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Objectives: This study aimed to evaluate the diagnostic performance of the lung zero-echo time (ZTE) sequence in FDG PET/MRI for detection and differentiation of lung lesions in oncologic patients in comparison with conventional two-point Dixon-based MR imaging., Methods: In this single-institution retrospective study approved by the institutional review board, 209 patients with malignancies (97 men and 112 women; age range, 17-89 years; mean age, 66.5 ± 12.9 years) underwent 18 F-FDG PET/MRI between August 2017 and August 2018, with diagnostic Dixon and ZTE under respiratory gating acquired simultaneously with PET. Image analysis was performed for PET/Dixon and PET/ZTE fused images by two readers to assess the detectability and differentiation of lung lesions. The reference standard was pathological findings and/or the data from a chest CT. The detection and differentiation abilities were evaluated for all lesions and subgroups divided by lesion size and maximum standardized uptake value (SUVmax)., Results: Based on the reference standard, 227 lung lesions were identified in 113 patients. The detectability of PET/ZTE was significantly better than that of PET/Dixon for overall lesions, lesions with a SUVmax less than 3.0 and lesions smaller than 4 mm (p < 0.01). The diagnostic performance of PET/ZTE was significantly better than that of PET/Dixon for overall lesions and lesions smaller than 4 mm (p < 0.01)., Conclusions: ZTE can improve diagnostic performance in the detection and differentiation of both FDG-avid and non-FDG-avid lung lesions smaller than 4 mm in size, yielding a promising tool to enhance the utility of FDG PET/MRI in oncology patients with lung lesions., Key Points: • The detection rate of PET/ZTE for lesions with a SUVmax of less than 1.0 was significantly better than that of PET/Dixon. • The performance for differentiation of PET/ZTE for lesions that were even smaller than 4 mm in size were significantly better than that of PET/Dixon. • Inter-rater agreement of PET/ZTE for the differentiation of lesions less than 4 mm in size was substantial and better than that of PET/Dixon.

Background: Systemic inflammation is present in chronic obstructive pulmonary disease (COPD). A whey peptide-based enteral diet reduce inflammation in patients with COPD, but its effect on COPD development has not been determined. On the other hand, it is known that short chain fatty acids (SCFAs), which are produced by micro-flora in the gut, attenuates bronchial asthma in mice model., Methods: Mice with elastase-induced emphysema were fed with 1 of 3 diets (control diet, whey peptide-based enteral diet, or standard enteral diet) to determine the effects of whey peptide-based enteral diet on emphysema and on cecal SCFAs., Results: The whey peptide-based enteral diet group exhibited fewer emphysematous changes; significantly lower total cell counts in bronchoalveolar lavage fluid (BALF); and significantly higher cecal SCFA levels than either the control or standard enteral diet groups. The total cell count was inversely correlated with total cecal SCFA levels in these three diet groups., Conclusions: The whey peptide-based enteral diet attenuates elastase-induced emphysema through the suppression of inflammation in the lung. This may be related to the increase in cecal SCFA.

Background: Oxidative stress is implicated in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). Analysis of the expired breath condensate (EBC) has been suggested to provide non-invasive inflammatory markers that reflect oxidative stress in the airways., Objective: The present study attempts to elucidate whether the hydrogen peroxide (H2O2) levels and pH values in EBC may be useful as biomarkers of the activity or severity of asthma and COPD., Methods: We measured the H2O2 levels and pH values using a derivatives of reactive oxygen metabolites exhalation test kit (Diacron) and a pH analyser, respectively, in EBC obtained using an EcoScreen from 29 patients with asthma, 33 with COPD, and 33 healthy individuals (all non-smokers). We then examined the relationships among oxidative stress and the asthma control test (ACT) or COPD assessment test (CAT) scores, pulmonary function, fractional exhaled nitric oxide (FeNO), and the extent of low attenuation areas on HRCT., Results: The H2O2 levels were elevated and pH was lower in both asthma (H2O2; 8.75 ± 0.88 μM, p < 0.01, pH; 7.14 ± 0.07, p < 0.05) and COPD (H2O2; 7.44 ± 0.89 μM, p < 0.01, pH; 6.87 ± 0.10, p < 0.01) compared with control subjects (H2O2; 3.42 ± 0.66 μM, pH; 7.35 ± 0.04). Neither the H2O2 levels nor pH correlated with the ACT scores and FeNO in asthma patients. Neither the H2O2 levels nor pH significantly correlated with the pulmonary function in asthma and COPD. However, the CAT scores significantly correlated with the H2O2 levels in patients with COPD (r = 0.52, p < 0.01)., Conclusions: These findings suggest that oxidative stress is involved in the pathogenesis of asthma and COPD and that the H2O2 levels in EBC might reflect the health status in COPD.

Background: The mechanisms underlying the association between smoking and mucus overproduction remain unknown. Because of its involvement in other airway diseases, such as asthma, we hypothesized that Ca²⁺-activated Cl⁻ channel 1 (CLCA1) was associated with overproduction of mucus in the airways of smokers and COPD patients., Methods: Using real-time quantitative PCR analyses, we compared the CLCA1 mRNA expression levels in induced-sputum cells from COPD patients (n = 20), smokers without COPD (n = 5), and non-smokers (n =13). We also examined the relationship between CLCA1 protein expression and mucus production in lung airway epithelia of COPD patients (n = 6), smokers without COPD (n = 7), and non-smokers (n = 7)., Results: CLCA1 mRNA expression was significantly up-regulated in the induced-sputum cells of COPD patients compared with cells of non-smokers (p = 0.02), but there was no significant difference compared with cells of smokers without COPD. Using immunostaining with an anti-CLCA1 antibody, semi-quantitative image analyses of airway epithelium demonstrated significantly increased CLCA1 expression in smokers without COPD (p = 0.02) and in COPD patients (p = 0.002) compared with non-smokers. There were significant negative correlations between CLCA1 protein expression and FEV1/FVC (r = -0.57, p = 0.01) and %predicted FEV1 (r = -0.56, p = 0.01). PAS staining for mucus showed that there was a significant positive correlation between CLCA1 protein expression and mucus production (r = 0.67, p = 0.001). These markers were significantly increased in smokers without COPD (p = 0.04) and in COPD patients (p = 0.003) compared with non-smokers (non-smokers < smokers ≤ COPD)., Conclusions: CLCA1 expression is significantly related to mucus production in the airway epithelia of smokers and COPD patients, and may contribute to the development and pathogenesis of COPD by inducing mucus production.

The aim of this study was to morphologically evaluate damage in the capillary endothelial cells of the respiratory tract in patients with sarcoidosis. We examined tissues of the bronchus and lung obtained from 16 patients with sarcoidosis consisting of 2 stage 0, 10 stage I and 4 stage II patients, and 11 controls. The morphology of capillary endothelial cells was studied using electron microscopy. In the samples from patients with sarcoidosis, lipid droplets exhibiting dark monophasic density (unsaturated fatty acids) were surrounded by abundant lysosomes in the capillary endothelial cells, and the double-membrane structure of the mitochondria attached to these lipid droplets was lost in three cases. Biphasic lipid droplets with dark and lucent (saturated fatty acids) densities were also observed, accompanied by a few lysosomes containing the residual bodies of undigested lipid-containing substances. Lucent monophasic droplets were also detected in the tissues from patients with sarcoidosis. The plasma membrane was more often damaged in capillary endothelial cells containing biphasic lipid droplets, lucent monophasic droplets as well as in those with dark monophasic droplets. However, no lipid droplets were detected in capillary endothelial cells obtained from the control subjects, except in a single case. This study demonstrated that a large number of mitochondria were mobilized and showed notable morphological changes including swelling in the capillary endothelial cells in patients with sarcoidosis. A close relationship between mitochondria and lipid droplets was observed in capillary endothelial cells of the respiratory tract, and this relation may be involved in the pathogenesis of sarcoidosis., (© 2011 Elsevier B.V. and Mitochondria Research Society. All rights reserved.)

Background: The purpose of this study was to clarify the association between morphological phenotypes according to the predominance of emphysema and efficacy of long-acting muscarinic antagonist and β(2) agonist bronchodilators in patients with chronic obstructive pulmonary disease (COPD)., Methods: Seventy-two patients with stable COPD treated with tiotropium (n = 41) or salmeterol (n = 31) were evaluated for pulmonary function, dynamic hyperinflation following metronome-paced incremental hyperventilation, six-minute walking distance, and St George's Respiratory Questionnaire (SGRQ) before and 2-3 months following treatment with tiotropium or salmeterol. They were then visually divided into an emphysema dominant phenotype (n = 25 in the tiotropium-treated group and n = 22 in the salmeterol-treated group) and an emphysema nondominant phenotype on high-resolution computed tomography, and the efficacy of the two drugs in each phenotype was retrospectively analyzed., Results: Tiotropium significantly improved airflow limitation, oxygenation, and respiratory impedance in both the emphysema dominant and emphysema nondominant phenotypes, and improved dynamic hyperinflation, exercise capacity, and SGRQ in the emphysema dominant phenotype but not in the emphysema nondominant phenotype. Salmeterol significantly improved total score for SGRQ in the emphysema phenotype, but no significant effects on other parameters were found for either of the phenotypes., Conclusion: These findings suggest that tiotropium is more effective than salmeterol for airflow limitation regardless of emphysema dominance, and also can improve dynamic hyperinflation in the emphysema dominant phenotype, which results in further improvement of exercise capacity and health-related quality of life.

