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Background: Quantitative computed tomography (CT) analysis has been proposed as a means of objectively assessing fibrotic interstitial pneumonia (IP) including idiopathic pulmonary fibrosis (IPF). We investigated whether percentages of high-attenuation areas (HAA%) and cystic areas (CA%) quantified from CT images were useful as indices of fibrotic IP., Methods: CT images of 74 patients with fibrotic idiopathic interstitial pneumonias (IPF, 36; non-specific interstitial pneumonia, 9; unclassifiable idiopathic interstitial pneumonia, 29) were analyzed via in-house computer software, which automatically calculated HAA%, CA%, mean lung density (MLD), standard deviation of lung density (SD-LD), kurtosis, and skewness from CT attenuation histograms. These indices were compared in each instance with physiologic measures, visual fibrosis score, clinical diagnosis, radiologic CT pattern, and prognosis., Results: HAA% correlated significantly with physiologic measures and visual fibrosis score to a moderate extent (%forced vital capacity, rs = -0.59; % carbon monoxide diffusion capacity, rs = -0.43; fibrosis score, rs = 0.23). Densitometric parameters (MLD, SD-LD, kurtosis, and skewness) correlated significantly with physiologic measures and fibrosis score (|rs| = 0.28-0.59). CA% showed no association with pulmonary functions but differed significantly between IPF and other interstitial pneumonias (IPs) (1.50 ± 2.41% vs. 0.41 ± 0.80%; P < 0.01) and between the definite usual interstitial pneumonia (UIP) pattern and other patterns (1.48 ± 2.38% vs. 0.55 ± 1.19%; P < 0.01). On univariate analysis, HAA%, MLD, SD-LD, kurtosis, skewness, fibrosis score, and definite UIP pattern all correlated with survival, with kurtosis alone identified as a significant predictor of mortality on multivariate analysis (hazard ratio = 0.67; 95% CI, 0.44-0.96; P = 0.03)., Conclusion: CA% and HAA% are novel quantitative CT indices with differing properties in fibrotic IP evaluations. HAA% largely reflects physiologic impairments, whereas CA% corresponds with diagnosis and HRCT pattern. Of the CT indices examined, kurtosis constituted the strongest predictor of mortality.

Laninamivir octanoate (LO) is an octanoyl ester prodrug of the neuraminidase inhibitor laninamivir. After inhaled administration, LO exhibits clinical efficacy for both treatment and prophylaxis of influenza virus infection, resulting from hydrolytic bioactivation into its pharmacologically active metabolite laninamivir in the pulmonary tissue. In this study, we focused on the identification of LO-hydrolyzing enzymes from human pulmonary tissue extract using proteomic correlation profiling-a technology integration of traditional biochemistry and proteomics. In a single elution step by gel-filtration chromatography, LO-hydrolyzing activity was separated into two distinct peaks, designated as peak I and peak II. By mass spectrometry, 1160 and 1003 proteins were identified and quantitated for peak I and peak II, respectively, and enzyme candidates were ranked based on the correlation coefficient between the enzyme activity and the proteomic profiles. Among proteins with a high correlation value, S-formylglutathione hydrolase (esterase D; ESD) and acyl-protein thioesterase 1 (APT1) were selected as the most likely candidates for peak I and peak II, respectively, which was confirmed by LO-hydrolyzing activity of recombinant proteins. In the case of peak II, LO-hydrolyzing activity was completely inhibited by treatment with a specific APT1 inhibitor, palmostatin B. Moreover, immunohistochemical analysis revealed that both enzymes were mainly localized in the pulmonary epithelia, a primary site of influenza virus infection. These findings demonstrate that ESD and APT1 are key enzymes responsible for the bioactivation of LO in human pulmonary tissue.

