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Biomedical subjects

W N Rom

Publications and source records attributed to W N Rom.

At least 109 records · Page 6Linked to original sources
PubMed1993

Mechanisms of stimulation of interleukin-1 beta and tumor necrosis factor-alpha by Mycobacterium tuberculosis components.

The granulomatous immune response in tuberculosis is characterized by delayed hypersensitivity and is mediated by various cytokines released by the stimulated mononuclear phagocytes, including tumor necrosis factor-alpha (TNF alpha) and IL-1 beta. We have demonstrated that Mycobacterium tuberculosis cell wall component lipoarabinomannan (LAM), mycobacterial heat shock protein-65 kD, and M. tuberculosis culture filtrate, devoid of LPS as assessed by the Amebocyte Lysate assay, stimulate the production of TNF alpha and IL-1 beta proteins and mRNA from mononuclear phagocytes (THP-1 cells). The effect of LAM on the release of these cytokines was specific, as only LAM stimulation was inhibited by anti-LAM monoclonal antibody. Interestingly, we found that LAM and Gram-negative bacterial cell wall-associated endotoxin LPS may share a similar mechanism in their stimulatory action as demonstrated by inhibition of TNF alpha and IL-1 beta release by monoclonal antibodies to CD14. Anti-CD14 monoclonal antibody MY4 inhibited both TNF alpha and IL-1 beta release with LAM and LPS but no effect was observed with other mycobacterial proteins. An isotype antibody control did not inhibit release of cytokines under the same experimental conditions. M. tuberculosis and its components upregulated IL-1 beta and TNF alpha mRNAs in THP-1 cells. Nuclear run-on assay for IL-1 beta demonstrated that LAM increased the transcription rate. The induction of IL-1 beta was regulated at the transcriptional level, in which these stimuli acted through cis-acting element(s) on the 5' flanking region of the IL-1 beta genomic DNA. M. tuberculosis cell wall component LAM acts similarly to LPS in activating mononuclear phagocyte cytokine TNF alpha and IL-1 beta release through CD14 and synthesis at the transcriptional level; both cytokines are key participants in the host immune response to tuberculosis.

Antibodies, Monoclonal↗
PubMed1993

Bronchogenic carcinoma in young patients at risk for acquired immunodeficiency syndrome.

Several case reports have suggested that bronchogenic carcinoma occurs more frequently in young patients who are human immunodeficiency virus (HIV) seropositive. We investigated the incidence of bronchogenic carcinoma and its clinical presentations in young patients at risk for HIV infection. The tumor registry of Bellevue Hospital was reviewed, and 261 cases of bronchogenic carcinoma during the period from 1976 to 1979 (pre-AIDS period) and 232 during the period from 1987 to 1990 (AIDS period) were identified. These cases were stratified into age groups: 45 or younger, 46 to 55, 56 to 65, and 66 years or older. All patients aged 45 years or younger in the AIDS period were subdivided by HIV risk, and clinical characteristics were compared among the subgroups. Results revealed no increased incidence of bronchogenic carcinoma from the pre-AIDS period compared with the AIDS period. These results suggest that HIV seropositivity is not a risk factor for bronchogenic carcinoma.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Intrathoracic adenopathy associated with pulmonary tuberculosis in patients with human immunodeficiency virus infection.

The role of computed tomography (CT) in the diagnosis of mediastinal tuberculous lymphadenitis was evaluated retrospectively in 25 human immunodeficiency virus (HIV)-infected patients (19 had AIDS). In all cases, the diagnosis of tuberculosis was established by mycobacterial culture and/or histologic evaluation. The most characteristic CT finding was the presence of low-density mediastinal and hilar lymph nodes in 16 of 19 (84 percent) patients with AIDS and four of six (67 percent) HIV-seropositive patients without AIDS. Marked enhancement of the periphery of nodes was identified in five cases, all in patients with documented AIDS. In most cases, lymphadenopathy proved to be massive, presenting as extensive, heterogenous soft-tissue lesions, presumably the result of coalescence of groups of matted nodes. We conclude that low-density mediastinal and/or hilar lymph nodes on CT, while not pathognomonic, is sufficiently characteristic for tuberculosis to warrant empiric antituberculosis therapy pending results of cultures.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Accelerated loss of lung function and alveolitis in a longitudinal study of non-smoking individuals with occupational exposure to asbestos.

