta), and transforming growth factor-beta were measured by enzyme-linked immunosorbent assay and tumor necrosis factor-alpha (TNF-alpha) bioactivity was determined. Endotoxin contents of saline (10 and 20 mL) infused through bronchoscopes as well as BAL fluids recovered from six subjects were assessed by limulus amebocyte assay., Results: At 4 h after the initial lavage, but not at later times, BAL fluid recovered from the RML contained increased concentrations of IL-8 and IL-1beta, and increased TNF-alpha bioactivity. BAL fluid recovered from the lingula contained increased concentrations of TNF-alpha only at 4 h. All BAL samples tested contained detectable endotoxin as did all saline aliquots instilled through bronchoscopes., Conclusions: There is intrapulmonary accumulation of the cytokines TNF-alpha, IL-8, and IL-1beta in the lavaged lung within 4 h after BAL; this accumulation resolves by 24 h. Endotoxin contamination of the lungs during bronchoscopy may contribute to BAL-induced lung inflammation.

Iron uptake by cells may increase the intracellular pool of prooxidant iron prior to storage of iron within ferritin. Because hyperoxia is toxic to alveolar macrophages (AM) via mechanisms involving oxidant stress, we hypothesized that iron uptake by AM might promote hyperoxia-induced injury. To assess this hypothesis, we cultured AM recovered from healthy volunteers under conditions of normoxia or hyperoxia (60% or 95% oxygen) in media of varying iron content, including control media (3 microM iron) and media supplemented with iron (FeCl3; total iron 10, 20, or 40 microM). AM injury was assessed by measuring release of lactate dehydrogenase (LDH), phagocytic activity for yeast, and cytosolic concentrations of calcium ([Ca2+]i) as determined by ratio image analysis of AM loaded with the fluorescent calcium probe indo-1. There was dose-dependent accumulation of iron and ferritin synthesis in AM exposed to iron-supplemented media. Exposure of AM to hyperoxia (60% and 95% oxygen, 18 h) in control media increased LDH release and impaired phagocytic activity for yeast; however, similar hyperoxic exposures in iron-supplemented media significantly increased the cells' LDH release and decreased phagocytosis. Exposure to 95% oxygen increased the [Ca2+]i of AM over 18 h, but similar exposure in iron-supplemented media induced greater increases in [Ca2+]i. As compared with exposure to normoxia, exposure to hyperoxia (60% and 95% oxygen) also decreased iron uptake and, to a greater extent, ferritin synthesis by AM in iron-supplemented media. These data suggest that: (1) iron uptake promotes hyperoxic injury to AM; and (2) hyperoxia impairs the capacity of AM to sequester iron in ferritin.

Human lungs accumulate iron with the aging process. In some circumstances associated with lung injury (eg, smoking), this acquisition of iron in lung tissue and alveolar macrophages (AMs) is escalated. We hypothesized that excess cellular iron interfered with the production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1-beta) by AMs. To examine this hypothesis, we acquired AMs from smokers and nonsmokers by bronchoalveolar lavage. AMs were stimulated by lipopolysaccharide (LPS), with and without deferoxamine (DFA), a chelator of iron. Enzyme-linked immunosorbent assay and Northern analysis were used to quantitate cytokine concentrations and mRNA. The addition of DFA increased the release of IL-1-beta, but not TNF-alpha, from AMs from smokers and nonsmokers. The DFA augmentation of LPS-induced IL-1-beta was more pronounced in smokers' AMs than in those from non-smokers (4.5-fold vs 2.6-fold increase). The addition of FeCl3 to DFA diminished the augmenting effect on the release of IL-1-beta, suggesting that the mechanism of action involved iron chelation. Conversely, as the intensity of iron chelation increased, the release of IL-1-beta and TNF-alpha decreased, as was also shown with hydroxyl radical scavenging by dimethylthiourea. This inhibition, however, occurred at very different thresholds for each cytokine. These data support a relationship between excess alveolar iron and the generation of inflammation within the lung.

