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Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In bleomycin-induced pulmonary fibrosis, lung injury is accompanied with inflammation and subsequent fibrosis. In this study, lung mRNA for several cytokines was measured in bleomycin-treated mice to evaluate their roles in lung fibrosis. Significant increases in tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta) mRNA were found in lungs of bleomycin-treated responder CBA mice but not in nonresponder BALB/c mice. Increases in responder animals peaked on day 7 after bleomycin administration, and subsequently returned toward control levels. This time course paralleled that for the increase in beta-actin mRNA, but preceded the peak increase in mRNA for collagens I and III. When lung macrophages were analyzed for cytokine secretion, differences were observed between alveolar macrophages and interstitial cells, and between cells from bleomycin-responsive CBA and nonresponsive BALB/c mice. Only alveolar macrophages from CBA mice secreted increased amounts of IL-1. TNF-alpha activity was increased in conditioned media of alveolar and interstitial cells of CBA mice, while only alveolar macrophages of nonresponder BALB/c mice secreted any activity. The kinetics of the increased secretion of TNF-alpha was dissimilar for these different cells. These results are consistent with the conclusion that increased production of TNF-alpha and TGF-beta is an important component of the fibrotic process.
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PMID:Lung cytokine production in bleomycin-induced pulmonary fibrosis. 137 23

As elevated bronchoalveolar lavage (BAL) fluid histamine levels are noted in patients with pulmonary fibrosis (PF), we assayed BAL fluid from 16 patients with PF for the presence of a histamine releasing factor (HRF). HRF activity was assayed by measuring release of the preformed mast cell-derived mediators, histamine, or beta-hexosaminidase (beta-hex) from a purified population of IL-3 dependent mouse bone marrow derived mast cells (MBMMC) or human blood basophils. Mean BAL cell free histamine levels in the patients with PF was 1226 +/- 1349 pg/ml, whereas BAL histamine levels in a comparison group of six non-PF patients was 118 +/- 60 pg/ml. HRF was significantly elevated in BAL fluid of patients with PF (mean beta-hex release 24.5 +/- 12.9%; range 6.8 to 52.4%) compared to the non-PF group of patients (mean beta-hex release 7.9 +/- 7.7%; range 1.8 to 20.7%). The PF HRF not only degranulated MBMMC, but also induced the generation of the arachidonic acid metabolite leukotriene C4 from MBMMC (24.6 +/- 4.2 ng leukotriene C4/10(6) MBMMC). The PF HRF did not appear to be a cytokine previously identified in BAL fluid of patients with PF (i.e., platelet derived growth factor or insulin growth factor-1) or a human cytokine able to degranulate human basophils (i.e., IL-1, or granulocyte-macrophage-CSF) as these recombinant human cytokines did not induce MBMMC beta-hex release. Physicochemical characterization of the HRF revealed that it was relatively heat stable, pronase sensitive and on Sephadex G-75 and G-200 column chromatography had an apparent molecular mass of 30 to 50 kDa. The ability of PF BAL to induce beta-hex release from MBMMC was not dependent on IgE as unsensitized or lactic acid treated MBMMC release similar amounts of beta-hex compared to MBMMC sensitized with IgE. Thus, BAL fluid of patients with PF contains an HRF that induces beta-hex release from MBMMC via an IgE-independent mechanism. The presence of the HRF could explain elevated BAL histamine levels in patients with PF.
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PMID:Mast cells and pulmonary fibrosis. Identification of a histamine releasing factor in bronchoalveolar lavage fluid. 169 11