Long-term asbestos workers who insulate pipes and boilers may develop interstitial lung disease associated with loss of lung function. To quantitate annual loss of lung function, 77 individuals with chest X-rays greater than or equal to 1/0 ILO category who were life-long non-smokers or ex-smokers for greater than 5 years were evaluated. Study parameters included pulmonary function tests and bronchoalveolar lavage for a mean of 3 visits over 30 +/- 2 months. The study participants were 56 +/- 1 years old and had 31 +/- 1 years' occupational exposure to asbestos. At the first visit, multiple regression analysis revealed significant associations between rales or radiographic opacities and VC, FEV1, and total lung capacity; significant associations were also found between neutrophils/ml lavage fluid with FEV1 and diffusing capacity (all p less than 0.05). Annual declines for the asbestos-exposed were VC -92 +/- 28 ml/yr and FEV1 -66 +/- 21 ml/yr. Declines in VC and FEV1 were less in those with reduced lung function at the initial visit. There were no significant associations between any of the annual declines and cells recovered by bronchoalveolar lavage. Compared to other asbestos-exposed cohorts followed longitudinally, asbestos insulators with radiographs greater than or equal to 1/0 and exposure greater than or equal to 20 years have larger rates of FVC and FEV1 decline for both non-smokers and ex-smokers.

Asbestos↗
PubMed1992

Lung inflammation in coal miners assessed by uptake of 67Ga-citrate and clearance of inhaled 99mTc-labeled diethylenetriamine pentaacetate aerosol.

We compared the diffuse lung uptake of 67Ga-citrate, an index of inflammatory lung activity, with the lung clearance of inhaled 99mTc-labeled diethylenetriamine pentaacetate (DTPA) aerosol, an index of pulmonary epithelial permeability, in a group of 19 West Virginia coal miners whose pulmonary status was compatible with coal worker's pneumoconiosis. 99mTc-DTPA clearance alone and 67Ga-citrate uptake alone were measured in nine and five additional subjects, respectively. The objective of this study was to determine if increased 99mTc-DTPA lung clearance was caused by inflammation at the lung epithelial surfaces. Subjects inhaled approximately 150 microCi (approximately 5.6 MBq) of 99mTc-DTPA aerosol, and quantitative gamma camera images of the lungs were acquired at 1-min increments for 25 min. Regions of interest (ROI) were selected to include (1) both lungs; (2) each individual lung; and (3) the upper, middle, and lower thirds of each lung. 99mTc-DTPA clearance was determined from the slopes of the respective time-activity plots for the different ROI. Each subject was intravenously administered 50 miCroCk (1.9 MBq)/kg 67Ga-citrate 48 to 72 h before imaging the body between neck and pelvis. The extent of 67Ga-citrate lung uptake was expressed as the gallium index (GI). Mean radioaerosol clearance half-time (T1/2) for the six nonsmoking coal miners (60.6 +/- 16.0 min) was significantly shorter (p less than 0.001) than for the nonsmoking control group (123.8 +/- 28.7 min). T1/2 for the 12 smoking miners (18.4 +/- 10.2 min) was shorter than for the smoking control group (33.1 +/- 17.8 min), but the difference did not attain statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Lymphocyte-macrophage alveolitis in nonsmoking individuals occupationally exposed to asbestos.