Purpose: Extracellular free iron, or iron bound to ferritin, may promote oxidative injury and bacterial growth in airways of patients with chronic airway inflammation due to cystic fibrosis (CF) or chronic bronchitis (CB). In this study, we assessed sputum content of total iron, ferritin, and transferrin in patients with CF or CB as well as sputum from normal subjects with acute airway inflammation caused by viral upper respiratory tract infections (URTIs)., Methods: Spontaneously produced sputum was obtained from 33 subjects, including 10 subjects with CF, 18 subjects with CB (10 acute exacerbations, 8 with stable CB), and 5 subjects with URTIs (control subjects). After lysing and dilution, total iron concentrations were determined by controlled coulometry, ferritin was measured by radioimmunoassay, and transferrin was measured by enzyme-linked immunosorbent assay., Results: Iron was not present in detectable amounts in control sputums, but ferritin was present (6+/-2 ng/mg protein, mean+/-SE), as was transferrin (2.37+/-0.44 microg/mg). Compared with control subjects, concentrations of iron in sputum were increased in patient groups with higher amounts in CF patients (242+/-47 ng/mg, p<0.01) than CB patients with acute exacerbations or patients with stable CB (98+/-50 and 42+/-12 ng/mg, p<0.05 for both). Ferritin content of sputum was also increased in each group, with CF patients (113+/-22 ng/mg, p<0.001) higher than CB patients (acute, 45+/-10 ng/mg; stable, 87+/-24 ng/mg; p<0.01 for both). Compared with control subjects, sputum transferrin was decreased in CF patients (1.09+/-0.40 microg/mg, p<0.05), but not CB patients., Conclusions: These findings indicate there are increased airway concentrations of total iron and ferritin-bound iron in patients with CB and, to a greater extent, in patients with CF. Particularly in CF patients who also demonstrated decreased airway concentrations of transferrin, ferritin-bound iron in airways may promote oxidative injury and enhance bacterial growth.

Inhalation of lipopolysaccharide (LPS) by humans rapidly recruits neutrophils to alveolar structures. Recruitment of neutrophils may be mediated in part by intrapulmonary release of cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-8, although the kinetics of cytokine accumulation and neutrophil recruitment to the lungs after LPS inhalation have not been determined. Release of some cytokines in response to LPS is reported to be decreased in smokers' alveolar macrophages compared with nonsmokers', suggesting responses to LPS may differ in smokers (S) and nonsmokers (NS). To assess the kinetics of early cytokine accumulation after LPS inhalation and to compare inflammation induced in LPS-exposed S and NS, we performed bronchoalveolar lavage (BAL) in 28 subjects (14 NS and 14 S) at 90 or 240 minutes after inhalation of aerosolized LPS (30 microg). BAL performed at 90 and 240 minutes after LPS inhalation recovered increased numbers of neutrophils and lymphocytes in both NS and S compared with an unexposed control group (10 NS, 10 S), with greater recovery of neutrophils in S than NS (p < 0.001). BAL fluid supernate concentrations of IL-8, IL-1beta, and tumor necrosis factor-alpha at 90 minutes were increased in S and NS compared with an unexposed control group. IL-8 and tumor necrosis factor-alpha concentrations were similar in S and NS; however, IL-1beta concentrations were greater in S (p < 0.005). BAL fluid concentrations of IL-1beta and IL-8 at 90 minutes correlated with absolute neutrophil recovery in S and NS. These findings suggest that the rapid accumulation of cytokines, particularly IL-1beta and IL-8, contributes to lung neutrophil recruitment after LPS inhalation. In addition, parameters of pulmonary inflammation present in S after LPS inhalation are similar to or increased compared with those present in NS.

Extracellular iron present in alveolar structures may contribute to oxidative lung injury induced by toxic mineral dusts by enhancing dust-induced generation of hydroxyl radicals. Alveolar macrophages (AMs) can sequester iron within ferritin and limit generation of hydroxyl radicals. In the current study we sought to assess whether AMs accumulate iron and ferritin after in vivo exposure to a dust with high iron content, to iron oxide, or to an inflammatory dust, calcium tungstate. We performed lung lavage 1, 7, 14, 28, 42, and 56 days after intratracheal instillation of mineral dust in saline solution or instillation of saline solution alone and quantitated cell recovery and AM content of iron and ferritin. Instillation of iron oxide increased neutrophil recovery only on a day 1 when compared with results in controls, whereas calcium tungstate increased neutrophil recovery through day 14. AMs recovered after instillation of iron oxide contained increased amounts of iron and ferritin, beginning on day 1 and progressing through day 56 after treatment (7.57 +/- 0.38 microgram iron per 10(6) AMs vs 1.54 +/- 0.28 microgram iron per 10(6) AMs for controls, p < 0.001; and 5908 +/- 768 ng ferritin per 10(6) AMs vs 395 +/- 20 ng ferritin per 10(6) AMs, p < 0.001). AMs recovered after calcium tungstate instillation also contained increased amounts of iron and ferritin beginning 14 days after treatment, with greatest content 42 days after treatment (4.85 +/- 0.68 microgram iron per 10(6) AMs, p < 0.001, and 2274 +/- 736 ng ferritin per 10(6) AMs, p < 0.001). Tumor necrosis factor, which can enhance iron accumulation by macrophages, was spontaneously released by AMs recovered from tungsten-treated rats. These studies indicate that AMs accumulate iron and ferritin in response to both iron loading of the lungs with iron oxide exposure and lung inflammation induced by calcium tungstate exposure.