Laninamivir octanoate (LO) (Inavir; Daiichi Sankyo, Japan) is an ester prodrug of the neuraminidase inhibitor laninamivir. We previously reported that a prolonged high retention of laninamivir in mouse respiratory tissues was achieved by intranasal administration of LO. In this study, we evaluated intrapulmonary pharmacokinetics both in vivo and in vitro to investigate the potential mechanism involved in such a preferable retention. After intranasal administration of LO to mice (0.5 μmol/kg), the drug was distributed from the airway space into the lungs, and laninamivir remained in the lung at 24 hours postdose (2680 pmol/g), with a higher concentration than that in the epithelial lining fluid. The laninamivir was localized mainly on the epithelial cells of airway tracts, determined by microautoradiography using (14)C-labeled LO. In mouse airway epithelial cells, the cellular uptake and hydrolysis of LO were observed over incubation time without any apparent saturation at the highest concentration tested (1000 μM). Furthermore, after additional incubation in drug-free medium, the intracellular laninamivir was released very slowly into the medium with an estimate rate constant of 0.0707 h(-1), which was regarded as a rate-limiting step in the cellular retention. These results demonstrated that the prolonged high retention of laninamivir in the respiratory tissues was attributed to a consecutive series of three steps: uptake of LO into the airway epithelial cells, hydrolysis of LO into laninamivir by intracellular esterase(s), and limited efflux of the generated laninamivir due to its poor membrane permeability. This prodrug approach could be useful for lung-targeting drug delivery.

Background: Chronic beryllium disease (CBD) is a rare disease, and there are no previous reports that have followed CBD patients over several decades. Thus, the long-term complications and prognosis of this illness still remain unclear., Objective: The aim of this study was to investigate long-term complications and prognosis of CBD patients., Study Design and Methods: This was a retrospective study based on the medical records of all CBD patients diagnosed at Kyoto University Hospital between the period 1973 to the present day. Ultimately, ten patients whose diagnoses had been made during the period 1973 to 1977 were included. Long-term physiological and radiological change, complications and prognosis of these patients were investigated., Results: Three patients completely remitted, and one died of cor-pulmonale. Among the remaining six patients, four have been followed up for more than thirty years in our institute. The majority developed mixed patterns of lung function impairment, cavity lesions of the lung, pneumothorax, and respiratory infections., Conclusions: Long-term prognosis of CBD was poor with several complications due to chronic parenchymal and airway lesions.

Background: It was previously reported that visual scores of the lung opacities were associated with lung function in patients with sarcoidosis. However, there are no reports on the evaluation of airway dimensions or lung density by computed tomography (CT) in sarcoidosis patients., Objectives: The aim of this study was to investigate whether airway dimensions and lung densities assessed by CT associate with pulmonary function in patients with sarcoidosis., Methods: CT scanning was performed in 43 sarcoidosis patients and lung densities were measured using in-house software. Means and standard deviations of lung density, kurtosis and skewness of lung density histograms were calculated. Tracheal area and airway wall area/total airway area (WA%) of the right apical bronchus were also measured. Pulmonary function tests were performed on the same day., Results: Increased standard deviation of lung density and decreased kurtosis and skewness of lung density histograms were all associated with decreased total lung capacity, vital capacity and diffusion capacity. Increased standard deviation of lung density was also associated with decreased percentages of forced expiratory volume in 1 s and peak expiratory flow (%PEF). There was a positive correlation between tracheal area corrected by body surface area and %PEF, and negative correlation between WA% and %PEF. Stepwise regression analysis showed that increased standard deviation of lung density and decreased tracheal area were independently associated with lower %PEF., Conclusions: Thus, in sarcoidosis, densitometric parameters reflect restrictive lung function impairment. In addition to parenchymal lesions, it is concluded that the luminal area of the central airways also affects PEF., (Copyright 2008 S. Karger AG, Basel.)

Rationale: Clinicopathologic pulmonary manifestations associated with primary Sjogren's syndrome have yet to be reviewed in a large series since the recognition of nonspecific interstitial pneumonia (NSIP) as a distinct histologic pattern., Objectives: To determine clinical presentations, high-resolution computed tomographic (HRCT) and histologic findings of the lung disease associated with primary Sjogren's syndrome in the light of NSIP, and to analyze prognosis of the disease., Methods: On the basis of 33 cases (31 surgical lung biopsies and 2 autopsies) collected consecutively from multiple centers, we have retrospectively evaluated clinical, radiologic, and pathologic manifestations of the disease. Prognostic factors were identified by univariate and multivariate analysis., Measurements and Main Results: We found that NSIP was the most frequently seen histologic pattern (20 of 33 cases [61%], 19 fibrosing and 1 cellular). Bronchiolar diseases and amyloid and malignant lymphoma were seen less frequently. HRCT-pathologic correlation resulted in a 94% positive predictive value of CT-NSIP pattern for pathologic diagnosis of NSIP, whereas the diagnostic value of HRCT was low (15%) with an HRCT pattern other than NSIP, data that may influence the decision to biopsy. The 5-year survival rate was 84% overall and 83% in patients with NSIP. Multivariate analysis on all patients showed that low Pa(O(2)) (p = 0.02) and presence of microscopic honeycombing (p = 0.04) were independently associated with survival. Patients with NSIP showed lower vital capacity (mean +/- SD: 68.5 +/- 16.6%pred) than patients without NSIP (92.5 +/- 18.6%pred; p < 0.001)., Conclusion: Among a diversity of pulmonary lesions in primary Sjogren's syndrome, NSIP was the commonest histologic pattern and had a favorable prognosis.

