Brief report: idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease.
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Adult↗
Biomedical subjects
T E King
Publications and source records attributed to T E King.
Urinary levels of bombesin-like peptides in asymptomatic cigarette smokers: a potential risk marker for smoking-related diseases.
Bombesin-like peptides (BLP) produced by pulmonary neuroendocrine cells have many physiological actions which are relevant to the pathobiology of cigarette smoking. The objectives of this study were to determine whether cigarette smokers excrete increased levels of BLP in their urine compared with nonsmokers, to determine the relationship between BLP levels in urine and bronchoalveolar lavage (BAL) fluid, and whether urinary BLP levels are merely a reflection of exposure to cigarette smoke. Simultaneous BAL fluid and urine samples were obtained from ten clinically normal smokers and 22 normal nonsmoker volunteers. Urine samples were also obtained from 39 normal smokers and 30 normal nonsmokers who did not have BAL performed. BLP levels were measured in urine and BAL fluid using an enzyme-linked immunoassay. Expired air content of carbon monoxide, which reflects recent exposure to cigarette smoke, was determined in 34 of the clinically normal smokers and correlated with urinary BLP levels. We found that, in addition to having increased BLP levels in BAL fluid (P = 0.04), asymptomatic cigarette smokers also have increased BLP levels in their urine compared with normal nonsmokers (P = 0.007). Of note, a subgroup of smokers have markedly increased BLP levels which do not overlap with the nonsmokers. Urinary BLP levels correlated with expired air content of carbon monoxide (r = 0.49, P less than 0.01). However, not all smokers with increased expired air content of carbon monoxide exhibited increased BLP levels. Finally, all smokers with detectable BLP levels in BAL fluid had detectable urinary BLP levels, and there was a positive correlation between BLP levels in urine and BAL fluid (r = 0.625, P less than 0.001). We conclude that a subgroup of asymptomatic cigarette smokers exhibited increased BLP levels, measurable in both urine and BAL fluid, which precede the onset of clinically detectable disease and which are not strictly dependent on smoking intensity. We speculate that smokers with increased BLP levels may have a greater risk for smoking-related diseases.
Biomarkers↗
Bronchoalveolar lavage in patients with connective tissue disease.
Bronchoalveolar lavage (BAL) allows the recovery of cellular and fluid constituents that are derived from the epithelial surface of the lower respiratory tract. BAL fluid and cell analysis has become an important tool for understanding human pulmonary disease. Changes in the quantities and patterns of BAL cells and secretions have been described in a number of chronic lung disorders, especially the diffuse interstitial lung diseases. Specific BAL alterations have correlated with patient outcome and response to therapy. The connective tissue diseases have been associated with serious pleural and/or pulmonary pathology and may be a major cause of morbidity and mortality. BAL appears to be a useful semi-invasive tool in the evaluation and management of lung disease in patients with connective tissue diseases. The article describes the BAL findings in various connective tissue diseases and assesses the usefulness of BAL in the clinical management of patients with pulmonary complications.
Bronchoalveolar Lavage Fluid↗
Imaging of pulmonary histiocytosis X.
Pulmonary histiocytosis X is an uncommon but important cause of pulmonary fibrosis and honeycombing in young adults. This article reviews the pathologic, clinical, radiographic, and high-resolution computed tomographic (HRCT) features of pulmonary histiocytosis X, focusing on differential diagnosis and disease progression. The main pathologic feature of pulmonary histiocytosis X is peribronchiolar inflammation, leading to fibrosis and cyst formation. Although the diagnosis of pulmonary histiocytosis X may be suspected on the basis of chest radiographic findings, the HRCT findings of predominantly upper lobe nodules and cysts are virtually pathognomonic of this disorder. As pulmonary histiocytosis X progresses, the nodules decrease in number, leaving multiple thin-walled cysts. HRCT can be useful in visually estimating the proportion of lung involved and is also valuable in distinguishing histiocytosis from other disorders that produce nodules or cysts. Chest HRCT helps confirm the pattern seen at radiography and is valuable in establishing the correct diagnosis.