Transferrin serves as the primary iron transport protein in serum, but it also is present in the lower respiratory tract where it has antioxidant and antibacterial properties. Prior studies indicate that patients with respiratory failure (RF) due to ARDS have increased concentrations of transferrin in the lower respiratory tract, which is attributed to increased lung vascular permeability. It is unclear whether mechanical ventilation contributes to increased lung transferrin content in patients with ARDS, although mechanical ventilation may increase lung microvascular permeability. To assess whether mechanical ventilation in patients with RF due to causes other than ARDS is also associated with increased respiratory tract concentrations of transferrin, we compared transferrin concentrations in serum and lung lavage fluid obtained from 12 mechanically ventilated patients with RF attributable to COPD, 6 patients with ARDS, and 15 healthy volunteers. Serum transferrin concentrations in patients with RF due to COPD were variable, but mean concentrations were similar to those in control subjects (336 +/- 58 vs 307 +/- 9 [SE] mg/dL), whereas serum transferrin concentrations were decreased in patients with ARDS (182 +/- 68 mg/dL; p < 0.05). Compared with control subjects, lavage fluid recovered from patients with RF due to COPD contained significantly decreased concentrations of transferrin (1.56 +/- 0.24 vs 4.27 +/- 0.44 micrograms/mL; p < 0.001), whereas transferrin concentrations in lavage fluid recovered from patients with ARDS were increased (15.72 +/- 2.01 micrograms/mL; p < 0.001). Transferrin concentrations of lavage fluid also were decreased in COPD patients when normalized for lavage fluid protein content (4.35 +/- 0.72 vs 19.96 +/- 3.13 micrograms/mg in control subjects, p < 0.001). These data indicate that mechanical ventilation of patients with COPD is associated with decreased lung transferrin concentrations, in contrast to an increased transferrin concentration found in patients with ARDS. Decreased transferrin concentrations in the lower respiratory tract may decrease defenses against oxidant injury and bacterial infection in patients with RF due to COPD.

Intratracheal (IT) instillation of human recombinant interleukin 1 (IL-1) in rats induces an influx of neutrophils into alveolar structures and a dose-dependent increase in lung vascular permeability. We sought to determine whether increased alveolar concentrations of tumor necrosis factor (TNF) enhanced lung injury induced by intrapulmonary administration of low-dose IL-1. Rats were divided into five groups and treated with IT instillation of saline (0.1 ml) containing (1) no additional compound (controls), (2) human recombinant IL-1 (10 ng), (3) human recombinant TNF (2 micrograms), (4) IL-1 + TNF (10 ng + 2 micrograms), or (5) lipopolysaccharide (LPS, 10 micrograms). At 3, 6, 24, and 48 hours after treatment, we counted neutrophils recovered by bronchoalveolar lavage (BAL), assessed TNF activity in BAL fluid, and measured lung wet:dry weight ratio. At 3 and 6 hours after treatment, we measured levels of the lipid peroxide derivative malondialdehyde (MDA) in lung homogenates. IT instillation of LPS, IL-1, or IL-1 + TNF rapidly increased BAL neutrophil recovery, whereas recovery was not increased by TNF alone. TNF activity in BAL fluid was markedly increased by LPS, TNF, and IL-1 + TNF, with a smaller increase induced by IL-1. Instillation of TNF or IL-1 alone at these doses did not increase the lung wet:dry ratio. IT administration of LPS increased the wet:dry ratio at 6 hours only (p < 0.05), whereas IL-1 + TNF increased this ratio beginning 3 hours (p < 0.01) after treatment with persistent increases through 48 hours (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Therapeutic thoracic irradiation may induce two late pulmonary injury syndromes: radiation pneumonitis and subsequent pulmonary fibrosis. The alveolar macrophage has been considered a radioresistant cell and not a target cell involved in the pathogenesis of either type of radiation-induced lung injury. Alveolar macrophage-derived cytokines, including interleukin-1 (IL-1) and tumor necrosis factor (TNF), have been demonstrated to participate in inflammatory and fibrotic responses in the lung after various other types of lung injury. To evaluate whether the release of cytokines by alveolar macrophages is induced by radiation doses used clinically, alveolar macrophages recovered from nonsmoking volunteers were exposed in vitro to a single dose of 2 Gy and then maintained in culture for 18 h. Culture supernatants and cell lysates were then recovered and analyzed for IL-1 alpha and IL-1 beta by radioimmunoassay. Supernatants of irradiated alveolar macrophages contained significantly increased amounts of IL-1 alpha (P < 0.04) and IL-1 beta (P < 0.02) as well as total IL-1 (IL-1 alpha and IL-1 beta) (P < 0.02) compared to nonirradiated alveolar macrophages. Cell lysates of irradiated alveolar macrophages also contained increased amounts of IL-1 alpha and IL-1 beta, although differences from controls were not significant. The finding of increased release of IL-1 by alveolar macrophages after exposure to a single, clinically relevant dose of radiation suggests that the function of human alveolar macrophages is likely altered during therapeutic use of thoracic irradiation. Whether this release of IL-1 by alveolar macrophages contributes to early lung inflammation induced by thoracic irradiation is unclear.