Background and Objective: Lung uptake of iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) is used as an indicator of pulmonary endothelial function. Decreased lung uptake of ¹²³I-MIBG has been demonstrated in patients with COPD as compared with normal subjects. The present study was performed to examine the relationship between lung uptake of ¹²³I-MIBG and pulmonary artery pressure (Ppa) at rest and during exercise, in patients with COPD., Methods: ¹²³I-MIBG scintigraphy was performed in 19 patients with COPD. Anterior planar images were acquired 15 min after the injection of ¹²³I-MIBG, and the total lung to upper mediastinum ratio (LMR) was calculated for both lungs. Right heart catheters were used to monitor Ppa continuously at rest and during exercise. Exercise was performed on an electrically braked bicycle ergometer at a constant workload of 25 W for 3 min., Results: In COPD patients the LMR were not correlated with the pulmonary function parameters measured before exercise, including FEV₁, PaO₂, DL(CO), or Ppa at rest. However, the percentage increase in Ppa during exercise was significantly correlated with LMR., Conclusions: Evaluation of the kinetics of lung uptake of ¹²³I-MIBG may be a novel scintigraphic tool for the assessment of exercise-induced pulmonary hypertension in patients with COPD., (© 2010 The Authors; Respirology © 2010 Asian Pacific Society of Respirology.)

Objective: To investigate whether the endothelin (ET) receptor antagonists have protective role in the development of emphysema., Methods: Sprague-Dawley rats (n = 24) were divided into four groups: control group, cigarette smoke extract (CSE) group, BQ123 group and Bosentan group. CSE was injected intraperitoneally once a week for three weeks and BQ123 and Bosentan were administered daily for the same duration. TdT-mediated dUTP nick end labeling (TUNEL) was performed to observe the deoxyribonucleic acid (DNA) damaged cells and the expression of caspase-3 was determined by immunohistochemistry and Western blot. Matrix metalloproteinase-2 (MMP-2) and MMP-9 activities were investigated by gelatin zymography and tumor necrosis factor α (TNFα) and interleukin-1ß (IL-1ß) concentrations were measured by enzyme linked immunosorbent assay (ELISA)., Results: We confirmed the emphysematous destruction in the lungs of experimental rats induced by the intraperitoneal injection of CSE within 3 weeks. The mean lining interval (MLI) and damage index (DI) were significantly increased in the CSE group compared with control group. However, the MLI and DI were significantly decreased in the BQ123 and bosentan groups compared with CSE rats (P < 0.01, respectively). The TUNEL-positive cells were markedly distributed in the peri-bronchioles, intra-alveoli, and septal areas of the emphysematous lungs in CSE rats comparing with the lungs of control rats. The apoptosis index (AI) was significantly higher in CSE group than control group. And the AI was significantly reduced in BQ123 group and bosentan group compared with that in CSE group. The caspase-3 positive cells were markedly distributed in the emphysematous lungs of CSE group comparing with the stained cells in the lungs of control rats. These positive cells were apparently reduced in the BQ123 and bosentan groups compared with the stained cells in CSE group. Comparing with the control group, expression of caspase-3 was prominently enhanced in CSE groups, but both BQ123 and bosentan treatments markedly inhabited the increases of the cleaved caspase-3 protein levels in rats injected with CSE. Rats injected with CSE showed increased MMP-2 and MMP-9 activities in their lung tissue homogenates and MMP-2 and MMP-9 activities were reduced significantly in both BQ123 and bosentan groups. The levels of TNFα and IL-1ß were significantly increased in the CSE group in comparison to those in controls. BQ123 and bosentan significantly prevented the increases of the levels of TNFα and IL-1ß in lungs of rats with injection of CSE., Conclusions: ET-1 may have an important role in the pathological process of emphysema and ET receptor antagonists protect against the development of emphysema probably by decelerating apoptosis, inhibiting proteolytic enzyme activity and reducing inflammatory cytokine levels.

Background: A wide variety of systemic lesions have been seen in patients with autoimmune pancreatitis. The pulmonary involvement of autoimmune pancreatitis was analysed to clarify the clinicopathological features of pulmonary lesions in comparison with pulmonary sarcoidosis., Materials and Methods: Nineteen patients had autoimmune pancreatitis and eight had pulmonary sarcoidosis. The symptoms, laboratory data, chest computed tomography, Gallium-67 scintigraphy, pulmonary function testing and bronchoscopy findings, including the histological IgG4-immunostaining and IgG subclasses in the bronchoalveolar lavage in autoimmune pancreatitis, were collected to compare them with pulmonary sarcoidosis., Results: The serum total protein, IgG and IgG4 levels were found to be significantly elevated in comparison with pulmonary sarcoidosis. In autoimmune pancreatitis, 17 patients showed bilateral hilar lymphadenopathy, while eight showed pulmonary nodules on chest computed tomography. Eighteen of 19 patients on Gallium-67 scintigraphy showed accumulation spots in either the hilar or mediastinal lymph nodes. Six patients with pulmonary nodules demonstrated accumulation spots in the corresponding lesions on chest computed tomography. All eight patients with pulmonary sarcoidosis showed accumulation spots in either the hilar or mediastinal lymph nodes. Bronchoalveolar lavage IgG4 in autoimmune pancreatitis showed a significant increase in comparison with pulmonary sarcoidosis. The histological findings obtained by a transbronchial lung biopsy showed the infiltration of lymphocytes and plasma cells in the thickened interstitum and alveoli with IgG4-positive plasma cell infiltration in patients with autoimmune pancreatitis., Conclusion: IgG4 in the bronchoalveolar lavage was seen at remarkably increased levels and IgG4-positive plasma cells were identified in the pulmonary lesions of patients with autoimmune pancreatitis.

Background and Objective: Iodine-123 metaiodobenzylguanidine ((123)I-MIBG) uptake in the lungs is a potentially suitable marker of pulmonary endothelial function because MIBG behaviour in the pulmonary circulation is quantitatively similar to that of norepinephrine. In addition, hypoxia reduces (123)I-MIBG transport in pulmonary endothelial cells in vitro. The present study was undertaken to evaluate (123)I-MIBG uptake in the lungs of patients with high-altitude pulmonary oedema (HAPE)., Methods: (123)I-MIBG scintigraphy was performed in eight patients with HAPE. The findings were compared with those in 24 patients with congestive heart failure due to idiopathic dilated cardiomyopathy (DCM) and in 13 normal control subjects. In patients with HAPE, the (123)I-MIBG examination was performed 7-14 days after admission. Anterior planar images were acquired 15 min after injection of (123)I-MIBG and the total lung to upper mediastinum ratio (L/M ratio) was calculated for both lungs., Results: The L/M ratio in patients with HAPE (1.39 +/- 0.15, mean +/- SD) was significantly lower than in those with congestive heart failure/DCM (1.66 +/- 0.16) or in normal controls (1.53 +/- 0.14). There were no significant differences among the groups in (123)I-MIBG accumulation in the heart., Conclusions: Although the mechanism of altered (123)I-MIBG kinetics in HAPE remains obscure, decreased (123)I-MIBG uptake in the lungs may potentially be a suitable technique for the assessment of pathological conditions associated with the pulmonary endothelium.

The aim of the current study was to assess the safety of bronchoscopy-guided radiofrequency ablation (RFA) and compare the effectiveness between new internal cooled-RFA and standard noncooled-RFA. Normal lungs from sheep were used (n=6). Internal cooled-RFA and standard noncooled-RFA were set to assess the most suitable RFA conditions, such as power output, flow rate and ablation time. Internal cooled-RFA was then applied under the most optimal conditions of power output and flow rate for 15, 30, 60 and 120 s, and two water temperatures either room temperature (RT) water or cold water. Criteria for the most appropriate conditions were set over 15 s of ablation time and 50 degrees C of the tip's temperature. Internal cooled-RFA had no complications. Standard noncooled-RFA was complicated with bronchial bleeding after RFA. On the basis of the histological findings, average temperature and average output, the most appropriate conditions of the cooled-RFA were a power output of 30 W and flow rate of 30 or 40 mL.min(-1). The cooled-RFA using cold water caused a smaller, more discrete, lesion compared with that using RT water. Bronchoscopy-guided internal cooled-radiofrequency ablation was an effective, safe and feasible procedure that could become a potential therapeutic tool in managing lung pathology.