Objective: The aim of this study was to determine whether the presence of lung shrinkage on CXR can predict diminished survival in patients with idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP)., Methodology: In a hospital-based cohort study 68 subjects diagnosed with IPF/UIP by surgical lung biopsy or at autopsy were observed for a mean of 7.6 years. The radiographic scores from Cherniack's method, pulmonary function tests, arterial blood gas, and haematological data were obtained at initial presentation. Longitudinal radiographic changes over a mean interval of 2.7 years were measured. Survival analysis was performed using Kaplan-Meier and Cox's proportional hazards regression analysis., Results: At some point during the observation period 36 (53%) of 68 patients did not exhibit lung shrinkage and 32 (47%) of 68 patients showed lung shrinkage. Patients with lung shrinkage were more likely to have a diminished survival than those with lung preservation; median survival was 4.4 vs 7.8 years, respectively. Lung shrinkage during the observation period (hazard ratio, 3.89; 95% CI = 1.68-9.01; P= 0.001) was associated with lower rates of survival., Conclusion: In patients with IPF/UIP, lung shrinkage on CXR during the observation period was a poor prognostic factor.

Cyclophosphamide is an alkylating antineoplastic agent used in several conditions. However, little is known about the mechanism of its pulmonary toxicity. In the present study, we determined that human lung fibroblasts release activity for neutrophils and monocytes in response to cyclophosphamide in a dose- and time-dependent manner. Checkerboard analysis revealed that both neutrophil and monocyte activities were chemotactic. The release of chemotactic activity was inhibited by lipoxygenase inhibitors and cycloheximide. Molecular-sieve column chromatography revealed that both neutrophil (NCA) and monocyte (MCA) chemotactic activities had multiple peaks. NCA was inhibited by a leukotriene B(4) receptor antagonist and anti-interleukin-8 and anti-granulocyte colony-stimulating factor antibodies. MCA was attenuated by a leukotriene B(4) receptor antagonist and anti-monocyte chemoattractant protein-1 and anti-granulocyte-macrophage colony-stimulating factor antibodies. The concentrations of interleukin-8, granulocyte colony-stimulating factor, monocyte chemoattractant protein-1, and granulocyte-macrophage colony-stimulating factor significantly increased in response to cyclophosphamide. These data suggest that lung fibroblasts may modulate inflammatory cell recruitment into the lung by releasing NCA and MCA in response to cyclophosphamide.

Background: It is known that natural killer (NK) cell activity in the lung of smokers (SM) is lower than in non-smokers (NS). However, little is known about the underlying mechanisms., Objective: The purpose of this work was to investigate the mechanisms of the inhibition of NK cell activity by alveolar macrophages (AM) in SM., Methods: Lung effector cells and AM were obtained using bronchoalveolar lavage. The NK cell activity was assayed by 51Cr release method after incubation of 4 and 24 h, using K562 as target cell. AM were added at a concentration of 25% to effector cells., Results: Following 24-hour culture, NK cell activity significantly increased in the NS but not in the SM. Lung NK cell activity was significantly augmented by interleukin-2 in the NS but not in the SM. Addition of AM to the NK cell preparation from SM exerted a significantly greater suppressive effect on autologous blood NK cell activity than in the NS. Indomethacin, catalase or thiourea did not prevent AM-mediated suppression of NK cell activity, in contrast to superoxide dismutase., Conclusions: These results suggest that the suppression of NK cell activity by AM in SM may be caused by O2- release rather than by prostaglandins, H2O2 or OH release from AM., (Copyright 2001 S. Karger AG, Basel)