Diagnosis, Differential↗
Controversies in hypersensitivity pneumonitis.
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Alveolitis, Extrinsic Allergic↗
Serum and bronchoalveolar lavage of N-terminal type III procollagen peptides in idiopathic pulmonary fibrosis.
Collagen deposition is a prime determinant of clinical course in idiopathic pulmonary fibrosis (IPF). Identification of a marker of connective tissue metabolism would significantly enhance the ability to stage the disease and monitor the course of these patients. Prior studies of IPF have indicated that N-terminal Type III procollagen peptide (N-PIIIP) levels in blood and bronchoalveolar lavage BAL fluid are elevated. We hypothesized that elevated levels of procollagen peptides are a marker of enhanced collagen deposition, which is associated with interstitial fibrosis characterizing active disease. The purpose of the present study was to explore the relationship between N-PIIIP recovery and physiologic parameters of lung function. N-PIIIP levels in sera and bronchoalveolar lavage (BAL) from 24 patients with IPF and 29 volunteers were measured by radioimmunoassay. The extent of disease in IPF was assessed by clinical history, physical examination, chest radiograph, pulmonary physiology evaluation, and confirmatory open-lung biopsy. The severity of disease was graded using a previously described clinical, radiologic, and physiologic (CRP) scoring system. N-PIIIP normalized to albumin was higher in BAL than in serum for both volunteers (1.6-fold; p less than 0.05) and IPF patients (24-fold; p less than 0.05), consistent with local pulmonary production. BAL N-PIIIP was significantly elevated in IPF patients, whether expressed as concentration (healthy volunteer 0.11 +/- 0.06 ng/ml; IPF, 5.0 +/- 14.4; mean +/- SD; p less than 0.05) or normalized to albumin (healthy volunteer, 2.8 +/- 1.2; IPF, 73 +/- 106; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Idiopathic pulmonary fibrosis. Quantitative assessment of lung pathology. Comparison of a semiquantitative and a morphometric histopathologic scoring system.
The objective of this study was to determine the accuracy of a semiquantitative method of assessing the relative degree of cellularity and fibrosis compared with a morphometric analysis of specific histopathologic features in idiopathic pulmonary fibrosis (IPF). Morphometric analysis was performed on biopsy tissue from 20 patients. Morphometry showed that approximately 70% of parenchymal tissue was abnormal: 35% cellular consolidation and fibrosis, 20% honeycomb changes, 10% thick alveolar septa, and 5% small airways within abnormal parenchymal tissue. The prominent components of the abnormal parenchymal tissue were extracellular fibers, an abundance of interstitial cells, and epithelial cell hyperplasia. Correlation between four groupings of pathologic features, identified by a semiquantitative analysis, and each of the components of the parenchymal lesions showed significant correlations between (1) the fibrotic or reparative factor (alveolar wall metaplasia, fibrosis, honeycombing, and smooth muscle and vascular changes) and components of honeycomb lesions (extracellular fibers, interstitial cells, and epithelial injury and repair), and (2) the inflammatory and exudative factor and extracellular fibers in the lesions. These results support that the scoring system used by the pathology panel provides an accurate assessment of pathologic features useful in the assessment of the extent and severity of the histopathologic lesions of IPF.
Biopsy↗
Hypersensitivity pneumonitis: sensitivity of high-resolution CT in a population-based study.