Multifocal systemic fibrosclerosis (MSF) is a multisystem disease, which often mimics malignancy. A 70-year-old asymptomatic man with lesions in the lung, prostate, submandibular glands and bile ducts appeared to have malignancy. Biopsy of a lung nodule showed IgG4-positive plasma cell infiltration and the serum IgG4 was elevated. A diagnosis of MSF was made and the patient treated with oral prednisolone at 1 mg/kg/day. Sclerosing cholangitis, retroperitoneal fibrosis, Riedel's thyroiditis, fibrotic pseudotumor of the orbit and fibrosis of the salivary glands have all been reported to be part of this disease. It is now necessary for MSF to be considered in patients with pulmonary lesions mimicking lung cancer.

Background: Iodine-123 metaiodobenzylguanidine ((123)I-MIBG) lung uptake in the early phase has been proposed as a potential marker of endothelial function because MIBG behaves qualitatively similarly to norepinephrine in pulmonary circulation., Objectives: The purpose of the present study was to examine the lung uptake of (123)I-MIBG in patients diagnosed with myeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA)-associated vasculitis without clinical or radiological abnormalities of the thorax., Methods: Six patients with MPO-ANCA-associated vasculitis were enrolled. They had severe renal damage (mean creatinine: 5.1 mg/dl, mean blood urea nitrogen: 54.6 mg/dl), but no respiratory symptoms clinically or radiographic findings on chest computed tomography. The total lung to upper mediastinum ratio of (123)I-MIBG uptake (L/M) 15 min after the injection was measured. The result was compared with those for 6 patients with renal damage due to other diseases (mean creatinine: 6.2 mg/dl, blood urea nitrogen: 51.7 mg/dl) and for 8 healthy subjects., Results: The mean value of L/M in patients with MPO-ANCA-positive vasculitis was 1.21 +/- 0.04, which was significantly less than that of other groups (1.41 +/- 0.06 for patients with renal failure and 1.45 +/- 0.03 for normal volunteers). There were no significant differences in MIBG accumulation in the heart among the groups., Conclusions: The reduction in kinetic behavior of MIBG in the lung reflects the presence of pulmonary endothelial impairment in patients with MPO-ANCA-associated vasculitis, even though there are no clinical manifestations in the lungs.

Background: The effect of nitric oxide synthase inhibitor on acute lung injury remains controversial. The current study was designed to examine effects of a newly synthesized and selective inducible nitric oxide synthase inhibitor, ONO1714, on endotoxin-induced lung injury in unanesthetized sheep., Methods: Thirteen unanesthetized sheep chronically instrumented with a lung lymph fistula and vascular catheters for monitoring were prepared. Animals were randomly allocated into two experimental groups. In experiment 1, sheep (n = 6) were infused only with endotoxin (1 microg/kg) for 30 min. In experiment 2, sheep (n = 7) were pretreated with ONO1714 (0.1 mg/kg) before 30 min of endotoxin administration, and the endotoxin was infused in the same manner as in experiment 1. Mean pulmonary arterial pressure, left atrial pressure, systemic arterial pressure, and lung lymph flow were measured. Observation was continued over 5 h after endotoxin administration., Results: ONO1714 did not cause any pulmonary hemodynamic changes at baseline or exert any influences on transient pulmonary hypertension and increased pulmonary vascular resistance during endotoxemia. However, inducible nitric oxide synthase inhibition with ONO1714 significantly reduced lung lymph filtration and improved abnormal oxygenation during endotoxemia. In addition, increased nitrate-nitrite in plasma and lung lymph in response to endotoxin was prevented by treatment with ONO1714., Conclusions: These findings suggest that nitric oxide release by the inducible nitric oxide synthase pathway partially contributes to the increased permeability of pulmonary edema and decreased oxygenation during endotoxemia in sheep.

The present study was designed to clarify the effects of (-)-ethyl N-[3,5-dichloro-2-hydroxy-4-[2-(4-methyl-piperazin-1-yl)ethoxy]benzoyl]-l-phenylalaninate dihydrochloride (JTE-607), a novel multiple cytokine inhibitor, on hydrochloric acid (HCl) aspiration lung injury in rats. HCl (0.1 N, 2 ml kg(-1)) was instilled into male Sprague-Dawley rats that were pretreated with or without JTE-607 (30 or 75 mg kg(-1) h(-1)). As a control, normal saline (2 ml kg(-1)) was instilled in rats. All the animals were anesthetized with intraperitoneally injected pentobarbital sodium (40 mg kg(-1)). Bronchoalveolar lavage was performed 5 h (h) after HCl or normal saline instillation. In bronchoalveolar lavage fluid, the increases in total nuclear cell counts, neutrophil counts, optical density at 412 nm as an indication of pulmonary hemorrhage, concentrations of albumin, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant induced by HCl instillation were significantly reduced by JTE-607 pretreatment. The level of expression of tumor necrosis factor-alpha and interleukin-6 mRNA in lung tissue was analyzed. The mean expression level of tumor necrosis factor-alpha and interleukin-6 mRNA in the JTE-607 group was lower than that in the HCl and NS groups. The wet-to-dry weight ratio was also determined, and JTE-607 at the dose of 75 mg kg(-1) h(-1) significantly attenuated the increased wet-to-dry weight ratio induced by HCl. These results suggest that JTE-607 can inhibit the production of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin-6 and cytokine-induced neutrophil chemoattractant and attenuate acid-induced lung injury in rats. This agent might be therapeutically useful for lung injury.

It has been suggested that overproduction of nitric oxide (NO) by nitric oxide synthase (NOS) contributes to blunted hypoxic pulmonary vasoconstriction (HPV) during endotoxemia. We investigated the effect of a selective inducible NOS (iNOS) inhibitor, ONO-1714, on the loss of HPV during endotoxemia in awake sheep to clarify the role of iNOS. We prepared 11 intubated, awake sheep with hemodynamic monitoring. Hypoxic challenges (FiO2; 12%) were performed before, and 5, 24, 48, 72 hours after endotoxin (1 microg/kg) infusion for 15 minutes. Pulmonary artery (Ppa) and left atrial pressure (Pla) were continuously measured and cardiac output (CO) was measured by the thermodilution method. Pulmonary vascular resistance (PVR) was calculated by (Ppa - Pla)/CO. The percent change in PVR (%PVR) before (pre-PVR) and after (post-PVR) hypoxia was calculated as (post-PVR - pre-PVR)/pre-HPV x 100. ONO-1714 (0.1 mg/kg, n=5, Exp 1) or normal saline (n=6, Exp 2) was administered 5 hours before hypoxic challenge every day. ONO-1714 did not affect the baseline pulmonary hemodynamics before endotoxin administration. % PVR before and after hypoxic exposure was significantly decreased 5 hours after endotoxin administration and gradually improved to baseline at 72 hours. Treatment with iNOS inhibition significantly restored % HPV (24.7+/-5.5% in Exp1 versus -3.1+/-3.6% in Exp 2, 5 hours, 25.3+/-2.5% in Exp 1 versus 7.7+/-2.2% in Exp 2, 24 hours). It is suggested that inducible nitric oxide is related to pulmonary vascular hyporesponsiveness to hypoxia during endotoxemia in sheep.

Since tacrolimus (FK-506) is known to suppress the proliferation and generation of T cells and to inhibit the production of T cell derived cytokines, we examined the effect of FK-506 on endotoxin-induced lung injury. We administered FK-506 (0.1 mg/kg) intravenously before the infusion of endotoxin (1 microgram/kg) into conscious sheep. We measured pulmonary hemodynamics, lung fluid balance, circulating leukocyte count and arterial blood gas tensions. The increase in pulmonary arterial pressure was significantly attenuated by FK-506 during the late period (3-5 h after endotoxin). Arterial oxygen gas tension was significantly higher in the FK-506 treated sheep during this phase. However, no significant differences were observed in lung lymph balance and circulating leukocyte count between the endotoxin alone group and the FK-506 treated group. These findings suggest that FK-506 may improve gas exchange in acute lung injury although there is an increased pulmonary vascular leakage. It is probable that FK-506 may have a beneficial potential on endotoxin-induced lung injury in sheep.