A disordered immunologic activity has been observed in humans and animal models of asbestosis and silicosis. To characterize the lung immunologic response following long-term occupational exposure to asbestos, bronchoalveolar lavage (BAL) was performed on 28 nonsmoking individuals. Increased BAL lymphocytes were observed in one third. Lung lymphocytes were predominantly of the CD4+ helper-inducer subtype with increased CD4+/CD8+ ratio and increased surface expression of DR antigen consistent with the activation phenotype. Histologic evaluation of lung tissue from two individuals with lymphocytic-macrophage alveolitis and asbestos exposure revealed an infiltration of alveolar walls with chronic inflammatory mononuclear cells (lymphocytes). Interferon gamma was spontaneously released by BAL cells from 19 (76 percent) of 25 of the individuals with asbestos exposure and only one of ten normal controls. The release of interferon gamma by BAL cells could be further stimulated with concanavalin A and suppressed by cyclosporine. Although asbestosis is characterized by a predominant alveolar macrophage alveolitis, there is a subgroup with lymphocytic alveolitis and activated lymphocytes participating in the inflammatory response, especially in those without respiratory impairment early in the course of the disease process.

Adult↗
PubMed1991

Relationship of inflammatory cell cytokines to disease severity in individuals with occupational inorganic dust exposure.

The pneumoconioses due to chronic occupational exposure to asbestos, coal, or silica are characterized by an alveolar macrophage-dominated alveolitis with exaggerated spontaneous release of mediators: oxidants, chemotaxins for neutrophils, and fibroblast growth factors. Bronchoalveolar lavage was performed on 66 non-smoking inorganic dust-exposed individuals with a chest x-ray greater than or equal to 1/0 stratified by presence or absence of restrictive respiratory impairment, and 28 unexposed non-smoking controls. Both dust-exposed groups stratified by presence or not of impairment had increased numbers of total cells recovered by lavage compared to normals, and those with respiratory impairment (n = 40) had a significant increase in percent and number of neutrophils recovered. Similarly, only those with respiratory impairment had macrophages that spontaneously released significant amounts of the oxidants superoxide anion and hydrogen peroxide. There was a significant trend for the release of fibronectin by macrophages from controls to dust-exposed without impairment to those with impairment. Both dust-exposed groups also had increased release of alveolar macrophage-derived progression growth factor, but this was significantly less than macrophages from patients with idiopathic pulmonary fibrosis. Since occupational exposure was virtually identical in inorganic dust-exposed individuals with versus without respiratory impairment, the quantitative differences in the release of macrophage mediators may be due to factors in host susceptibility.

Asbestos↗
PubMed1991

Dehydroepiandrosterone inhibits the spontaneous release of superoxide radical by alveolar macrophages in vitro in asbestosis.

Asbestosis is characterized by an alveolar macrophage alveolitis with injury and fibrosis of the lower respiratory tract. Alveolar macrophages recovered by bronchoalveolar lavage spontaneously release exaggerated amounts of oxidants including superoxide anion and hydrogen peroxide that may mediate alveolar epithelial cell injury. Dehydroepiandrosterone (DHEA) is a normally occurring adrenal androgen that inhibits glucose-6-phosphate dehydrogenase, the initial enzyme in the pentose phosphate shunt necessary for NADPH generation and superoxide anion formation. In this regard, we hypothesized that DHEA may reduce asbestos-induced oxidant release. DHEA added in vitro to alveolar macrophages lavaged from 11 nonsmoking asbestos workers significantly reduced superoxide anion release. DHEA was measured in bronchoalveolar lavage and found to be similar to serum concentrations. DHEA is an antioxidant and potential anticarcinogenic agent that may have a therapeutic role in reducing the increased oxidant burden in asbestos-induced alveolitis of the lower respiratory tract.

Asbestosis↗
PubMed1991

Cellular and molecular basis of the asbestos-related diseases.