OBJECTIVE: Hypersensitivity pneumonitis refers to a group of pulmonary disorders caused by inhalation of organic or inorganic particulates by sensitized persons. The diagnosis relies on a constellation of findings: exposure to an offending antigen, characteristic signs and symptoms, abnormal chest findings on physical examination, and abnormalities on pulmonary function tests and radiographic evaluation. In population-based studies, the sensitivity of chest radiography for detection of this disease is relatively low. The aim of this study was to determine the sensitivity of high-resolution CT (HRCT) for detection of hypersensitivity pneumonitis diagnosed in a population of swimming-pool employees. SUBJECTS AND METHODS: Thirty-one symptomatic employees of a recreation center who were referred because of possible hypersensitivity pneumonitis were examined by using chest radiography, HRCT, and fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial biopsy. Hypersensitivity pneumonitis was diagnosed in subjects who had two or more work-related signs or symptoms, abnormal results on transbronchial biopsies, and abnormal lymphocytosis as shown by examination of bronchoalveolar lavage fluid. The chest radiographs and HRCT scans were interpreted by consensus by two observers who were unaware of the clinical diagnosis. RESULTS: Only one of 11 subjects with a diagnosis of hypersensitivity pneumonitis had abnormal findings on a chest radiograph. Five had abnormal HRCT findings. The abnormality in each case consisted of small, poorly defined centrilobular nodules with variable profusion. No subject without the disease had abnormal HRCT findings. Those who had granulomas shown by lung biopsy were more likely to have abnormal HRCT findings than were those who had more subtle histologic abnormalities. CONCLUSION: The sensitivity of HRCT for the detection of hypersensitivity pneumonitis in a population-based study is greater than that of chest radiography. The finding of poorly defined centrilobular nodules on HRCT scans should prompt consideration of this disease.
Adolescent↗
Chronic hypersensitivity pneumonitis: use of CT in diagnosis.
OBJECTIVE: In its subacute or chronic form, hypersensitivity pneumonitis is often difficult to distinguish clinically and physiologically from other idiopathic diffuse lung diseases. The aim of this study was to identify high-resolution CT features that allow distinction of chronic hypersensitivity pneumonitis from other chronic diffuse parenchymal lung diseases. MATERIALS AND METHODS: Six patients with chronic hypersensitivity pneumonitis were examined with pulmonary function testing, bronchoalveolar lavage, lung biopsy, chest radiography, and high-resolution CT. The chest radiographs and high-resolution CT scans were reviewed independently by three observers without knowledge of the patients' clinical status. Discrepancies between the observers were resolved by consensus. RESULTS: The chest radiographs revealed normal lung volumes with a combination of abnormalities: a mixed alveolar/interstitial pattern in five cases, peribronchiolar thickening in three, a diffuse granular pattern in one, and a linear fibrotic pattern in one. In general, the high-resolution CT scans showed more abnormalities than were apparent on the plain chest radiographs. High-resolution CT revealed centrilobular, peribronchiolar, indistinct nodular opacities, of various numbers, in all cases. Four cases had areas of ground-glass density, three cases had lobular areas of hyperlucency, and one case had areas of pulmonary fibrosis and honeycombing. CONCLUSION: We confirm that high-resolution CT can most clearly show the type and distribution of parenchymal abnormalities in patients with hypersensitivity pneumonitis. Importantly, although not pathognomonic, the high-resolution CT finding of centrilobular, peribronchiolar, indistinct nodules should suggest the diagnosis of chronic hypersensitivity pneumonitis.
Alveolitis, Extrinsic Allergic↗
Restrictive lung disease in pregnancy.
Restrictive ventilatory defects characterized by a reduction in lung volumes and an increase in the ratio of forced expiratory volume in 1 second to forced vital capacity occur when lung expansion is limited because of alterations in the lung parenchyma or because of abnormalities in the pleura, chest wall, or neuromuscular apparatus. Few studies have examined pregnant women with carefully defined restrictive lung disorders. The majority of pulmonary diseases have their onset after the childbearing years. When present, most do not alter fertility. Further, these disorders are only a relative contraindication to pregnancy because both the fetus and mother are able to survive without a high risk of increased morbidity or mortality. The clinical course of sarcoidosis is generally not altered by pregnancy. Factors indicative of a poor prognosis in sarcoidosis and pregnancy include parenchymal lesions on chest radiography, advanced roentgenologic staging, advanced maternal age, low inflammatory activity, requirement for drugs other than corticosteroids, and the presence of extrapulmonary sarcoidosis. Pregnancy seldom has a significant effect on the course of the connective tissue diseases. In PSS with significant renal involvement, pregnancy has the potential for poor fetal prognosis and the risk of maternal death due to a lethal progression of renal failure. Worsening of SLE is uncommon in pregnancy, and prophylactic therapy is generally not necessary. Most women with LAM are advised to avoid pregnancy or the use of estrogens because of the concern that it will lead to worsening of their disease. The incidence of kyphoscoliosis in pregnancy is relatively high. Premature birth rates are higher than that in the normal population. The risk of progression of the abnormal curve in a scoliotic patient appears low. However, women with unstable scolioses at the time of pregnancy can demonstrate progression of the curve with the pregnancy. Respiratory complications during pregnancy in patients with kyphoscoliosis have been reported but in general are not serious if appropriately managed. As a rule, patients with severe restrictive lung disease (i.e., vital capacity < 1 L) should be advised to avoid pregnancy or consider therapeutic abortion. If such a patient decides to continue the pregnancy she should be provided with optimal medical management of her underlying disease and should consider delivery by cesarean section.