Synthetic starch solution, such as hydroxyethyl starch (HES), has been used clinically to restore cardiovascular volume in patients with hemorrhagic shock. Several HES solutions are available clinically, but each HES has a broad range of molecular mass fractions. We performed comparative studies of extremely low and high molecular HES to evaluate the effects of these HES solutions on lung lymph filtration during resuscitation. We prepared awake sheep with vascular monitoring and lung lymph fistulas. After baseline measurements, animals were bled from an arterial line to maintain shock. After 2 h of hemorrhagic period, the following three solutions were infused over 1 h, respectively. Experiment (Exp) 1 (n=6); low molecular HES; (molecular weight (MW) 70000, substitution fractions 0.5-0.55, Exp 2 (n=6); high molecular HES; (MW 450000, substitution fractions 0.65). Exp 3 (n=6); normal saline (NS). The quantity of solution was determined as the same volume of blood lost to induce hemorrhagic situation in each animal (Exp 1; 940+/-36 ml, Exp 2; 910+/-50 ml, Exp 3; 920+/-42 ml). Both low and high molecular HES could restore the systemic artery pressure and cardiac output, and significantly increased pulmonary microvascular pressure equally, which were significantly higher than those in normal saline. However, actual oncotic pressure gradient (plasma-lymph) rose transiently during low molecular HES infusion, while high molecular HES widened the oncotic pressure gradient even after the cessation of the infusion. Lung lymph flow during and after resuscitation with low molecular HES and NS rose significantly from the pre-shock baseline. There was no significant difference in increased lung lymph flow between low molecular HES and NS. However, lung lymph flow after high molecular HES was significantly less than that after low molecular HES. These data suggest that low molecular HES is as useful a plasma substitute as high molecular HES, but has a possibility to increase lung lymph filtration during the early phase of resuscitation.

The aim of the present study is to study the pharmacokinetics in plasma, lung lymph and bronchial washing fluid after intravenous infusion of grepafloxacin (GPFX), in comparison with those of levofloxacin (LVFX). Four conscious sheep with chronically instrumented lung lymph fistulas and tracheotomy were prepared. GPFX and LVFX concentrations in plasma and lung lymph after intravenous infusion of the drugs (10 mg/kg) for over 10 min were measured. In addition serial bronchial washing with 50 mL normal saline was performed to obtain epithelial lining fluid (ELF) at 2, 4, 6, 8, 12, 24 h after the intravenous administration. The time courses of lung lymph concentration were almost identical to those of the concomitant levels of both GPFX and LVFX in plasma, suggesting that both GPFX and LVFX could be easily moved from plasma to pulmonary interstitium and/or lung lymph circulation. However, GPFX concentrations of ELF were significantly higher than LVFX concentrations over time after the administration. In addition, intracellular concentrations in ELF of GPFX were also extremely high compared with those of LVFX. These results demonstrated that penetration of GPFX in bronchial wall, bronchial epithelium and/or phagocytic cells was superior to that of LVFX. These observations suggest that the pharmacokinetic characteristics of GPFX in the lung may provide a new insight into the strategy for clinical treatment of various pulmonary infections, especially cytotropic bacterial infections.

Background: Several hydroxyethyl starch (HES) solutions are available clinically. We performed comparative studies of low and high molecular weight HES to evaluate the effects on lung lymph flow in sheep, to see the difference in the types of HES., Methods: We prepared awake sheep with vascular monitorings and lung lymph fistulas. We measured systemic artery pressure (Psa), pulmonary artery pressure (Ppa), and left atrial pressure (Pla) continuously. Cardiac output (CO) was measured every 30 min. Lung lymph flow (Qlym) was collected every 15 min. After baseline measurements, two HES solutions were infused over 2 h, respectively. Experiment 1 (n=6): low molecular weight HES (MW 70 000, substitution ratio 0.5-0.55), Experiment 2 (n=5): high molecular weight HES (MW 450 000, substitution ratio 0.7)., Results: Both low and high molecular HES behaved similarly as a volume expander, increasing Psa, CO, Pla and Ppa, and decreasing hematocrit. In addition, the actual oncotic pressure gradient (plasma - lymph) was widened after the start of either low or high molecular HES, but the value for high molecular HES was significantly higher than that for low molecular HES. Qlym of low molecular HES rose significantly from the baseline and the percent increase in Qlym for low molecular HES was significantly higher than that for high molecular HES., Conclusion: These data suggest that low molecular HES is as useful a plasma substitute as high molecular HES, but may increase lung fluid filtration in the overinfused state.

Tl-201 lung uptake in 74 patients (85 lesions) and pulmonary perfusion in 105 patients were studied to evaluate clinical usefulness of Tl-201 lung uptake and perfusion lung scintigraphy in pulmonary tuberculosis, using a scintillation camera with a mini-computer system. As indices of Tl-201 lung uptake, lung (lesion) to upper mediastinum uptake ratio (L/M) and visual grading were used. L/M in pulmonary tuberculosis was 1.96 +/- 0.66, which was significantly larger than 1.04 +/- 0.24 in healthy controls and lower than that in heart diseases with left heart failure and idiopathic interstitial pneumonia, and showed no significant differences with that in acute pneumonia, pyothorax, primary lung cancer and malignant mediastinal tumor. L/M in pulmonary tuberculosis did not correlate with CRP, erythrocyte sedimentation rate, Gaffky number of sputum and body temperature. It correlated with the type of pulmonary tuberculosis according to the Gakken Classification reflecting the disease activity. It was larger in the exudative type, caseo-infiltrative one, disseminated one, one with cavity in infiltrative lesion than the fibro-caseous one. On perfusion lung scintigram, impairment of pulmonary perfusion larger than area of the entire unilateral lung was observed in 68 cases (64.8%). Area of hypoperfused lung field, which correlated with % vital capacity (r = 0.60, p = 0.0002) and PaO2 (r = 0.39, p = 0.0024), was significantly larger in patients with silicosis and those with bilateral pleural involvements such as pleural callosity than in those with type III according to the Gakkai Classification. Most of the patients showed decreased pulmonary perfusion and Tl-201 accumulation of which grade reflects the disease activity in active tuberculous lesion. Patients with miliary tuberculosis and those with silicotuberculosis showed diffuse Tl-201, accumulation in the both lungs. Tl-201 lung scintigraphy seems to be useful for visualizing active tuberculous lesions, particularly the ones that could not be detected by the chest radiograph in patients with destroyed lung and with pleural callosity. Joint use of Tl-201 and perfusion lung scintigraphies provides useful informations about the pathophysiology and disease process in pulmonary tuberculosis.

Activation of the kallikrein-kinin system in lung injury has long been recognized. However, the effects of bradykinin (BK) on human lung fibroblasts (HLF) remain to be elucidated. We determined whether BK stimulates HLF to release chemotactic activity for neutrophils and monocytes (NCA and MCA, respectively). We evaluated HLF supernatant fluids for chemotactic activity through a blind-well chamber technique. HLF released NCA and MCA in a dose- and time-dependent manner in response to BK. The release of chemotactic activity was inhibited by lipoxygenase inhibitors and cycloheximide. Molecular sieve column chromatography revealed that both NCA and MCA had multiple chemotactic peaks. NCA was inhibited by a leukotriene (LT) B(4) receptor antagonist and by antibodies to interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF). MCA was attenuated by the LTB(4) receptor antagonist and by antibodies to monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and transforming growth factor (TGF)-beta. Both the LTB(4) receptor antagonist and these antibodies inhibited chemotactic activity of the molecular weights corresponding to MCP-1, GM-CSF, and TGF-beta, separated by column chromatography. The concentrations of IL-8, G-CSF, MCP-1, GM-CSF, and TGF-beta in supernatant fluids increased significantly in a time-dependent manner in response to BK. The receptors responsible for the release of NCA, MCA, and individual chemokines included both BKB(1) and BKB(2) receptors. These data suggest that BK may stimulate lung fibroblasts to release inflammatory cytokines, which may modulate lung inflammation.