Background: Imbalance between proteinases and their inhibitors released from alveolar type II pneumocytes may cause development of inflammatory lung diseases., Objectives and Methods: We examined mRNA expressions of matrix metalloproteinase-3 (MMP-3) and tissue inhibitor of metalloproteinase-3 (TIMP-3) in a cell line (A549) and in primary culture of normal adult human type II pneumocytes using reverse transcription-competitive polymerase chain reaction., Results: Interleukin-1beta (IL-1beta) and transforming growth factor-beta1 (TGF-beta1) increased MMP-3 and TIMP-3 expressions in A549 cells in a time- and concentration-dependent manner. IL-1beta mainly augmented MMP-3 expression, while TGF-beta1 mainly augmented TIMP-3 expression. Dexamethasone attenuated both IL-1beta- and TGF-beta1-stimulated expressions of MMP-3 and TIMP-3. Interleukin-10 had no significant effect. Hepatocyte growth factor alone had no effect on constitutive MMP-3 expression or TIMP-3 expression, but it augmented TGF-beta1-stimulated MMP-3 expression. The constitutive expressions were higher in normal type II pneumocytes than in A549 cells, but the regulations were similar., Conclusions: These data indicated that the matrix degradation is enhanced by IL-1beta and suppressed by TGF-beta1 via regulations in the balance between MMP-3 and TIMP-3. Further, these regulations were shown to be modulated by glucocorticoids and growth factors., (Copyright 2001 S. Karger AG, Basel)

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.

To evaluate the effects of prior chemotherapy on pulmonary function after bone marrow transplantation(BMT), pulmonary function tests were performed prior to and after BMT on 7 acute leukemia (AL) and 13 chronic myelogenous leukemia (CML) patients given with CY (60 mg/kg x 2 days), total body irradiation (3 Gy x 4 days, 10 cGy/min), and CyA plus short-term MTX. No patient had graft-versus-host disease or lung complications. Pulmonary function after BMT did not deteriorate in the AL patients; however, both %Vital Capacity(%VC) and DL/VA decreased significantly in the CML patients (%VC before BMT: 112.1 +/- 11.5%, after BMT: 93.7 +/- 9.4%; DL/VA before BMT: 79.2 +/- 14.6%, after BMT: 54.1 +/- 10.6%). Although prior regimens of busulfan (BU) or interferon (IFN) were equal risk factors for decreased %VC after BMT, decreases in DV/VA were more significant in CML patients who received IFN. CML patients, especially those who have received BU or IFN, should be carefully monitored for pulmonary function to prevent respiratory failure after BMT.

Fibroblast contractility plays a useful role in the wound healing process but contributes to architectural distortion in the lungs. Glucocorticoids (GCs) have been reported to reduce dermal fibroblast contractility, which may result in delaying wound healing, but the effects on lung fibroblasts are unknown. In this study, we examined how human lung fibroblast contractility is altered in the presence of GCs. Lung fibroblast cell lines (n = 5) were established from normal parts of surgically resected lung tissue. The effects of GCs on contractility were investigated with a type I collagen gel contraction assay. Filamentous actin (F-actin) content was detected by confocal microscopy and measured with a fluorescent phalloidin binding assay. GCs augmented fibroblast contraction in a concentration-dependent manner, with an approximate EC(50) of 1.8 x 10(-8) M, whereas other steroid derivatives had no effects. GC contractility needed de novo protein synthesis. The GC-induced increase in contractility was found to be consistent with an increase in F-actin content. In conclusion, lung fibroblast contractility was enhanced with GCs through an upregulation of lung fibroblast F-actin.

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.

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.

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.

Background: We investigated the expression of the IL-1 receptor on lung fibroblasts in patients with idiopathic pulmonary fibrosis (IPF) the histology of which was diagnosed as usual interstitial pneumonia., Methods: 125I-labeled IL-1alpha bound to lung fibroblasts in a specific and saturable manner in lung fibroblasts obtained from both IPF patients and control subjects., Results: Scatchard plot analysis revealed a single type of binding site in both groups. In total, 8,600 +/- 1,450 (mean +/-SD) sites/cell with a dissociation constant (Kd) of 1.83 +/- 0.28 (mean +/-SD) nM in patients with IPF and 7,920 +/- 1,470 sites/cell with a Kd of 2.43 +/- 0.49 nM in control subjects were counted. Furthermore, affinity cross-linking experiments revealed that the IL-1 receptor on lung fibroblasts in patients with IPF and control subjects had a molecular size of 80 kD., Conclusion: In conclusion, type I receptor was present on human lung fibroblasts, but there were no differences in number or affinity between IPF patients and controls.

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.