Alveolitis, Extrinsic Allergic↗
Two-site property of thenoyltrifluoroacetone inhibiting succinate-ubiquinone reductase.
It is proved by using the Dixon plot and the Lineweaver-Burk plot that thenoyltrifluoroacetone (TTFA) has two inhibitive sites affecting the reduction of ubiquinone catalyzed by succinate-ubiquinone reductase. The high affinity site (inhibited at the concentration of thenoyltrifluoroacetone less than 20 mumol/L) shows noncompetitive with substrate Q2, while the low affinity site (inhibited at the concentration of TTFA over 20 mumol/L) shows competitive. It is suggested that both the reducing steps of Q----QH-. and QH-.----QH2 are inhibited by thenoyltrifluoroacetone.
Animals↗
Cryptogenic organizing pneumonitis. The North American experience.
Cryptogenic organizing pneumonitis is a clinical and pathologic syndrome characterized by a "pneumonia-like" illness with excessive proliferation of granulation tissue within small airways and alveolar ducts associated with chronic inflammation in the surrounding alveoli. The duration of illness prior to lung biopsy is short, usually less than 2 months, and it is markedly different from that of IPF. Interestingly, unlike in IPF where the patient has difficulty remembering the exact onset of symptoms, patients with COP are frequently very specific about the timing of their disease onset. This is because the disease onset is recent and is often dramatic with the development of a severe flulike illness, ie, cough, fever, malaise, fatigue, and weight loss. Inspiratory crackles are frequently present on chest examination. Pulmonary function is usually impaired with a restrictive defect being most common. Gas exchange abnormalities are extremely common with a reduction in Dco and resting hypoxemia being almost universal findings. The roentgenographic manifestations are quite distinctive with a pattern of bilateral, diffuse but inhomogeneous, ground-glass or alveolar opacities being present in the majority of the cases. Bronchoalveolar lavage findings are nonspecific but usually reveal a lymphocytosis. The response to corticosteroid treatment is quite favorable and death from progressive disease is uncommon in COP, especially if treatment is instituted early in the course of the disease. In our experience, the cases with the worse prognosis are those associated with another disease process, in particular, connective tissue disorders like rheumatoid arthritis. In fact, these patients are prone to develop a rapidly progressive form of BOOP with a clinical course similar to the "Hamman-Rich syndrome." Recurrences are relatively frequent, consequently, withdrawal of treatment should be done with extreme caution. Corticosteroids have been the conventional initial treatment of COP, although to our knowledge, there are no controlled clinical trials to support it use. Antibiotics are not effective in treating this syndrome. Thus, based solely on our experience and that of others, we believe that high-dose corticosteroid therapy should be used to treat COP, usually initiated with 1 to 1.5 mg/kg/day (using ideal body weight) not to exceed 100 mg/day. Prednisone is given as a single oral dose in the morning. We recommended maintaining this dose for 4 to 8 weeks. If the patient's condition is stable or improved, the prednisone dosage is gradually tapered to 0.5 to 1 mg/kg/day (using ideal body weight) for the ensuing 4 to 6 weeks.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Role of transferrin, transferrin receptors, and iron in macrophage listericidal activity.