Mucinous cystic tumors of the lung are exceedingly rare. We describe the case of a 59-year-old white man with a left upper lobe mass documented on chest radiographs 11 years before thoracotomy. Grossly, the lobectomy specimen contained a 4.5 x 4.5 x 4.0 cm cystic gelatinous mass with complete occlusion of the anterior segmental bronchus by mucinous material. Although microscopically this pulmonary mucinous cystic tumor contained a focus of marked glandular atypia consistent with adenocarcinoma, the patient has remained free of recurrence or metastasis during 5 years of close postoperative follow-up. Pulmonary mucinous cystic tumors appear to have a remarkably favorable prognosis and should be distinguished from other common lung neoplasms.

Lung mast cell hyperplasia and fibrosis is induced by bleomycin lung injury. The role of the mast cell in this process of injury and resultant fibrosis is unclear. Mutant mi/mi mice, profoundly mast-cell-deficient, were treated with intraperitoneal bleomycin and demonstrated minimal acute inflammatory and chronic fibrotic responses. Lung histamine values determined at 14 and 42 days after bleomycin injury in mi/mi mice were not increased compared to untreated mi/mi animals. However, lung histamine levels in normal mice demonstrated a 300% increase over controls on Day 14 after bleomycin injury, and then returned to baseline by Day 42. The mi/mi BAL cell recovery at 2 weeks after injury and lung hydroxyproline levels at 4 weeks after injury were not altered from baseline. The normal litter mates, in contrast, demonstrated significant increases compared to controls in both of these parameters (p < 0.01, p < 0.04). Although the mi/mi mouse is also deficient in basophils, natural killer cells and functional osteoclasts, there is no evidence of lowered pulmonary defense mechanism and neutrophils and alveolar macrophages are present in normal numbers. This investigation supports the hypothesis that the mast cell contributes to bleomycin-induced lung injury and fibrosis.

Significant improvements in the result of cancer treatment have resulted in longer survival for many of these patients and increasing numbers of patients who are cured. Unfortunately, the toxic effect of cancer therapy on other organs, and particularly the lung, has become an increasingly recognized problem in these patients. There are no specific tests that are diagnostic for chemotherapy or radiation-induced lung injury so the clinician must keep this diagnosis in mind and attempt to evaluate other possibilities. If treatment induced lung injury is considered likely, whether radiation pneumonitis or drug-induced pneumonitis, corticosteroid therapy may be of benefit. Therapy should be initiated at high doses and then tapered slowly following the clinical response. Most of these patients will do well, however, pulmonary toxicity may lead to respiratory impairment or mortality in some patients. Hopefully, as we gain more understanding of the risk factors and mechanisms of treatment-induced lung toxicity, new methods will be developed to decrease lung impairment due to cancer treatment.