Objective: To clarify the effects of lung volume reduction surgery (LVRS) on cardiopulmonary circulation during exercise in comparison with pulmonary lobectomy for lung cancer., Summary Background Data: LVRS improves pulmonary function and dyspnea symptoms acutely in selected patients with heterogeneous emphysema. However, there are few data concerning the effects of LVRS on the cardiopulmonary circulation, especially during exercise., Methods: Pulmonary function tests and pulmonary hemodynamic study at rest and during exercise were performed before and 6 months after LVRS (seven patients) or pulmonary lobectomy (eight patients). In the workload test, an electrically braked bicycle ergometer (25 w) was used in the supine position for at least 2 minutes or until exhaustion or breathlessness developed., Results: After lung lobectomy, the values of vital capacity, percentage of predicted vital capacity, forced expiratory volume in 1 second, percentage of predicted forced expiratory volume in 1 second, residual volume/total lung capacity, and maximal voluntary ventilation deteriorated significantly. Six months after LVRS, however, vital capacity, percentage vital capacity showed no significant change, and forced expiratory volume in 1 second, percentage of forced expiratory volume in 1 second, diffusing capacity for carbon monoxide, and maximal voluntary ventilation showed marked improvement. Cardiac index was changed neither at rest nor during exercise in either group by the operation. Although postoperative pulmonary arterial pressure in the lobectomy group was significantly increased by the exercise, LVRS did not affect postoperative pulmonary arterial pressure at rest or during exercise. Pulmonary capillary wedge pressure in the lobectomy group showed no significant change after the operation, whereas LVRS ameliorated the marked elevation of pulmonary capillary wedge pressure observed during exercise. After lobectomy, significant increases in the pulmonary vascular resistance index were observed at rest and during exercise. LVRS markedly increased the pulmonary vascular resistance index at rest but not during exercise. In the lobectomy group, the postoperative flow-pressure curve moved upward, and its gradient became steeper than the preoperative one. In the LVRS group, the curve moved upward in a parallel fashion. These results show that much more right-sided heart work is needed to achieve the same cardiac output against higher pulmonary arterial pressure, not only after lobectomy but also LVRS., Conclusion: The current study demonstrated that the effects of LVRS on the cardiopulmonary circulation were not negligible, especially during exercise, and successful LVRS may depend on improved respiratory function and also preserved cardiac function that can tolerate the damage to the pulmonary vascular bed induced by this operation.

Accumulation of monocytes and neutrophils and fibrous distortion of the airway are characteristics of airway disease secondary to smoking. The presence of inflammatory cells and fibrosis correlate, and, therefore, we postulated that lung fibroblasts might release chemotactic activity for neutrophils and monocytes in response to smoke extract. To test this hypothesis, human fetal lung (HFL1) fibroblasts were cultured, and the supernatant fluid was evaluated for neutrophil (NCA) and monocyte (MCA) chemotactic activities with a blind well chamber technique. HFL1 fibroblasts released chemotactic activity in response to smoke extract in a dose- and time-dependent manner (P < 0.05). Checkerboard analysis showed that the activity was predominantly chemotactic. Partial characterization of the released chemotactic activity revealed that the activity was partly heat labile, trypsin sensitive, and ethyl acetate extractable. Lipoxygenase inhibitors and cycloheximide inhibited the release of both NCA and MCA. Molecular-sieve chromatography revealed that NCA and MCA were heterogeneous. NCA was inhibited by anti-human interleukin (IL)-8 and anti-granulocyte colony-stimulating factor antibodies and a leukotriene (LT) B(4)-receptor antagonist. Anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) and anti-monocyte chemoattractant protein (MCP)-1 antibodies and an LTB(4)-receptor antagonist inhibited MCA. Immunoreactive IL-8, granulocyte colony-stimulating factor, GM-CSF, and MCP-1 significantly increased in culture supernatant fluid in response to smoke extract. Finally, smoke extract augmented the expression of mRNAs of IL-8, GM-CSF, and MCP-1. These data demonstrate that lung fibroblasts release NCA and MCA in response to smoke extract and suggest that lung fibroblasts may modulate the inflammatory cell recruitment into the lung.

Although the cytotoxicity of lipopolysaccharide (LPS) derived from Pseudomonas aeruginosa, i.e. Limulus amoebocyte lysate activity, is less potent than that from Escherichia coli 0127:B8, P. aeruginosa induces prominent sustained lung inflammation, as in cystic fibrosis. The present study was designed to examine the potential for several LPSs obtained from E. coli and P. aeruginosa to release monocyte chemotactic activity (MCA) from lung cells. LPSs differentially stimulated A549 cells, BEAS-2B cells and lung fibroblasts to release MCA (P. aeruginosa >E. coli 0127:B8 from Difco >055:B5 from Sigma >026:B6 (Sigma)). E. coli 0127:B8 (Sigma) and 0111:B4 (Sigma) did not stimulate these cells. MCA was determined by means of checkerboard analysis. Molecular sieve column chromatography revealed four chemotactic peaks. The release of MCA was inhibited by cycloheximide and lipoxygenase inhibitors. Experiments with blocking antibodies suggested that much of the MCA was secondary to monocyte chemoattractant protein-1 (MCP-1) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Thus, the concentrations of these chemoattractants were examined and it was found that the potency of the various LPSs to stimulate MCA closely paralleled their potency in releasing MCP-1 and GM-GSF. Serum augmented the release of MCP-1 and GM-CSF. However, the differences among LPSs from E. coli and P. aeruginosa in stimulating A549 cells were observed. These data suggest that Pseudomonas aeruginosa lipopolysaccharide may stimulate lung cells to release more monocyte chemotactic activity than lipopolysaccharides derived from Escherichia coli, leading to sustained prominent lung inflammation.

Background: Major lung resection decreases ventilatory capacity and reduces exercise tolerance, impairing postoperative quality of life. But we have often seen respiratory symptoms improve during several years of postoperative followup. In the current study, we evaluated postoperative changes in cardiopulmonary function on exertion of patients with lung cancer surviving for more than three years, and the corresponding changes of their respiratory symptoms., Methods: The effects of pulmonary resection on cardiopulmonary function were evaluated in eight patients with lung cancer. Pulmonary function tests and hemodynamic study at rest and during exercise were performed before, in the early (4 to 6 months) and late (42 to 48 months) postoperative phases after major lung resection., Results: None of the eight patients had any remarkable symptoms before lung resection. In the early postoperative study, the general condition of five patients deteriorated compared with their preoperative status. In the late postoperative study, four patients showed an improvement of their daily activities from the early postoperative phase. Pulmonary function in the late postoperative phase did not show major changes except for airway resistance and percentage of carbon monoxide diffusing capacity as compared with the early phase, which showed deterioration as compared with the preoperative period. Cardiac index and stroke volume index were significantly decreased during exercise on maximal effort in the late postoperative phase compared with other phases. These results suggest that the peak blood flow per unit of remaining lung during exercise becomes lower with time after lung resection, indicating deterioration of the condition of the pulmonary vascular bed. The deterioration was also revealed from the pressure-flow curve., Conclusions: The condition of the pulmonary vascular bed after major lung resection does not improve, even in the late postoperative phase, although clinical symptoms were sometimes improved compared with the early postoperative period.

Although bleomycin, an antineoplastic drug, is used in the treatment of a variety of tumors, the mechanisms of bleomycin-induced lung injury and fibrosis are not fully elucidated. We postulated that bleomycin might stimulate A549 cells, a type II pneumocyte cell line, to release neutrophil and monocyte chemotactic activities (NCA and MCA, respectively). To test this hypothesis, A549 cell supernatant fluids were harvested and evaluated for NCA and MCA. A549 cell supernatant fluids showed NCA and MCA in response to bleomycin in a dose- and time-dependent manner (P < 0.05). Checkerboard analysis revealed that both NCA and MCA were predominantly chemotactic. Partial characterization of the released NCA and MCA showed that the activities were partially heat labile, trypsin digested, and predominantly ethyl acetate extractable. Lipoxygenase inhibitors and cycloheximide inhibited the release of chemotactic activities significantly. Molecular-sieve column chromatography revealed that the released activities were heterogeneous. However, low-molecular-weight activity was prominent. Leukotriene B4-receptor antagonist, anti-interleukin-8, anti-granulocyte colony-stimulating factor, and anti-monocyte chemoattractant protein-1 antibodies attenuated the chemotactic activities. Immunoreactive leukotriene B4 receptor, interleukin-8, granulocyte colony-stimulating factor, and monocyte chemoattractant protein-1 significantly increased in supernatant fluids in response to bleomycin. These data demonstrate that bleomycin stimulates type II epithelial cells to release chemotactic activities and plays a role in inflammatory cell recruitment into the lung.

To estimate pulmonary hypertension, we measured postural differences in pulmonary blood flow for the lateral decubitus positions on perfusion lung scintigrams with Tc-99 m macro-aggregated albumin, applying the method devised by Tanaka et al (Eur J Nucl Med 17: 320-326, 1990). Utilizing a scintillation camera coupled to a minicomputer system, changes in the distribution of pulmonary blood flow caused by gravitational effects, namely, changes in the total count ratios for the right lung versus the left lung in the right and left lateral decubitus positions (R/L), were obtained for 44 patients with lung disease, 95 patients with valvular heart disease, and 23 normal subjects. Mean standard deviation in the R/L ratios was 3.09 +/- 1.28 for the normal subjects, 1.97 +/- 0.89 for the patients with lung disease, and 1.59 +/- 0.59 for the patients with valvular heart disease. The R/L ratios correlated with mean pulmonary arterial pressure and cardio-thoracic ratios in the lung disease and valvular heart disease groups, with pulmonary arteriolar resistance in the former, and with pulmonary capillary wedge pressure in the latter. Defining pulmonary hypertension (> 20 mmHg) as an R/L ratio of less than 1.81, which is the mean-1 standard deviation for normal subjects, the sensitivity and the specificity of the R/L ratio for the diagnosis of pulmonary hypertension were 62.9% and 76.2%, respectively, for the lung disease patients, and 80.3% and 61.8%, respectively, for the valvular heart disease patients. This method seems to be useful for the pathophysiologic evaluation of pulmonary perfusion in cases of lung disease and valvular heart disease.