Asbestosis is an inflammatory and fibrotic process of the alveolar structures mediated, at least in part, by cytokines released by "activated" alveolar macrophages. The process of phagocytosis and "activation" of alveolar macrophages is poorly understood. Are all macrophages activated or only subpopulations? Which cytokines are up-regulated? How does the local milieu modulate profibrotic and antifibrotic mediators? Is protein release accompanied by up-regulation of gene transcription? Is there an ordered sequence of cytokine activity? What roles do neutrophils and lymphocytes play? How can disease progression best be quantified absent further exposure? Answers to these questions are important to direct rational strategies at interdicting the fibrotic process. The question of cancer and asbestos is more vexing. The processes of inflammation, fibrosis, and carcinogenesis appear to be closely intertwined. For example, proto-oncogenes such as c-sis (PDGF B-chain) are up-regulated in activated alveolar macrophages from fibrotic lungs; these and possibly others may play an important role in asbestos carcinogenesis. Second, asbestos can transfect DNA into cells. Furthermore, DNA can adhere to asbestos fibers, and these fibers are capable of direct transmigration into cells. The questions of the mechanisms of cigarette smoke cocarcinogenicity and latency remain. Lastly, if the bronchial epithelium is highly metaplastic throughout from cigarette smoking, what triggers a single (or several) nidus of cells to transform into carcinoma? Malignant mesothelioma poses the most challenging questions because of association with brief asbestos exposure by history. Mesothelial cells are susceptible to minute environmental manipulations, and changes occur after exposure to all fiber types. Yet epidemiologic studies point toward long amphiboles as having greater mesothelioma risk. To test this hypothesis, experimental data must be generated differentiating tumorigenesis risk from short, chrysotile fibers that can migrate to the parietal pleura from the associations of long amphiboles persisting in lung tissue. Despite the future decreasing numbers of clinical cases of asbestos-related disease, solving the important mechanistic questions remaining will contribute significantly to our understanding of fibrosis and cancer.

Animals↗
PubMed1991

Activated alveolar macrophages express the insulin-like growth factor-I receptor.

Alveolar macrophages (AM) recovered from the lower respiratory tract of individuals with interstitial lung disease (ILD) proliferate at a 2- to 15-fold increased rate (P.B. Bitterman et al. 1984. J. Clin. Invest. 74:460-469). Normal AM stimulated with immune complexes or asbestos release platelet-derived growth factor and insulin-like growth factor-I (IGF-I), and AM activated in vivo in ILD release these growth factors. We evaluated normal unstimulated and activated AM for the receptor for IGF-I to determine if macrophage IGF-I could be involved in the enhanced macrophage proliferation. Although normal AM did not have specific 125I-labeled recombinant IGF-I binding, AM activated by chrysotile asbestos or lipopolysaccharide in vitro or from individuals with ILD had detectable binding that could be inhibited by an anti-IGF-I receptor monoclonal antibody in a dose-dependent fashion. Autoradiography with 125I-labeled recombinant IGF-I revealed binding to the IGF-I receptor on the surface of activated AM, and the percentage of labeled cells was reduced with anti-IGF-I receptor monoclonal antibody or excess unlabeled recombinant IGF-I. Hybridization of total AM RNA to a 32P-labeled IGF-I receptor riboprobe using solution hybridization demonstrated IGF-I receptor mRNA transcripts in AM from an individual with asbestosis, consistent with active expression of the IGF-I receptor gene. In the context of the known role of IGF-I as a growth factor for many cells, these data are consistent with the concept that IGF-I and its receptor may play an important role in the proliferation of AM in the inflamed lower respiratory tract.

Adult↗
PubMed1991

Human mononuclear phagocytes express the insulin-like growth factor-II/mannose-6-phosphate receptor.

The insulin-like growth factor (IGF)-II/mannose-6-phosphate (M6P) receptor, which targets acid hydrolases to lysosomes, is a multifunctional protein with separate binding sites for IGF-II and M6P. The purpose of this study was to determine if alveolar macrophages (AM) and their precursor cells, blood monocytes, expressed this receptor. AM expressed IGF-II/M6P receptors as detected by [125]IGF-II surface binding that was not reduced by recombinant IGF-I or IGF-I receptor monoclonal antibody (alpha IR3). Surface binding was also detected on blood monocytes and could be upregulated approximately 4-fold by incubation with lipopolysaccharide. There were no differences in surface binding by AM lavaged from individuals with asbestos exposure or from normal volunteers. Using the polymerase chain reaction and reverse transcriptase to reverse-transcribe mRNA from mononuclear phagocytes, specific IGF-II/M6P receptor cDNA was amplified and detected by agarose gel electrophoresis from both AM and blood monocytes. The IGF-II/M6P receptor has an intracellular transport role in many cells cycling from the cell surface to the cytoplasm, or binding to phosphorylated acid hydrolases in the Golgi and transporting them to an acidic prelysosomal site where they dissociate and fuse to the lysosomes and IGF-II/M6P recycles to the trans-Golgi. These functions may be particularly important in asbestosis and other interstitial lung diseases where AM are activated, intracellular lysosomes are a prominent morphologic feature, and acid hydrolases are found in recovered lavage fluid.