Twenty-one patients, aged 16-41 years, were prospectively followed for pulmonary function prior to and up to nine months after bone marrow transplantation (BMT). All patients had normal radiographs and no clinical signs of pulmonary disease. The FEV1.0%, V25, and of V50/V25 were within the normal ranges for all patients. Percent vital capacity (%VC) and percent diffusing capacity of lung for CO (% DLco) dropped progressively in most of the patients up to 9 months following BMT. Pulmonary function decreased earlier in patients with GVHD as well as patients who received total body irradiation either at a high dose rate (10 cGy/min) or a high lung dose (12 Gy). These asymptomatic declines in pulmonary function were measured by frequent tests of lung function.

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.

Pulmonary function tests were performed in 12 patients who underwent posterior retroperitoneoscopic surgery, before and on the 3rd and 7th days after operation. Forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), FEV1/FCV, vital capacity (VC), total lung capacity (TLC), residual volume (RV) and functional residual capacity (FRC) were not significantly different between before and after surgery. It is assumed that posterior retroperitoneoscopic surgery could be performed without impairment of pulmonary function after surgery.

In this review, we focus on the heterogeneity of interstitial lung diseases detected in patients with collagen vascular diseases. By recognizing the heterogeneity of histopathology and comparing them with bronchoalveolar lavage fluid cell findings, we can understand profiles of lung inflammation and injuries and fibrosis in collagen vascular diseases. We focus on the significance of lung lymphocytosis in the lesions of patients with collagen vascular diseases, looking most closely at lesions in unusual interstitial pneumonia. The current understanding of immunopathogenesis and immunopathological findings is reviewed in the context of subsets of collagen vascular diseases.

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.

In CT the presence of mediastinal or hilar lymphadenopathies and thickened bronchovascular bundles are landmarks for the diagnosis of pulmonary sarcoidosis. The major CT findings for parenchymal involvement are thickened bronchovascular bundles, large parenchymal nodules, pleural or subpleural nodules, ground-glass opacities, local lung volume loss (distortion of the lung parenchyma), and microscopic and macroscopic honeycombing. The thickened bronchovascular bundles correspond histologically to granulomas, either with or without perigranulomatous fibrosis in the connective tissue sheath around the pulmonary vessels and airways. Conglomerate granulomas are represented on CT by high-attenuation nodules, and the ground-glass opacities are caused by the summation of a number of small granulomas in the interstitium.

The effect of isoflurane on hypoxic pulmonary vasoconstriction (HPV) was examined using the separately ventilated left lower lobe lung model in dogs. When the HPV was induced with anoxic gas ventilation of the left lower lobe, the magnitude of HPV inhibition by isoflurane of 2 MAC was predominant, as assessed by the index of pressure-flow curve which is a novel indicator of pulmonary vascular tone in the left lower lobe. However, isoflurane 2 MAC attenuated the HPV by only 16%, as assessed by indices of the changes in left lower lobe blood flow rate and PaO2. This weak HPV inhibition, as shown by the latter parameters, may result from the net effect of isoflurane-induced HPV inhibition and secondary HPV enhancement due to decreases in cardiac output and pulmonary arterial pressure by isoflurane. However, none of the parameters showed inhibition of HPV when the HPV was induced by collapse of the left lower lobe. This discrepancy in the results may be caused by a lack of isoflurane reaching the hypoxic lobe when the HPV is induced with atelectasis. These results show that potency of HPV inhibition with isoflurane depends on the method of induction or evaluation of HPV, and that inhibition of HPV response with isoflurane at clinical concentrations is negligible in an atelectasis-induced HPV, in which no isoflurane is directly reaching the hypoxic lobe.

The expression of surface antigens on human type II pneumocytes is unknown but may be important in diagnostic cytology of bronchoalveolar lavage specimens. Thus, the immunocytochemical reactivity of isolated human type II pneumocytes was determined using a panel of commercially available monoclonal antibodies (MAbs). Type II pneumocytes were isolated from fresh human lung tissue obtained from surgical specimens (four non-smokers, six heavy smokers) after enzymatic digestion with dispase and subsequent discontinuous metrizamide gradient centrifugation. MAbs OKIa; EMA; OKT9; BMA 130a, b and c; EP4; TAG 72; HEA 125; and Leu M1 were studied using the peroxidase-antiperoxidase adhesive slide assay method. In all cases, type II pneumocytes reacted positively with OKIa, BMA 130a, BMA 130b, EMA, EP4, TAG 72 and HEA 125 and negatively with OKT9, BMA 130c and Leu M1. The percentage of positively reacting type II pneumocytes was 90 for OKIa, HEA 125 and EP4; 80 for EMA; 50 for TAG 72 and BMA 130a; and 5 for BMA 130b. Human type II pneumocytes share the expression of several antigens with epithelial tumor cells. This limits the usefulness of these markers with respect to differentiating between reactive type II pneumocytes and malignant cells.