We determined whether human lung fibroblasts might release chemotactic activity for neutrophils (NCA) and monocytes (MCA) in response to bleomycin. The human lung fibroblasts supernatant fluids were evaluated for chemotactic activity by a blind well chamber technique. Human lung fibroblasts released NCA and MCA in a dose- and time-dependent manner in response to bleomycin. Checkerboard analysis of supernatant fluids revealed that both NCA and MCA were chemotactic. Partial characterization revealed that NCA was partly heat labile, trypsin sensitive, and predominantly ethyl acetate extractable. In contrast, MCA was partly trypsin sensitive and ethyl acetate extractable. The release of chemotactic activity was inhibited by lipoxygenase inhibitors and cycloheximide. Molecular sieve column chromatography revealed that both NCA and MCA had multiple chemotactic peaks. NCA was inhibited by leukotriene B4 receptor antagonist and anti-IL-8 and G-CSF Abs. MCA was attenuated by leukotriene B4 receptor antagonist, and monocyte chemoattractant protein-1, GM-CSF, and TGF-beta Abs. Leukotriene B4 receptor antagonist and these Abs inhibited the corresponding m.w. chemotactic activity separated by column chromatography. The concentrations of IL-8, G-CSF, monocyte chemoattractant protein-1, GM-CSF, and TGF-beta in the supernatant fluids significantly increased in response to bleomycin. These data suggest that lung fibroblasts may modulate inflammatory cell recruitment into the lung by releasing NCA and MCA in response to bleomycin.

We tested the effect of interferon-alpha on lung function to examine whether interferon-alpha causes some pathophysiological change in the lung. We prepared awake sheep with chronic lung lymph fistula, and measured the pulmonary hemodynamics, lung fluid balance and concentrations of prostanoid products. At 1 h after intravenous interferon-alpha administration (18 x 10(6) I.U.), pulmonary arterial pressure and pulmonary vascular resistance were significantly increased compared to the baseline values. The levels of thromboxane B2 in both plasma and lung lymph were increased concomitant with early elevation on pulmonary arterial pressure. In addition, OKY-046 [sodium-3[4-(1-imidazolylmethyl)phenyl]-2-propenoic acid] (10 mg kg(-1)), a selective thromboxane synthase inhibitor, significantly prevented the interferon-alpha-induced pulmonary hypertension and thromboxane B2 production. While no evidence of increased pulmonary vascular leakage was observed. These findings suggest that a single infusion of interferon-alpha stimulates a thromboxane cascade and causes transient pulmonary hypertension. However, interferon-alpha itself or increased thromboxane A2 might not affect the pulmonary vascular permeability in sheep.

Background and Aim of the Work: We previously reported the presence of definite morphological alterations in the capillary endothelium of sarcoid lung. The aim of this study was to examine ultrastructural changes and distribution of lipid droplets in the endothelium of lung capillaries of patients with sarcoidosis., Methods: Tissue specimens were obtained by transbronchial lung biopsy or open lung biopsy from 16 patients with sarcoidosis and 13 controls. Biopsies were evaluated by electron microscopy following lead citrate and uranyl acetate staining., Results: Typical lipid droplets were observed in pulmonary capillaries of 11 out of 16 sarcoid patients (69%); the droplet frequency was higher in sarcoid patients than in control specimens. Lipid droplets were characterized by biphasic density: most droplets contained eccentrically located vacuoles (saturated fatty acids) others were characterized by low density areas (unsaturated fatty acids). Biphasic droplets were covered by large lysosomal granules and were mainly distributed in the endothelium and pericytes. Interestingly, in the latter, vacuoles increased in size while small amounts of lysosomal granules were detectable., Conclusion: Our findings suggest that biphasic droplets increase in number in pulmonary capillaries of patients with sarcoidosis with a characteristic distribution pattern from the endothelium to pericytes.

This study evaluated small airway dysfunction and emphysematous destruction of lung parenchyma in cigarette smokers, using chest expiratory high-resolution computed tomography (HRCT) and pulmonary function tests (PFT). The degree of emphysematous destruction was classified by visual scoring (VS) and the average HRCT number at full expiration/full inspiration (E/I ratio) calculated in 63 male smokers and 10 male nonsmokers (group A). The Brinkman smoking index (BI), defined as cigarettes x day(-1) x yrs, was estimated. Sixty-three smokers were divided into three groups by PFT: group B1 (n=7), with normal PFT; group B2 (n=21), with diffusing capacity of the lung for carbon monoxide (DL,CO) > or = 80% predicted, forced expiratory volume in one second (FEV1) < 80% pred and/or residual volume (RV) > 120% pred; and group B3 (n=35), with DL,CO < 80% pred, FEV1 < 80% pred and/or RV > 120% pred. Heavy smokers (BI > or = 600) (n=48) showed a significant increase in emphysema by both VS and E/I. E/I was significantly elevated in both group B2 (mean+/-SD 0.95+/-0.05) and B3 (0.96+/-0.06) compared with group B1 (0.89+/-0.03). VS could not differentiate group B2 (3.9+/-5.0) from B1 (1.1+/-1.6). These findings suggest that the expiration/inspiration ratio reflects hyperinflation and airway obstruction, regardless of the functional characteristics of emphysema, in cigarette smokers.

Monoclonal antibodies and lectins were used to examine the expression patterns of apical membrane oligosaccharide sequences specific to type II pneumocytes in atypical adenomatous hyperplasia (AAH) and lung cancer. Atypical cells of AAH and papillary adenocarcinoma cells expressed abundant sialyl Thomsen-Friedenreich (TF) antigen: this was not observed in acinar adenocarcinoma, bronchioloalveolar carcinoma with mucin production or squamous cell carcinoma. Sialyl Tn antigens was also detected on a few cells in AAH and papillary adenocarcinomas. Asialo TF and Tn antigen were not observed on the surface of carcinoma cells of any type. Alpha(alpha)2,3-linked sialic acids predominated in type II pneumocyte, AAH and papillary adenocarcinoma, whereas ciliated columnar cells expressed alpha2,6-linked sialic acids. Lewisx and sialyl Lewisx antigens capped the TF antigen in both O- and N-linked side chains on the surface of AAH and papillary adenocarcinoma cells, but were not expressed by type II pneumocytes. The findings demonstrate that papillary adenocarcinoma cells resemble type II pneumocytes in that they express abundant sialyl TF surface antigen, but they also express TF-related antigens not found in type II pneumocytes. Apical surface glycoconjugates of AAH have structural characteristics shared by both type II pneumocytes and papillary adenocarcinoma cells.

Phorbol myristate acetate (PMA) activates neutrophils and causes acute lung injury. We determined the effect of ONO-5046, a specific neutrophil elastase inhibitor, on the increase in microvascular permeability induced by PMA in isolated dog lung perfused with autologous blood at a constant perfusion flow. The vascular permeability was assessed by the capillary filtration coefficient (Kf, c) and the solvent-drag reflection coefficient (sigma f). PMA (13.3 micrograms) increased vascular permeability, as evidenced by an increase in Kf, c from 0.18 +/- 0.02 to 0.92 +/- 0.14 mL/min/cmH2O/100 g and a decrease in sigma f to 0.35 +/- 0.01 as compared to control values of 0.69 +/- 0.06. The PMA-induced changes in Kf, c and sigma f were dose-dependently attenuated by pretreatment with ONO-5046 (2-20 mg). We conclude that ONO-5046 can effectively attenuate the PMA-induced injury in the isolated blood-perfused dog lungs.

Inflammatory cells accumulate within the lungs of cigarette smokers. Current concepts suggest that these cells can induce protease-antiprotease and/or oxidant-antioxidant imbalance(s), which may damage the normal lung alveolar and interstitial structures. Because type II pneumocytes line the alveolar space, and because the inflammatory cells migrate and reside at the alveolus, we postulated that the type II pneumocytes might release chemotactic activity for neutrophils and monocytes in response to smoke extract. To test this hypothesis, A549 cells were cultured and the supernatant fluids were evaluated for the neutrophil and monocyte chemotactic activity (NCA and MCA) by a blind-well chamber technique. A549 cells released NCA and MCA in response to smoke extract in a dose- and time-dependent manner (P < 0.05). Checkerboard analysis showed that the activity was chemotactic. Partial characterization of NCA and MCA revealed that the activity was partly heat labile, trypsin sensitive, and ethyl acetate extractable. Lipoxygenase inhibitors and cycloheximide inhibited the release of NCA and MCA. Molecular sieve column chromatography showed multiple peaks for both NCA and MCA. NCA was inhibited by anti-human-interleukin (IL)-8 antibody, granulocyte colony-stimulating factor (G-CSF) antibody, or leukotriene (LT)B4 receptor antagonist. Monocyte chemoattractant protein (MCP)-1 antibody or LTB4 receptor antagonist inhibited MCA. Immunoreactive IL-8, G-CSF, MCP-1, and LTB4 significantly increased in the supernatant fluids in response to smoke extract. These data suggest that the type II pneumocytes may release NCA and MCA and modulate the inflammatory cell recruitment into the lung.