Alveolar macrophages (AM) contain iron and ferritin, and concentrations of both are increased in AM of smokers compared with nonsmokers. Ferritin stores iron in a nontoxic form but can release iron in the presence of reducing agents and thereby catalyze the generation of toxic hydroxyl radicals via the Haber-Weiss reaction. Two distinct isoferritins are found in peripheral monocytes, L ferritin and H ferritin. H ferritin is the predominant isoferritin in human monocytes and is more effective than L ferritin in detoxifying iron in vitro. In this study we quantitated content of H and L ferritins, transferrin, and iron in AM recovered by bronchoalveolar lavage (BAL) of 24 subjects, including eight nonsmokers, eight smokers with normal spirometry, and eight smokers with chronic airflow obstruction (CAO). Of total AM ferritin in nonsmokers 95% was composed of L ferritin. Smokers without CAO demonstrated a 6.5-fold increase in the AM content of L ferritin (1,886 +/- 266 versus 290 +/- 51 ng, mean +/- SEM; p less than 0.0001) and a 3.8-fold increase in H ferritin (61 +/- 18 versus 16 +/- 2 ng per 1 x 10(6) AM, p less than 0.01) compared with nonsmokers. Compared with smokers without CAO, AM recovered from smokers with CAO demonstrated a greater increase in L ferritin (5,059 +/- 493 versus 1,886 +/- 266 ng per 1 x 10(6) AM, p less than 0.002) but a similar increase in H ferritin (64 +/- 8 versus 61 +/- 18 per 1 x 10(6) AM).(ABSTRACT TRUNCATED AT 250 WORDS)

This prospective study evaluated the incidence and severity of arterial oxygen desaturation during gastrointestinal endoscopy. Following pulmonary function testing, 115 male patients underwent esophagogastroduodenoscopy (EGD), colonoscopy, or colonoscopy followed by EGD, with continuous recording of arterial oxygen saturation (SaO2). Most patients (80/115, 70%) showed arterial oxygen desaturation (greater than 4% decrease from baseline SaO2); severe arterial oxygen desaturation (SaO2 less than or equal to 85%) reflecting hypoxemia (PaO2 less than or equal to 50 mm Hg) was noted in one-third of patients overall (37/115, 32%). Severe arterial oxygen desaturation occurred in 9/62 EGD patients (15%), 23/46 colonoscopy patients (50%), and 4/7 patients having colonoscopy followed by EGD (57%). Arterial oxygen desaturation occurs frequently during gastrointestinal endoscopy and is often severe. These data support the concept that continuous monitoring of SaO2 should be standard procedure during all gastrointestinal endoscopic procedures.

To determine the clinical utility of airway carcinoembryonic antigen (CEA) concentrations to distinguish malignant from inflammatory airway disease in patients undergoing bronchoscopy, we determined CEA concentrations by enzyme immunoassay in bronchial washings recovered in 48 subjects, including 20 patients with central lung cancer, 18 patients with chronic bronchitis, and ten nonsmoking patients with a diagnosis of pneumonia or peripheral granuloma. Concentrations of CEA in bronchial washings were standardized by using the total protein concentration in recovered fluid (CEA/TP). Concentrations of CEA were significantly increased in bronchial washings recovered from both patients with chronic bronchitis and lung cancer compared with patients with pneumonia or granuloma (252 +/- 47 ng/mg and 199 +/- 64 ng/ml vs 62 +/- 11 ng/mg, SEM, p less than 0.005). Airway CEA concentrations in patients with chronic bronchitis were somewhat increased compared with concentrations recovered from a cancer-involved airway (252 +/- 47 ng/ml vs 199 +/- 64 ng/mg, SEM, p less than 0.05). Measurement of airway CEA concentrations is not useful in distinguishing malignant from inflammatory airway disease as airway concentrations of CEA may be markedly increased in patients with both conditions.

Saline lavage was performed on rat lungs after the intratracheal injection of saline or bleomycin. An increase (p less than 0.025) in total cells recovered, an increase (p less than 0.001) in neutrophils, and an increase (p less than 0.001) in albumin concentration were noted in lavage fluid recovered from rats subsequent to bleomycin injury. At 5, 10, 15, and 20 days after injury, macrophages recovered from bleomycin-treated rats generated increased (p less than 0.05) amounts of neutrophil chemotactic activity in vitro compared with macrophages recovered from saline-treated rats. The chemotactic activity was attributable to a factor or factors of low molecular weight and hydrophobic in nature, characteristics similar to previously described alveolar macrophage-derived neutrophil chemotactic factors. The generation of neutrophil chemotactic activity was suppressed (p less than 0.025) by hydrocortisone and 5,8,11,14-eicosatetraynoic acid (ETYA), suggesting that the neutrophil chemotactic activity generation is dependent upon the lipoxygenase pathway of arachidonic acid metabolism.