Background: Diffuse panbronchiolitis (DPB) is characterised clinically by chronic airflow limitation and respiratory tract infection, and pathologically by chronic bronchiolar inflammation. To elucidate the functional differences between chronic obstructive pulmonary disease (COPD) and DPB the bronchial responsiveness to methacholine was compared in 64 patients with COPD and 32 patients with DPB, and the bronchodilator response was compared in 72 patients with COPD and 49 with DPB., Methods: Bronchial responsiveness to methacholine was determined by the dosimeter method and expressed as PD20FEV1, and bronchodilator response was measured as the change in percentage predicted response with 5 mg nebulised salbutamol., Results: Baseline FEV1 was similar in the two groups of patients. Patients with COPD were more responsive to methacholine than were those with DPB (geometric mean PD20FEV1 8.87 v 48.0 cumulative units). Reversibility of air flow obstruction, expressed as the difference between the percentage predicted postbronchodilator FEV1 and prebronchodilator FEV1, was significantly larger in patients with COPD than in those with DPB (7.87 (6.52)% v 4.16 (4.43)%)., Conclusions: The observation that patients with DPB differ substantially in bronchial responsiveness from those with COPD is thought to reflect the difference in the mechanisms of these two diseases--that is, airway disease in DPB and more parenchymal disease in the group of patients with COPD. The nature of bronchiolar inflammation in COPD and DPB is also different, possibly explaining the difference in bronchial responsiveness. More fixed airflow limitation as a result of structural bronchiolar lesions in DPB will explain the smaller reversibility of airflow obstruction.

In our study of 52 patients with idiopathic pulmonary fibrosis (IPF), we found that the incidence of clubbing of the fingers was significantly more frequent in male than in female patients and in patients who showed lesser grades of honeycombing and higher grades of smooth-muscle proliferation in the pulmonary fibrotic changes (p < 0.01). Smooth-muscle proliferation in fibrotic changes of open lung biopsy specimens correlated with the mode of detection of IPF and the presence of clubbing of the fingers, duration of symptoms of the lower respiratory tract, and a higher extent of pulmonary infiltrates on chest radiographs (p < 0.05). However, the presence of clubbing of the fingers or grades of smooth-muscle proliferation in the pulmonary fibrotic changes did not correlate with the 2-year survival after open lung biopsy.

The purpose of this study was to evaluate the role of high-resolution computed tomography (HRCT) in the clinical diagnosis of diffuse infiltrative lung disease (DILD). Diagnostic accuracy was compared using both chest radiography and HRCT. One hundred thirty-four cases of DILD, representing 21 different diseases, were selected for study, and the disease state was confirmed either histologically or microbiologically. The HRCT images and chest radiographs, available in all cases, were reviewed separately and in random order by 20 physicians who were provided only with information on each patient's age and sex. Overall, a correct first-choice diagnosis was made in 38 percent using radiographs and in 46 percent using HRCT images (p < 0.01). The correct diagnosis was among the top three choices in 49 percent when chest radiographs were used, and in 59 percent when HRCT images were viewed (p < 0.01). The correct first-choice diagnosis increased remarkably when the HRCT was used in usual interstitial pneumonia, sarcoidosis, alveolar proteinosis, bronchiolitis obliterans organizing pneumonia, hypersensitivity pneumonitis, and pulmonary lymphangiomyomatosis. High-resolution computed tomography was confirmed to be superior to conventional radiography in the accurate diagnosis of DILD in clinical practice.

High-resolution computed tomography (HRCT) allows accurate assessment of the pattern and distribution of diffuse lung diseases. Optimal interpretation of the HRCT images requires understanding of some basic concepts of normal anatomy, as well as the pathologic basis for the HRCT findings in diffuse lung disease. This review summarizes our experience with over 400 radiologic-pathologic correlations in diffuse lung disease. These correlations include contact radiography with stereo views and stereomicroscopic images of lung specimens. We describe our technique to inflate and fix the lung specimens and illustrate normal and abnormal lung morphology.

cDNA clones encoding three types of Gi alpha, the alpha subunit of GTP-binding protein (Gi1 alpha, Gi2 alpha, and Gi3 alpha), were isolated from a cDNA library of the guinea-pig lung. Nucleotide sequence analysis revealed a high degree of homology with other mammalian Gi alpha cDNAs. By RNA blot analysis, the expression pattern of Gi1 alpha was more tissue-specific than those of other types of Gi alphas in the guinea-pig tissues examined. While Gi2 alpha and Gi3 alpha mRNAs were ubiquitously expressed in all tissues examined, Gi1 alpha mRNA was mainly expressed in the brain, lung and kidney. These results suggest that each Gi alpha protein may have a different role.