7-Ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11, 100286-90-6) is one of the most promising novel anticancer agents, especially for lung cancer. 7-Ethyl-10-hydroxycamptothecin (SN-38), an active metabolic of CPT-11, has much stronger cytotoxicity than CPT-11. The present study was designed to evaluate the distribution and behavior of CPT-11 and SN-38 in lung lymph circulation following intravenous infusion. Awake sheep with chronically instrumented lung lymph fistulas were prepared. The concentrations of CPT-11 and SN-38 in plasma and lung lymph fluid were measured after intravenous infusion of 100 mg/body of CPT-11 for 90 min. SN-38 constantly showed higher lymph to plasma concentration ratios than those of CPT-11, and the % area under the curve (AUC) ratio of SN-38/CPT-11 in lymph fluid was significantly higher than that in plasma. These data indicated that SN-38 distributed in lung tissue moved more easily into lung lymph fluid than CPT-11, and might be more rapidly metabolized in lung tissue than plasma. CPT-11 may have favorable therapeutic effects on intrathoracic malignancies such as lung cancer and lymph metastasis.

We determined whether human lung fibroblasts (HLFs) might release mediators that are responsible for monocyte chemokinetic activity (MCA) constitutively. HLF supernatant fluids showed MCA in a time-dependent manner (P < 0.001). Checkerboard analysis of 24- and 72-h supernatant fluids showed that the activity was chemokinetic. Partial characterization of 24- and 72-h supernatant fluids revealed that the mediators released after 24 h were predominantly composed of lipid-soluble activity, and MCA was blocked by lipoxygenase inhibitors. The mediators released after 72 h were predominantly trypsin sensitive and blocked by cycloheximide. Molecular-sieve column chromatography identified four peaks of MCA. A polyclonal antibody to monocyte chemoattractant protein-1 (MCP-1) inhibited MCA by 20% after 24 h and by 40% after 72 h. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor-beta (TGF-beta) antibodies attenuated MCA released after 72 h by 30 and 10%, respectively. These antibodies inhibited corresponding molecular-weight peaks separated by molecular-sieve column. The concentrations of MCP-1, GM-CSF, and TGF-beta were 4,698 +/- 242, 26.8 +/- 3.8, and 550 +/- 15 pg/ml, respectively. A leukotriene B4 (LTB4)-receptor antagonist attenuated the total MCA and the lowest molecular weight peak of MCA. The concentrations of LTB4 were 153.4 +/- 12.4 (24 h) and 212 +/- 16.6 (72 h) pg/ml. These findings suggest that HLFs may modulate the recruitment of monocytes into the lung by releasing MCP-1, GM-CSF, TGF-beta, and LTB4 constitutively.

We have studied the pharmacokinetics of amphotericin B (AmB) in lung lymph circulation and bronchial-wash fluid after intravenous infusion and inhalation, respectively. For two experiments with awake sheep, we used lung lymph fistulas and tracheotomy. In experiment 1, AmB concentrations in plasma and lung lymph after intravenous infusion of AmB (1 mg/kg of body weight) over 1.5 h were measured. The mean peak in plasma level was 756.0 +/- 188.8 ng/ml at 3 h after the start of infusion, and the level then decreased gradually to 194.8 +/- 28.9 ng/ml at 24 h. The stable and maximal levels in lung lymph last 5 to 9 h after the start of AmB infusion. The concentrations in lung lymph after 9 h were slightly higher than those in plasma. Thus, the lung lymph-to-plasma ratio of AmB concentrations increased gradually during infusion, and the ratio was more than 1.0 after the end of infusion, suggesting that AmB could be easily moved from plasma to pulmonary interstitium and/or lung lymph circulation. In another experiment, 5 or 30 mg of aerosol AmB was inhaled, and the concentration of AmB in the bronchial-wash fluid was determined by bronchoalveolar lavage. The peak AmB concentration in the fluid was observed at 0.5 h. After that, AmB was slowly eliminated over 24 h. The area under the concentration-time curve for 30 mg of inhaled AmB was higher than that for 5 mg, but maximum concentrations of AmB in serum for 5 and 30 mg were almost similar. These observations identify the pharmacokinetic characteristics of AmB in the lung and may provide a new insight into the strategy for clinical treatment of fungal pneumonia.

To investigate the mechanism of short-term improvement in exercise tolerance after lung volume reduction surgery (LVRS) for severe emphysema, we performed six-minute walk tests and pulmonary-function tests, and studied their correlation before and 3-to-5 months after LVRS in 7 patients with severe emphysema who underwent bilateral lung reduction via median sternotomy. Results of the tests showed a 59% increase in the 1-second forced expiratory volume (FEV1), a 25% reduction in the functional residual capacity (FRC), a 49% increase in the maximum voluntary ventilation (MVV), and a 20% increase in the distance walked in 6 minutes (6 MD). The degree of improvement in 6 MD correlated significantly with the degree of improvement in FEV1 (r = 0.97, p < 0.01), in FRC (r = 0.86, p < 0.05), and in MVV (r = 0.87, p < 0.05), and did not correlate with the degree of improvement in pulmonary gas exchange. These results support the hypothesis that an increase in lung elastic recoil after targeted emphysematous resection reduces airflow limitation, and thus leads to a short-term improvement in exercise tolerance after LVRS.

Lecithinized superoxide dismutase, a lecithin derivative bound to recombinant human CuZn superoxide dismutase, has a higher affinity for cells such as polymorphonuclear leukocytes and endothelial cells than recombinant human CuZn superoxide dismutase has. We determined the protective effects of lecithinized superoxide dismutase on the increased microvascular permeability induced by phorbol myristate acetate (PMA) in isolated dog lungs. Microvascular permeability was assessed by the capillary filtration coefficient (Kf,c) and solvent drag reflection coefficient (sigma(f)). PMA (13.3 microg) increased microvascular permeability, as evidenced by an increase in Kf,c and the small sigma(f) value. Lecithinized superoxide dismutase at both low (4800 U) and high doses (48,000 U) inhibited the PMA-induced increase in Kf,c, but only the high dose of lecithinized superoxide dismutase attenuated the decrease in sigma(f). Recombinant human CuZn superoxide dismutase did not affect the PMA-induced increase in vascular permeability at either a low (4800 U) or a high dose (48,000 U). These findings suggest that lecithinized superoxide dismutase has a protective effect against oxygen radical-induced lung injury in isolated dog lungs.

A 46-year-old man was admitted for evaluation of a solitary pulmonary cavity in the apey of the left lung. Because two transbronchial biopsies followed by brushing and washing and sputum cytology did not yield any diagnostic findings, the patient was treated with INH, RFP and SM under a tentative diagnosis of pulmonary tuberculosis. The shadow decreased over two months with combination therapy, but increased again after the dose of SM was decreased. We performed a left upper lobectomy to diagnose either multi-drug-resistant pulmonary tuberculosis or lung cancer. Pathological examination of the resected lung revealed epitheloid cell granulomas with areas of caseous necrosis. Smooth chromophoric colonies were isolated on an Ogawa egg medium, and were identified as M. avium by PCR and DDH. A diagnosis of pulmonary M. avium was made. A chest X-ray film taken two years later was normal. Pulmonary M. avium disease developed in this patient, who had no predisposing lung pathologies.

In the present investigation, we determined whether A549 cells, a type II pneumocyte cell line, might release mediators that are responsible for monocyte chemoattractant activity (MCA) constitutively. To test this hypothesis, A549 cell supernatant fluids were harvested and evaluated for monocyte chemotaxis. A549 cell supernatant fluids showed MCA in a time-dependent manner (P < 0.001). Checkerboard analysis of 24- and 72-h supernatant fluids showed that the activity was chemokinetic rather than chemotactic. Partial characterization of 24- and 72-h supernatant fluids revealed that the mediator was composed of lipid-soluble activity that was blocked by lipoxygenase inhibitors and trypsin-sensitive activity blocked by cycloheximide. Molecular sieve column chromatography identified four molecular weight peaks. Two of four peaks were blocked by anti-monocyte chemoattractant protein-1 (MCP-1) and anti-transforming growth factor-beta (TGF-beta) polyclonal antibodies. MCP-1 and TGF-beta were detected by enzyme-linked immunosorbent assay. Leukotriene B4 (LTB4) receptor antagonist attenuated the lowest-molecular-weight peak chemotactic response, and the concentration of LTB4 was high enough for chemotactic activity. These findings suggest that type II pneumocytes may modulate the recruitment of monocytes into the alveolar space by releasing MCP-1, TGF-beta, and LTB4 constitutively.