The pulmonary uptake of 87Ga citrate has been proposed as an index that assists clinical decision-making in patients with certain interstitial lung diseases. Such use, however, requires definition of the range of normal values, the range of values in patients with various interstitial diseases, and interobserver and intraobserver variability. We studied 9 normal subjects and 15 patients with interstitial lung diseases. The 87Ga indexes were determined by visual analysis and by a computer-assisted method. We found that the variation among experienced observers in visual index values was substantial in both normal subjects and patients, and that the computer-assisted indexes were less variable. These data suggest that if this approach is to be used in clinical decision-making: (1) the variability of visual indexes, and of normal values, should be recognized; (2) consideration should be given to a less subjective, computer-assisted method of index calculation; (3) each institution should establish standardized methodology and consider determination of its range of variability and normal index values.

Interstitial lung disorders are a heterogeneous group of diseases that result in a similar clinical presentation and have similar physiologic consequences on lung function. Our current understanding of these disorders indicates that there is an inflammatory component of these diseases that is reversible and that precedes the development of interstitial pulmonary fibrosis, which is irreversible. Although conclusive clinical studies are still lacking, treatment of pulmonary disease in these patients is based on the concept that treatment of the inflammatory component of the disease with immunosuppressive agents will prevent or reduce the amount of pulmonary fibrosis that develops. Because of the significant side effects associated with immunosuppressive drugs, therapy should be used only when there is likely to be therapeutic benefit. The use of immunosuppressive agents is, therefore, indicated in selected groups of patients. If there is a known precipitating agent for the interstitial disorder, such as asbestos exposure, the primary therapy is to avoid further exposure to the agent. Sarcoidosis is one of the most common systemic disorders associated with interstitial lung disease, and in this disease, corticosteroids clearly are of benefit. In pulmonary sarcoidosis, patients who are symptomatic or patients who demonstrate progressive clinical deterioration of pulmonary function should be treated. Recent studies also suggest that patients with a high degree of pulmonary inflammation as demonstrated by a positive gallium scan and a high percentage (greater than 28%) of lymphocytes obtained on lung lavage may also benefit from corticosteroid therapy. Idiopathic pulmonary fibrosis is a progressive disease and is usually symptomatic at the time of presentation, so it is reasonable to give all patients a therapeutic trial with corticosteroids.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of bronchial brush size on cell recovery during fiberoptic bronchoscopy was investigated. In 20 patients undergoing diagnostic bronchoscopy, 3 additional brushings in normal peripheral airways were performed using sheathed brushes of 1.0, 1.73, and 3.0 mm in diameter. Mean cell recovery was 5.7, 8.1, and 9.0 x 10(4) cells per brush, respectively. There were no significant differences in cell recovery between the 3 brushes. Brush size does not appear to significantly influence cell recovery in normal peripheral airways.

The purpose of this study was to quantitate cell populations recovered by lung lavage up to 6 weeks following thoracic irradiation (24 Gy) as an index of the acute inflammatory response within lung structures. Additionally, rats were treated five times weekly with intraperitoneal saline (0.3 cc) or methylprednisolone (7.5 mg/kg/week). Lung lavage of irradiated rats recovered increased numbers of total cells compared to controls beginning 3 weeks after irradiation (P less than 0.05). The initial increase in number of cells recovered was attributable to an influx of neutrophils (P less than 0.05), and further increases at 4 and 6 weeks were associated with increased numbers of recovered macrophages (P less than 0.05). Lung lavage of steroid-treated rats at 6 weeks after irradiation recovered increased numbers of all cell populations compared to controls (P less than 0.05); however, numbers of recovered total cells, macrophages, neutrophils, and lymphocytes were all significantly decreased compared to saline-treated rats (P less than 0.05). The number of inflammatory cells recovered by lung lavage during acute radiation-induced lung injury is significantly diminished by corticosteroid treatment. Changes in cells recovered by lung lavage can also be correlated with alteration in body weight and respiration rate subsequent to treatment with thoracic irradiation and/or corticosteroids.