We assessed pulmonary function and exercise tolerance in 10 BMT patients. Their underlying disorders were as follows; chronic myeloid leukemia 5 cases, acute lymphoblastic leukemia 2 cases, aplastic anemia, acute myeloid leukemia and non-Hodgkin's lymphoma one case each. Their mean age was 26 +/- 9 years old. When the patients were healthy and free of serious complications and anemia, arterial blood gas examination, pulmonary function tests and incremental treadmill exercise test were examined repeatedly. Although %VC and FEV1.0% kept within normal range, PaO2 at rest, %DLCO, VO2max, VO2max/kg and O2-pulsemax remained low at one year after BMT. There were significant correlations between VO2max and O2-pulsemax [r = 0.955 (p < 0.001)], %VC [r = 0.758 (p < 0.02)], VE/VO2max [r = -0.749 (p < 0.02)] and delta SaO2/VO2/kg [r = -0.731 (p < 0.02)], suggesting that exercise intolerance in BMT patients may be based on both cardiac and gas exchange abnormalities. To evaluate cardiac dysfunction, we compared exercise parameters obtained at an exercise level of 75% predicted heart rate max in five age-matched normal subjects to those in six BMT patients who did not demonstrate desaturation during exercise. As a result, the mean values of VO2max/kg and O2-pulse/m2 in BMT patients were significantly lower than those in normal subjects, suggesting that cardiac dysfunction may be due to insufficiency of stroke volume during exercise. It is concluded that exercise intolerance in BMT patients may be mainly due to cardiac dysfunction.

We compared the doubling time of fibroblasts derived from idiopathic pulmonary fibrosis (usual interstitial pneumonia) (IPF [UIP]) lung tissues and control fibroblasts, cultured in usual growth medium, and examined the response of these fibroblasts to platelet-derived growth factor (PDGF) and prostaglandin E2 (PGE2). Ten fibroblast lines from open lung biopsy specimens of patients with IPF (UIP) and ten control fibroblast lines from surgically resected lung tissue of patients with limited lung diseases were established. The average doubling time of fibroblast lines was 32.0 +/- 6.0 h (mean +/- SD) in UIP and 33.2 +/- 10.4 h in controls, showing no difference between the two groups. To examine the responses of fibroblasts to PDGF and PGE2 and the differences between fibroblasts derived from fibrotic tissues with different intensity of fibrosis, lung specimens from five patients with IPF were subdivided into two groups, higher-intensity fibrotic lesions (H) and lower-intensity fibrotic lesions (L). The fibroblast lines were established separately. 3H-thymidine uptake with or without PDGF or PGE2 was examined. Results were expressed as the index of thymidine incorporation into the fibroblasts. There were no differences in the doubling times and the responses to PDGF and PGE2 between H and L. There were no differences between control and H regarding their response to PDGF. In response to PGE2, the growth inhibition for H was significantly decreased compared with the control (p less than 0.05). There was no difference in growth inhibition between H and L. The finding that PGE2 inhibits fibroblast proliferation less in UIP lung tissue suggests that fibroblasts from UIP were functionally altered cells or, to some extent, out of normal regulation. These results suggest an abnormal proliferation of fibroblasts observed in IPF (UIP).

A 49 year-old Japanese female with a clinical history of rheumatoid arthritis for 15 years developed fever, cough, sputa and exertional dyspnea. A chest x-ray showed right-sided pleural lesions in addition to persistent hyperinflation of the lungs for about four years. Pulmonary function tests showed combined obstructive and restrictive dysfunction, increased residual volume and reduced diffusing capacity. After an improvement of the pleural lesions, she underwent a right open lung biopsy in December 1988 which revealed follicular bronchiolitis and fibrino-fibrous pleural thickening. The pulmonary lesion of follicular bronchitis/bronchiolitis was reported in 1985 as a newly recognized pulmonary disorder among open lung biopsy cases. The present case was the second biopsy proven case of follicular bronchiolitis among the Japanese.