The purpose of this investigation was to determine whether subpopulations of murine lung fibroblasts produced interleukin 1 (IL 1). We previously identified two major populations of pulmonary fibroblasts based on the presence or absence of Thy-1. Thy-1+ and Thy-1- subsets synthesize fibronectin and type I and III collagen, but only the Thy-1- population displays class II major histocompatibility complex antigens after stimulation with interferon-gamma and presents antigen to T helper clones. Interestingly, in the current study we determined that only Thy-1- fibroblast lines and clones synthesized IL 1. Although constitutive production was low, tumor necrosis factor -alpha (TNF-alpha) stimulated 5-20-fold increases in IL 1 production in Thy-1- fibroblasts. The Thy-1+ fibroblasts did not produce IL 1 even after TNF-alpha treatment. Northern blot analysis of TNF-alpha treated cells revealed that in the Thy-1- subset increased mRNA levels for IL 1 alpha were detected, while IL 1 beta mRNA was not detected. Furthermore, IL 1 activity from TNF-alpha-treated Thy-1- fibroblast membranes and supernatants was completely neutralized by IL 1 alpha-specific antibodies. These observations support the hypothesis that the antigen-presenting Thy-1- subset is important for promoting the inflammation associated with pulmonary fibrosis. In addition, the existence of functional subsets of lung fibroblasts is further substantiated by differential expression of IL 1.
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PMID:Differential expression of interleukin 1 alpha by Thy-1+ and Thy-1- lung fibroblast subpopulations: enhancement of interleukin 1 alpha production by tumor necrosis factor-alpha. 197 21

To better understand how the activity of inflammatory cells collected by bronchoalveolar lavage (BAL) could affect the outcome of granulomatous and fibrotic pulmonary diseases, we studied secretory products and messenger ribonucleic acid (mRNA) expression for certain cytokines of BAL cells in 10 controls, 14 patients with interstitial pulmonary fibrosis (IPF) and 22 patients with sarcoidosis. We assayed the activity of 48 h conditioned media for: 1) their biological action on fibroblast proliferation and prostaglandin E2 (PGE2), collagenase and collagen production by fibroblasts; 2) TNF alpha levels by bioassay and radioimmunoassay; 3) interleukin 1 (IL-1) alpha and beta and beta levels by solid phase enzyme immunoassay (EIA); 4) tumor necrosis factor (TNF) and IL-1 inhibitory activity. We also measured, in freshly isolated BAL cells: 1) mRNA levels for IL-1 alpha and beta and TNF alpha; 2) cell-associated IL-1 alpha and beta by EIA. The only difference found in the assessment of the biological activity of BAL cells conditioned medium was an increase in fibroblast proliferation in sarcoidosis vs IPF patients. The IL-1 alpha and beta, and TNF alpha contents of conditioned media were similar in the three groups. Inhibitory activity against IL-1 and TNF alpha was found in a few patients. Further analysis revealed two peaks of inhibitory activity against IL-1 (20-25 kD and 35-40 kD), as well as a distinct TNF alpha inhibitory activity which could be retained on a TNF alpha-binding affinity column. No mRNA expression for TNF alpha was found in freshly isolated BAL cells, whereas very variable levels of IL-1 alpha and beta mRNA levels were detected in the three groups. Because of these variable results of differences in functional state between freshly isolated and cultured BAL cells, and of the presence of inhibitory substances against IL-1 and TNF alpha, it is unlikely that the development of fibrosis could be ascribed to a single disorder or abnormality.
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PMID:Fibroblast-alveolar cell interactions in sarcoidosis and idiopathic pulmonary fibrosis: evidence for stimulatory and inhibitory cytokine production by alveolar cells. 219 8