It is not yet known what properties distinguish macrophages which can kill facultative intracellular bacteria, such as Listeria monocytogenes, from those which cannot. Listeria is an organism which requires iron for growth, yet macrophage listericidal mechanisms are also likely to be iron dependent. We show here that resident peritoneal macrophages and thioglycollate-elicited macrophages cannot kill listeria, but proteose peptone-elicited and FCS-elicited macrophages can. All these cell populations phagocytose listeria. Transferrin receptor expression is low on resident cells, intermediate on peptone- and FCS-elicited cells, and high on thioglycollate-elicited cells. Transferrin transports iron into cells via the transferrin receptor: thus, iron content of resident cells is low, of peptone- and FCS-elicited cells is intermediate, and of thioglycollate-elicited cells is high. Moreover, antibody to transferrin, which prevents it binding its receptor, inhibits listericidal macrophages from killing this bacterium. Finally, nonlistericidal cells with high transferrin receptor expression and high intracellular iron become listericidal if they are incubated with apotransferrin, an iron-free ligand which prevents iron uptake by cells. These data suggest that macrophages must have enough available intracellular iron to support listericidal mechanisms, but too much iron favors growth of the bacterium, which no longer can be killed by the macrophage.
Animals↗
Intrinsic tryptophan phosphorescence as a marker of conformation and oxygen diffusion in purified cytochrome oxidase.
Cytochrome oxidase exhibits phosphorescence from tryptophan in aqueous solution in the absence of oxygen. The lifetime for the resting reduced enzyme suspended in Tween-20 is around 30 ms at pH 8. The lifetime is longest between pH 7 and 8 and decreases with lowering of pH. Oxygen quenches the phosphorescence with a Stern-Volmer quenching constant of approximately 5 x 10(7) M-1.s-1 at 5 degrees C whereas cytochrome c has no effect. We interpret these results to indicate that room temperature tryptophan phosphorescence arises from tryptophan(s) in structured region(s) remote from the hemes and that the protein does not impose a significant barrier for the diffusion of oxygen.
Animals↗
Structure and variability of mammalian peroxisomal membrane proteins.
Peroxisomal membrane proteins (PMPs) from the Swiss-Webster mouse are analyzed and compared to those of rats and humans using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. A purification procedure for fresh mouse, rat, or human biopsy liver which enriches peroxisomal/mitochondrial marker enzyme ratios over 100-fold is characterized. When analyzed by SDS-PAGE, membranes of purified liver peroxisomes are shown to contain the same complement of 145-, 70-, 55-, 36-, and 22-kDa PMPs in rats, mice, and humans. A rabbit polyclonal antibody raised against mouse peroxisomal membranes demonstrates immunoreactivity to 145- and 70-kDa proteins in fresh liver homogenates from all three species and in control or Zellweger syndrome fibroblasts from humans. Human autopsy or placental tissues which were refrigerated before analysis exhibited 105-, 55-, and 36-kDa peptides which may be derived from the 145- and 70-kDa peptides. Such conversions, if related to degradation, may explain difficulties in purifying peroxisomes from human autopsy specimens. Variable amounts of the 55-kDa peptide also occurred in mouse adrenal and lung, and the conversion of higher to lower molecular weight PMPs could not be demonstrated by in vitro incubation of mouse liver. Further definition of the structure and variability of mammalian PMPs should be helpful in understanding polyenzymopathies such as Zellweger syndrome.
Animals↗
Pathogenesis of pulmonary fibrosis in interstitial lung disease. Alveolar macrophage PDGF(B) gene activation and up-regulation by interferon gamma.