Asbestos↗
PubMed1990

Basic mechanisms leading to focal emphysema in coal workers' pneumoconiosis.

Coal miners develop focal emphysema characterized by dilatation of second- and third-order respiratory bronchioles with coal mine dust-laden macrophages infiltrating the wall. A reticulin network with small amounts of collagen and atrophy of smooth muscle occurs. To evaluate the mechanisms of lung injury associated with this lesion, 17 long-term non- or ex-smoking West Virginia underground coal miners underwent bronchoalveolar lavage (BAL) and were compared to healthy nonsmoker and smoker controls. The coal miners had evidence of an alveolar macrophage-neutrophil alveolitis with a significant increase in neutrophils/microliter of epithelial lining fluid and an increased gallium lung scan index (206 +/- 26 units). Alveolar macrophages lavaged from coal miners spontaneously released exaggerated amounts of superoxide anion and hydrogen peroxide in vitro compared to nonsmoking controls. Coal workers had significantly elevated levels of neutrophil elastase in BAL fluid complexed with alpha 1-antitrypsin (P less than 0.01) and normal levels of alpha 1-antitrypsin. An accumulation of activated, dust-laden inflammatory cells with increased release of oxidants and elastase may contribute to the development of focal emphysema identified at postmortem in miners with coal workers' pneumoconiosis.

Adult↗
PubMed1990

Persistent lower respiratory tract inflammation associated with interstitial lung disease in patients with tropical pulmonary eosinophilia following conventional treatment with diethylcarbamazine.

Tropical pulmonary eosinophilia (TPE) presents as an acute syndrome with dyspnea, fluffy infiltrates, and rounded opacities on the chest radiograph, reduced lung function, marked eosinophilia in the blood and lower respiratory tract, and high titers of specific IgE and IgG antifilarial antibodies. The standard therapy for TPE is a 3-wk course of diethylcarbamazine (DEC) following which there is almost always a marked improvement in all parameters. However, clinical observations suggest that the disease can persist despite DEC therapy and lead to chronic dyspnea with restrictive lung impairment. To evaluate the concept that DEC therapy is not completely "curative" for TPE, but rather leaves most individuals with a mild, chronic form of TPE defined by persistent inflammation of the lower respiratory tract, we evaluated 23 individuals an average of 12 +/- 2 months following a standard 3-wk course of diethylcarbamazine for acute TPE. In the majority there were mild, persistent symptoms referrable to the lung, chest X-ray abnormalities, blood eosinophilia, and elevated serum IgE and filarial specific IgG. On the average, lung function was consistent with the presence of chronic, mild interstitial lung disease. When the inflammatory cells from the lower respiratory tract were examined, there was a persistent eosinophilic alveolitis (TPE/post-DEC 1769 +/- 376 eosinophils/microliters epithelial lining fluid; normal subjects 256 +/- 38, p less than 0.02). Evaluation of the lower respiratory tract inflammatory cells recovered from the TPE/post-DEC-treated individuals demonstrated spontaneous release of exaggerated amounts of O2-. and H2O2 compared to normal subjects (p less than 0.05, both comparisons).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1989

Morphologic characterization of alveolar macrophages from subjects with occupational exposure to inorganic particles.