Foamy alveolar macrophages (FAM) are observed in lungs injured by Bleomycin (BLM), but their relation to pulmonary fibrosis is not clearly understood. We purified FAM from BLM-instilled rat lungs by density gradient centrifugation on Percoll, and studied the effect of FAM on pulmonary fibrosis. The cells lavaged from the rat lungs 14 days after the administration of BLM (B) or saline (S), were applied on Percoll. After centrifugation, the cells layered on each interface were collected and named as SI, SII, SIII, and BI, BII, BIII in order of gravity. The BI layer included 8.5% of unfractionated cells (U). These BI cells were viable (88%), significantly larger than the others, nonspecific esterase positive cells, and included much ferritin and lysozyme, and were morphologically identified as alveolar macrophages (AM). Therefore, we called the BI cells FAM. We estimated the capacity of FAM (2.5 X 10(5] to synthesize DNA (3H-thymidine uptake) and RNA (3H-uridine uptake), and the activities of silica-stimulated FAM to cause proliferation of mouse thymocytes (IL-1 activity) and rat lung fibroblasts (FP activity), and to produce PGE2. FAM has a lower mitogenic activity but did not have been protein synthetic activity as compared with the others. Silica-stimulated FAM released less IL-1 than BII or BIII, and induced less fibroblast growth than BII, but induced as much as BIII, possibly because of the increased capacity of BIII cells to produce PGE2, which is known to inhibit fibroblast growth. In this way, FAM were considered to be "already activated" rather than "highly activated" cells, but the presence of FAM suggested that smaller or denser AM might receive bleomycin stimulation and release fibrogenic mediators (IL-1 or MDGF) into the alveolar spaces during FAM formation, and that AM might participate in the fibrogenic responses.
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PMID:[The effect of foamy alveolar macrophages presented in bleomycin-injured rat lungs in pulmonary fibrosis]. 247 35

In order to elucidate the mechanism of pulmonary fibrosis development, analysis of bronchoalveolar lavage fluid (BALF), alveolar macrophage function and histological examination were performed in bleomycin (BLM) treated mice and MRL/lpr mice. In the BLM-treated group, swelling of type II alveolar cells, increase of phospholipids and total cell counts in BALF were observed at the early stage following BLM administration. Lysosomal enzyme activities, total protein volume, superoxide production and IL-1 production of alveolar macrophages peaked at the second week after completing BLM administration. In MRL/lpr mice, lymphocytes infiltration in the interstitium, perivascular and peribronchial granuloma formation were observed at 24 weeks old. Analysis of BALF revealed the increase of total cell counts, lymphocyte counts, and fibronectin volume. No significant difference was observed in total protein and phospholipid volume between MRL/lpr mice and MRL/n mice (control mice).
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PMID:[Experimental studies on the pathogenesis and development of interstitial pneumonia and pulmonary fibrosis]. 247 77

Initial studies on mononuclear cell-fibroblast interactions have shown that stimulated human lymphocytes produced a fibroblast growth inhibitory factor and that asbestos, a fibrogenic dust, interferes with this process in vitro. To investigate the role of these interactions in pathologies characterized by pulmonary fibrosis, we used a rat model of asbestos-induced fibrosis. Rats received a single intratracheal instillation of either saline or 10 mg of chrysotile asbestos fibres. Three months after treatment, peripheral blood mononuclear leucocytes (PBML) supernatant fractions were prepared and their effects on lung fibroblast growth measured. As for human PBML, rat PBML stimulated with Concanavalin A (Con A) produced 24 h after initiation of the cultures a soluble factor which inhibits lung fibroblast DNA synthesis and growth in a dose-dependent fashion. By contrast, Con A-stimulated PBML from rats exposed to asbestos failed to produce significant levels of fibroblast growth inhibitory activity. No significant change of total PBML number or in the proportion of circulating mononuclear cell populations was observed. Furthermore, upon stimulation with lipopolysaccharide (LPS), monocytes from asbestotic animals retained their capacity to produce interleukin (IL-1), a mediator required for lymphokine production. Our study demonstrates that suppression of FGIF production by circulating PBML occurs in animals with lung fibrosis and suggests that mechanisms other than impairment of IL-1 production may be responsible for the suppressive effect of asbestos on the production of such fibroblast regulatory lymphokine.
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PMID:Immunoregulation of lung fibroblast growth: alteration in asbestos-induced pulmonary fibrosis. 302 99