Chest computed tomography (CT) and pulmonary function tests are usually used for the evaluation of emphysema. We performed the present study to evaluate more accurately the relationship between the degree of morphological change and the functional abnormality in emphysema. We used a helical CT apparatus to obtain the CT images both at full inspiration and full expiration. We classed the degree of emphysema into 5 grades (0-4) by visual observation on CT image obtained at the two levels, upper and lower fields, on each side. We assigned each of these grades a visual score. We also calculated the average ratio of CT numbers of each of the lung fields at full expiration to that at full inspiration for each level. We designated this the E/I ratio. We then examined the relationship between the findings acquired by each of these two methods and pulmonary function test results. The visual score showed correlations with FEV1(% predicted) (-0.592, p < 0.0001), RV/TLC(%)(0.425, p < 0.025), and DL(CO)/VA(% predicted)(-0.538, p < 0.0001). The E/I ratio showed correlations with FEV1(% predicted) (-0.620, p < 0.0001), RV/TLC(%)(0.661, p < 0.0001), and DL(CO)/VA(% predicted) (-0.299, p < 0.05). Compared with the E/I ratio, the visual score showed much higher correlation with DL(CO)/VA(% predicted), but the E/I ratio showed stronger correlation with RV/TLC(%) than did the visual score. The visual score may reflect the degree of emphysema, whereas the E/I ratio reflects the air trapping. These findings suggest that the helical CT is useful in the evaluation of emphysematous changes and that the E/I ratio reflects the air trapping.

We examined relationships among the distance walked in 10 minutes (10 MD), pulmonary function, and pulmonary hemodynamics during exercise on a bicycle ergometer, in patients with chronic pulmonary emphysema who had dyspnea of grade III to IV on the Hugh-Jones scale. The 10 MD did not correlate significantly with desaturation during the 10-minute walk, but it did correlate significantly with the percent of predicted maximum voluntary ventilation, and it correlated negatively with airway resistance. These findings indicate that ventilatory impairment is an important factor limiting 10 MD in these patients. Also 10 MD correlated significantly and positively with %DLco; and it correlated negatively with the index of pulmonary vascular resistance and with the ratio of the change in pulmonary arterial pressure to the change in cardiac index during exercise. (delta Ppa/delta CI). These findings indicate that impairment of pulmonary circulation may also limit the 10 MD and exercise tolerance in patients with chronic pulmonary emphysema.

We examined eosinophil chemotactic activity (ECA) in bronchoalveolar lavage fluid (BALF) obtained from rats infected with Toxocara canis. For 4 weeks after infection, the number of eosinophils was determined in peripheral blood and BALF. ECA was assayed using a microchemotaxis chamber. Eosinophils in peripheral blood and BALF increased markedly after infection, peaking at 12 days and 2 weeks, respectively. ECA in BALF also increased significantly and peaked 2 weeks after infection. Partial characterization revealed that ECA was heat labile, lipid soluble, and resistant to trypsin digestion. Two ECA peaks were identified by molecular sieve column chromatography: one near the egg albumin marker (MW 45,000) and the other observed after elution with quinacrine (MW 472.9). Treatment with a specific leukotriene (LT) B4 receptor antagonist (ONO-4057), a platelet activating factor (PAF) receptor antagonist (TCV-309), and an anti-interleukin (IL)-5 monoclonal antibody (TB13) significantly reduced the ECA, suggesting that LTB4, PAF, and IL-5 contribute to the accumulation of eosinophils in the lungs of rats infected with T. canis.

We report two cases of primary Sjögren's syndrome with pulmonary involvement, in which open lung biopsies were done. The patient in the first case was a 58-year-old woman and the patient in the second case was a 54-year-old woman. Both patients were admitted to our hospital because of dry coughing and exertional dyspnea. Chest X-ray films and CT scans showed interstitial shadows in both cases and multiple bullae in the first case. Pulmonary-function tests showed decreased diffusing capacity, and examination of bronchoalveolar lavage fluid revealed increased percentages of lymphocytes. Open-lung biopsy specimens showed thickening of the alveolar septa and interstitial mononuclear cell infiltration, composed predominantly of lymphocytes, with lymphoid follicles in both cases, and peribronchiolar mononuclear cell infiltration in the first case. Therefore, the histopathological diagnosis was cellular interstitial pneumonia with lymphoid follicles. Both patients were treated with oral corticosteroids. Symptoms were relieved and laboratory findings improved.

Exercise in normal human subjects causes deterioration of matching of ventilation to blood flow in the lungs, but only in about 50% of those examined. A previous study (Wagner et al. 1989) of 5 horses showed no significant worsening of ventilation/blood flow (VA/Q) relationships during heavy exercise as determined by multiple inert gas elimination technique (MIGET). Because of the small number of horses in that study and the 50% human incidence of exercise induced VA/Q mismatch, we studied an additional 6 Thoroughbreds, comparing VA/Q relationships at the walk (1.4 m/s, 0 degrees incline) and during galloping (9.6 +/- 0.3 m/s, 7% incline). Such data were collected under 4 different conditions wherein inspired gas was 1) air, 2) 21% O2 in helium, 3) 15% O2 in N2 and 4) 15% O2 in helium. Each horse exercised 4 times (morning and afternoon of 2 days, with inspired gas conditions randomised). There was a small but significant increase in VA/Q mismatch (similar under all 4 conditions). The second moment of the VA/Q distribution (determined by the MIGET) increased significantly (P < 0.01) from 0.31 +/- 0.01 at the walk to 0.38 +/- 0.02 during gallop. This increase however is small: 0.38 is well within the range of this parameter for normal human subjects (where the 95% upper confidence limit is 0.60). This study shows that a small amount of exercise induced VA/Q mismatch can occur in the horse as in man, but the mechanism remains to be elucidated and its clinical significance remains to be established.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumor necrosis factor alpha (TNF) is a mediator of acute lung injury after endotoxemia, but the precise mechanism of TNF-induced lung injury remains unclear. To clarify the role of oxygen radicals, especially superoxide anion, in TNF-induced lung injury, we examined the effects of recombinant human superoxide dismutase (rhSOD; 4,200 U/mg) on lung physiological and biochemical changes after TNF infusion in awake sheep (n = 17). We prepared chronically instrumented sheep for lung lymph collection and hemodynamic monitoring. Recombinant human TNF (3.5 micrograms/kg iv) induced a biphasic response in awake sheep. Pulmonary hypertension peaked within 15 min of initiation of TNF and remained elevated for 3 h, followed by increased lung vascular permeability. rhSOD attenuated the pulmonary hypertension in both early and late phases but caused no change in the timing or magnitude of lung fluid balance changes during the late phase. Thromboxane A2 (thromboxane B2) and prostacyclin (6-ketoprostaglandin F1 alpha) metabolite levels in plasma and lymph increased after the TNF infusion, and rhSOD attenuated these changes. The intravenous infusion of rhSOD resulted in the appearance of significant levels of SOD activity in both plasma and lung lymph before and after TNF infusion. These findings suggest that superoxide anion may be implicated in the pathogenesis of the pulmonary hypertension induced by TNF in sheep.

The pharmacokinetics of (glycolato-O,O')diammine platinum(II) (254-S), especially the distribution and behavior in the lung lymph in sheep, was investigated and compared with that of cis-diamminedichloroplatinum(II) (CDDP). The blood and lung lymph fluid were collected from the carotid artery and a lung lymph fistula, respectively, in conscious sheep following intravenous infusion of 100 mg/body of 254-S and CDDP for 30 min. The concentrations of these platinum complexes were measured by using atomic absorption spectrometry. We analyzed the data using an anatomically based model including part of the lymphatic circulation. The ultrafilterable platinum of 254-S showed much larger area under the curve (AUC) and transfer rate constants than that of CDDP, even though the mean residence times were the same. The total platinum showed the opposite pharmacokinetic behavior. In anesthetized sheep, when lung tissue samples were obtained by biopsy at the same times as those of blood and lung lymph sampling after infusion of these drugs, 254-S distributed in lung tissue appeared to move more easily into lung lymph than CDDP, which tended to be retained in lung tissue. These differences in pharmacokinetic behavior between 254-S and CDDP seemed to be caused by differences in their strength of protein binding; the association constants of 254-S for plasma and lymph protein were much less than those of CDDP. From these results, 254-S may have favorable therapeutic effects on intrathoracic malignancies such as lung cancer and lymph metastasis.