Saline lavage was performed on rat lungs at weekly intervals for as long as 6 wk after thoracic irradiation (24 Gy). The number of alveolar macrophages recovered by lavage was significantly increased compared with that in control animals beginning at 4 wk after irradiation (p less than 0.05). Autoradiographic analysis of macrophages recovered demonstrated an increased labeling index compared with that in control animals beginning 3 wk after irradiation (p less than 0.05). Macrophage proliferation in vivo was also assessed by injecting rats with vincristine and evaluating macrophages recovered by lung lavage for arrested mitoses. The number of arrested mitoses noted was significantly increased in rats at 4 wk after irradiation compared with that in control animals (p less than 0.05). These data indicate that after high dose thoracic irradiation there is an expansion of the alveolar macrophage population that is due at least in part to increased local proliferation of alveolar macrophages.

Bronchoalveolar lavage has not been subjected to careful standardization. We examined the variables of lung lavage location and lavage fluid composition (pH and temperature) upon the percent of fluid recovered, cell count and differential, protein and pH in normal subjects. In the first part of the study, random order lavages of the right middle lobe (RML), right lower lobe (RLL), left lingula, and left lower lobe (LLL) were performed with 100-ml aliquots of normal saline (pH, 5.5) at room temperature (25 degrees C). Percent fluid recovery was greater in the RML and lingula than in the RLL (p less than 0.05). Cell count, cell differential, and protein were similar between lobes. In the second part of the study, each lobe was lavaged with 50-ml aliquots: the RML with normal saline at 37 degrees C, the RLL with normal saline buffered to a pH of 7.0 at 37 degrees C, the left lingula with normal saline at 25 degrees C, and the LLL with normal saline buffered to a pH of 7.0 at 25 degrees C. Percent fluid recovery was greater in the RML than in the lingula and greater in both the RML and lingula than in the lower lobes (p less than 0.05). Total cell count was significantly higher in the RML than in the LLL (p less than 0.05). Cell count per milliliter and protein recovered were not different between any lobe lavaged. The pH of recovered fluid was greater with buffered saline. Complications of fever and chills occurred in almost 50% of subjects in both parts of the study. Lavage location can affect fluid recovery. Alteration of lavage fluid composition did not affect cell or protein recovery. We suggest lavage of the RML to ensure larger fluid recovery and the highest total cell count.

Altered cellular immune function has been demonstrated in patients with lung cancer, including decreased numbers of circulating lymphocytes and changes in the percentage of lymphocytes in various functional subsets. We quantitated lymphocyte subsets in 54 patients with lung cancer including patients with limited (stages 1 and 2) nonsmall cell lung cancer (NSCLC, n = 23), advanced (stage 3) NSCLC (n = 16), and small cell cancer (SCLC, n = 15). Serum albumin was decreased in 15 lung cancer patients, and lymphocyte subsets were separately evaluated in these patients. Lymphocyte populations in cancer patients were compared to those of nonsmokers and a smoking patient population. No difference from smokers was noted in patients with limited NSCLC. Patients with SCLC and advanced NSCLC had significantly decreased numbers of T-helper and T-suppressor cells (p less than 0.05). Patients with lung cancer and hypoalbuminemia had the greatest decrease in number of circulating T-helper cells (p less than 0.001). B-lymphocytes were also decreased in patients with advanced NSCLC and patients with hypoalbuminemia (p less than 0.05). A decrease in population of T-lymphocytes subsets is frequent in patients with SCLC, advanced NSCLC, and lung cancer patients with hypoalbuminemia.

To determine whether concentrations of the primary airway immunoglobulins (SIgA, IgG) are altered in the uninvolved lung of patients with lung cancer, we determined concentrations of SIgA and IgG in bronchial washings recovered from a proximal airway of the uninvolved lung in 24 patients with lung cancer and in ten patients with benign lung disease. When standardized for the amount of total protein recovered (SIgA/TP, IgG/TP), bronchial washings recovered from the uninvolved lung of lung cancer patients demonstrated a significantly decreased SIgA/TP ratio compared to control subjects (.14 +/- .02 vs .31 +/- .05, SEM, p less than 0.05). There were no differences in the IgG/TP ratios. Lung cancer patients with a decreased serum albumin (less than 3.2 g/dl) had a significantly decreased SIgA/TP ratio in bronchial washings compared to patients with a higher serum albumin (.08 +/- .03 vs .18 +/- .04, SEM, p less than 0.05). The decreased relative concentration of airway SIgA in lung cancer patients may adversely affect airway defenses against bacterial colonization.