Alveolar macrophages recovered by bronchoalveolar lavage from 43 nonsmoking or greater than 5-yr ex-smoking subjects with occupational exposure to inorganic particles (asbestos, n 1/2 19; silica, n 1/2 10; coal, n 1/2 14) were evaluated by light microscopy and transmission and scanning electron microscopy to determine the morphologic changes resulting in these cells from chronic inorganic particulate inhalation. Alveolar macrophages from dust-exposed subjects, including those who had been free of exposure to particles for more than 1 yr, contained particles of higher proportion than did those of normal unexposed subjects. Most of these particles were located within phagolysosomes. The frequency of multinucleated alveolar macrophages was significantly higher in the dust-exposed groups. Ultrastructural studies showed alterations of the morphologic aspects of the surfaces of alveolar macrophages from the dust-exposed subjects, including increased numbers of rufflings, filopodia, pinocytotic vesicles, subplasmalemmal linear densities, and increased frequency of macrophage-macrophage and macrophage-lymphocyte interactions. Furthermore, the numbers of lysosomes were significantly increased in alveolar macrophages from the dust-exposed subjects. Together, these morphologic changes are consistent with the sequelae of phagocytosis, and they emphasize both the role of alveolar macrophages in eliminating inorganic particles from the alveolar spaces and the consequences this role has in alveolar macrophage activation.

Adult↗
PubMed1988

Colchicine suppresses the release of fibroblast growth factors from alveolar macrophages in vitro. The basis of a possible therapeutic approach ot the fibrotic disorders.

Fibrosis is the accumulation of fibroblasts and the connective tissue products secreted by these cells, usually subsequent to tissue injury. While fibrosis can be useful in preserving the general structural integrity of a tissue, it often alters cell-cell and cell-connective tissue interactions, which leads to loss of tissue function. On the basis of the concept that mononuclear phagocytes can direct the development of fibrosis through the release of specific mediators that stimulate fibroblast proliferation, we propose a therapeutic strategy to prevent fibrosis by preventing the release of these specific mediators. The present study demonstrated that colchicine, a widely used and well-tolerated drug, can block alveolar macrophage release of 2 mediators associated with the development of fibrosis in interstitial lung diseases, fibronectin, and the alveolar-macrophage-derived growth factor (AMDGF). Colchicine blocked the spontaneous release of fibronectin by alveolar macrophages obtained from patients with fibrotic lung disease by 23 +/- 4% after 24 h and by greater than 90% after 72 h. AMDGF release was blocked by 68 +/- 10% after 4 h (p less than 0.01, all comparisons). The effect of colchicine was not due to nonspecific toxicity since [14C]proline tracer studies demonstrated that macrophages treated with colchicine were capable of de novo protein synthesis and the secretion of several protein products, despite the fact that fibronectin and AMDGF release were suppressed. The effect of colchicine on the spontaneous release of both fibronectin and AMDGF could be observed at concentrations less than 10 ng/ml, levels that can be achieved in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Colchicine↗
PubMed1988

Alveolar macrophages release an insulin-like growth factor I-type molecule.

Human alveolar macrophages, when activated, release a progression-type growth factor for fibroblasts that signals "competent" fibroblasts to replicate. The present study demonstrates that this growth activity is an insulin-like growth factor I (IGF-I)-type molecule. Partial purification of medium conditioned by activated alveolar macrophages using ion exchange and gel filtration chromatography revealed an IGF-I molecule as detected by an anti-IGF-I polyclonal antibody and that the specific activity of the progression-type growth activity tracked with the amount of IGF-I present. In a serum-free complementation test, the increase in fibroblast proliferation by alveolar macrophage IGF-I was reduced in a dose-response manner with an anti-IGF-I monoclonal antibody. The alveolar macrophage IGF-I displaced 125I-IGF-I from its receptor in a binding assay utilizing human lung fibroblasts and it stimulated type I IGF receptors purified from human lung fibroblasts to phosphorylate a tyrosine-containing artificial substrate. In contrast to the 7.6-kD serum IGF-I, gel chromatography revealed that the alveolar macrophage IGF-I had an apparent molecular mass of 26 kD, similar to other tissue IGF-Is. Alveolar macrophages expressed IGF-I mRNA transcripts as detected by solution hybridization using a 32P-labeled riboprobe complementary to exons I-II-III of the IGF-I gene. In the context of the known functions of the family of IGF-I molecules in cell growth, IGF-I released by activated alveolar macrophages may play a role in acute and chronic inflammatory disorders.

Binding, Competitive↗