The X-ray CT findings of two cases of pulmonary lymphangioleiomyomatosis were reported. The correlation between high-resolution CT findings and inflated biopsy specimens was studied. The X-ray CT findings are 1) multiple low attenuation areas, 2) diffuse areas of slightly increased density and 3) irregular enlargement of pulmonary vascular images. Each low attenuation are turned out to correspond to emphysematous lesions. Slightly increased densities on CT images seemed to be caused by a summation of many small nodules of a proliferation of smooth muscle cells located in the wall of respiratory bronchioles and alveolar ducts, with or without intraalveolar hemosiderosis. Some nodular lesions in bronchiolar walls were so close to neighboring vessels that they could not be separated from vascular images on CT, so peripheral vascular images were irregularly thickened. X-ray CT reflected more actual pathological findings than routine chest radiographs. As low attenuation areas on CT images have been reported to be representative of pulmonary emphysema, it is thought that the above CT findings must be differentiated from those of pulmonary emphysema. While pulmonary vascular images were thin and stretched on the CT in patients with emphysema, they were irregularly thickened on the CT of patients with LAM. Furthermore, while CT of emphysema often revealed overinflation or decreased density, diffuse areas of slightly increased density were never found in emphysema.

Enzymic activities catalyzing allylic epoxide, leukotriene A4, to leukotriene C4 by conjugation with glutathione were present mainly in microsomal fractions of spleens and lungs of guinea pigs and rats. Leukotriene C4 (LTC4) synthase was solubilized from the microsomes of guinea-pig lung by the new procedures of a combination of 3-[3-cholamidopropyl)dimethylammonio)-1-propanesulfonate (CHAPS), digitonin and KCl. The enzyme was partially purified by two steps of column chromatography which resulted in a complete resolution of the enzyme from glutathione S-transferases (EC 2.5.1.18). The partially purified LTC4 synthase showed a Vmax value of 40 nmol/min per mg, and the apparent Km values for LTA4 and glutathione were 36 microM and 1.6 mM, respectively. The enzyme was unstable, and half of the activity was lost by incubation at 37 degrees C for 3 min. Glutathione at 10 mM completely protected the enzyme against this inactivation, while other sulfhydryl-group-reducing reagents were ineffective. The partially purified enzyme revealed a high specificity towards 5,6-epoxide leukotrienes (LTA4 and its methyl ester), while rat cytosolic glutathione S-transferases catalyzed conjugation of glutathione to various positional isomers of epoxide leukotrienes.

Leukotriene A4 hydrolase from the human lung was purified to apparent homogeneity. The molecular weight (68,000-71,000), the amino acid composition, and the N-terminal amino acid sequence were similar to those of the human neutrophil enzyme but different from those of human erythrocyte enzyme. The lung enzyme was inactivated by its substrate, leukotriene A4. To elucidate the substrate and the inactivator specificity of this enzyme, we synthesized various geometric and positional isomers of leukotriene A4. 14,15-Leukotriene A4, leukotriene A4 methyl ester, and geometric isomers of leukotriene A4 could not serve as substrates, but they inactivated the enzyme. On the other hand, styrene oxide and (5S)-trans-5,6-oxide-8,10,14-cis-12-trans-eicosatetraenoic acid neither served as substrates nor inactivated the enzyme. These results indicate that whereas allylic epoxide structures of arachidonic acids are responsible for inactivation of the enzyme, the free carboxylic acid, 5,6-oxide, and the tetraene structure with the 7,9-trans-11,14-cis configuration are required as a substrate for leukotriene A4 hydrolase.

Positron emission tomography with radioactive nitrogen gas as well as CT were performed in seven patients with diffuse panbronchiolitis (DPB) to evaluate regional changes on pulmonary ventilation and lung attenuation values. Special focus of this study was on the difference between the central and peripheral parts of the lung. Mean ventilatory time constants measured in the peripheral parts of the lung were significantly greater than those in the central parts. Moreover, mean CT attenuation values in the peripheral parts were also significantly lower than those in the central parts, indicating that hyperinflation of the lung in DPB was located mainly in the peripheral parts. Such stratified distribution of ventilatory impairment is considered to be characteristic of diffuse bronchiolar narrowing because, in the peripheral parts of the lung, there are no large airways. In addition, different branching patterns of airways between the central and peripheral parts of the lung may play an important role in the mechanism of selective injury of bronchioles in the peripheral parts.