Alveolar macrophages are believed to be central in orchestrating the fibrotic response in interstitial lung disease (ILD). To test the hypothesis that macrophages from patients with ILD were dedicated to growth factor production and that this was independent of other indices of macrophage activation, we measured the mRNA of the B chain of PDGF and TGF-beta, as well as HLA-DR-alpha in alveolar macrophages from patients with ILD and from normal control subjects. When alveolar macrophages were examined immediately after lavage, cells from patients with ILD had increased PDGF(B) but similar TGF-beta and HLA-DR-alpha mRNA when compared with control subjects. Discoordinate regulation of these genes was observed when alveolar macrophage PDGF(B) mRNA increased while TGF-beta and HLA-DR-alpha mRNA decreased after culture for 24 h. This response was not disease-related as these changes were similar in cells from patients with ILD and from control subjects. Because a lymphocytic alveolitis is present in many cases of ILD, we asked whether interferon gamma (IFN-gamma) modulated the activation of these genes. In both the patients and the control subjects, PDGF(B) and HLA-DR-alpha, but not TGF-beta, mRNA were increased after incubation with IFN-gamma. These results indicate that PDGF(B) mRNA may be increased in alveolar macrophages in ILD and that PDGF(B), TGF-beta, and HLA-DR-alpha are independently regulated genes in alveolar macrophages, but that IFN-gamma increases both PDGF(B) and HLA-DR-alpha mRNA. We speculate that IFN-gamma induced PDGF(B) gene activation may be an important mechanism by which lymphocytes promote pulmonary fibrosis.
Adult↗
Idiopathic pulmonary fibrosis. Abnormalities in the bronchoalveolar lavage content of surfactant protein A.
Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung characterized by an inflammatory infiltrate, alveolar type II cell hypertrophy and hyperplasia, and ultimate parenchymal scarring. The phospholipid composition of the surface-active material recovered by bronchoalveolar lavage (BAL) is abnormal in this disease. In the present study we have extended the analysis of surfactant components in IPF to include the major surfactant-associated protein, surfactant protein A (SP-A). SP-A has been reported to be essential for the formation of tubular myelin, to facilitate the adsorption of phospholipid to the air/liquid interface, and to stimulate uptake and inhibit secretion of surfactant in vitro. The BAL of 25 normal volunteers and 42 patients with interstitial lung disease (ILD) was analyzed for surfactant protein A content by ELISA and for phospholipids. The changes in BAL components were correlated to histopathologic markers at open-lung biopsy, clinical status, and survival. The total phospholipid (PL) recovered at lavage was reduced in patients with IPF relative to normal volunteers (p less than 0.0005). In addition, the percentage of phosphatidyl-glycerol (% PG) was decreased in patients with IPF (p less than 0.0001), whereas the percentage of phosphatidylcholine that was saturated was not altered. The content of surfactant protein A in lavage was reduced, even when normalized for the total amount of surface-active material recovered (SP-A/PL) (p less than 0.007). The reduction in SP-A was not specific to IPF but also occurred in other interstitial lung diseases.(ABSTRACT TRUNCATED AT 250 WORDS)
Bronchoalveolar Lavage Fluid↗
Quantitative assessment of lung pathology in idiopathic pulmonary fibrosis. The BAL Cooperative Group Steering Committee.
The diagnosis and classification of most interstitial lung diseases requires histologic evaluation of lung tissue, obtained by an open lung biopsy to confirm the diagnosis. In addition, it is generally accepted that response to therapy in idiopathic pulmonary fibrosis (IPF) is related to the relative degree of cellularity and fibrosis present. Because only a qualitative assessment of the relative extent and severity of these changes is generally provided, correlation with clinical and physiologic alterations is difficult. This report describes results of a semiquantitative assessment by four pathologists of inflammatory/exudative changes, fibrotic/reparative changes, and airway alterations, in addition to an overall assessment of cellularity and fibrosis in 50 patients with IPF. In 10 randomly selected biopsies examined twice in a blinded fashion, absolute agreement between assessments for a given pathologist varied between 54 and 64% (mean = 57.5%) and in the majority of instances the agreement was greater than would have occurred by chance. There was good agreement for most variables across the four raters on the 101 samples. The mean score for some of the parameters reported by a given rater deviated occasionally from those of the other raters, but no single rater was consistently different from the other raters. A principal component factor analysis revealed that the pathologic features fell into four general groupings: alveolar wall metaplasia, fibrosis, honeycombing, smooth muscle, and vascular changes fell into one group; severity and extent of cellularity in the alveolar wall into a second group; severity and extent of cellularity in the alveolar space into a third group; and interstitial young connective tissue along with granulation tissue in the airways formed the fourth group.(ABSTRACT TRUNCATED AT 250 WORDS)
Biopsy↗