Pulmonary fibrosis is characterized by an alteration in lung collagen synthesis and deposition, as well as by increased fibroblast proliferation. It is also characterized by an intermittent influx of immune and inflammatory cells in the lung. To investigate the nature of the target cell in this disorder, we established a series of primary lines of human adult lung fibroblasts and studied the effect of mediators released from activated normal human alveolar macrophages (AM) and peripheral blood monocytes (PBM) on the proliferation of both normal lung fibroblasts and fibroblasts established from lung tissue of patients with active fibrosis. Our data show that monocyte supernatants containing a 15-18 kD monokine from either AM or PBM inhibits growth of logarithmic phase proliferating lung fibroblasts in a dose-dependent manner. This effect can be entirely abrogated by treating the fibroblasts with indomethacin and is reconstituted by adding exogenous PGE2. A study of the kinetics of this interaction shows that exposure to monocyte supernatant for 30 min to 1 hr is sufficient to cause significant inhibition of fibroblast proliferation and that this effect can be halted, but not reversed, at any stage by incubation with indomethacin. We also show that fibroblasts derived from patients with pulmonary fibrosis are affected more quickly by exposure to the mediators, although the final extent of inhibition seen at each concentration of mediators is similar in normal and "fibrotic" fibroblasts. These studies indicate that activated AM or PBM release cytokines (including IL-1) which inhibit the growth of proliferating normal and fibrotic fibroblasts through activation of the intrinsic arachidonic acid pathway of this cell and also that this effect requires a continuous activation of this pathway to be fully expressed.
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PMID:Alveolar macrophage/peripheral blood monocyte-derived factors modulate proliferation of primary lines of human lung fibroblasts. 329 14

Human C5a anaphylatoxin is a potent bioactive molecule that possesses both spasmogenic and leukocyte-related properties. As such, it normally serves as a local mediator of the acute inflammatory response. Additionally, C5a, through its actions of mononuclear phagocytes, may act to bridge the gap in the acute-chronic inflammatory continuum. While these properties are critical to normal host defense mechanisms, it is now apparent that this anaphylatoxin and/or its des-Arg74 derivative, may exert significant systemic effects that are manifest as cardiopulmonary abnormalities and intravascular activation of granulocytes. Knowledge of these properties is critically important for understanding the clinical sequelae exhibited by patients undergoing extracorporeal circulation since we now know that both hemodialysis and cardiopulmonary bypass [28-30] procedures promote intravascular complement activation and C5a formation. Viewed in this context, it seems reasonable to postulate that many of the immediate and delayed responses to extracorporeal circulation might be mediated by C5a formed in the extracorporeal circuit (table IV). For example, it is now recognized that a few particularly susceptible patients display adverse reactions during the initial phases of hemodialysis. The symptoms of this so-called 'first-use syndrome' may range from severe urticaria and angioedema to life-threatening bronchospasm, hypotension, and cardiopulmonary collapse. Some investigators have presented data which suggest that complement-derived products may be causative of these symptoms in some patients [31]. While this hypothesis remains to be confirmed, present evidence clearly demonstrates that C5a alone may produce many of the observed phenomena. In addition to the acute effects produced by C5a, both our own basic studies and the clinical investigations presented by others at this conference suggest that the long-term effects of repeated C5a exposure in the dialyzed patient may be considerable. Thus, there has been a great deal of interest in the role of complement-derived mediators as initiators of leukocyte degranulation and toxic oxygen radical production and an exploration of the significance of these events in the eventual development of chronic pulmonary fibrosis in the dialyzed patient. Similarly, the effects of repeated exposure to IL-1 that has been postulated to occur as a result of C5a triggering of monocytes during dialysis is currently an active area of investigation.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The properties of human C5a anaphylatoxin. The significance of C5a formation during hemodialysis. 332 50

Interleukin 1 secretion from human alveolar macrophages was studied in patients with interstitial pulmonary fibrosis, sarcoidosis, and the acquired immunodeficiency syndrome with pneumonitis and compared to secretion from alveolar macrophages of normal volunteers. Macrophages lavaged from the lungs were stimulated with 10 micrograms/ml of lipopolysaccharide and cultured for 24 hr. In some cases macrophages were also stimulated with 1 microgram/ml lipopolysaccharide. After dialysis of the culture supernatants, interleukin 1 secretion was quantified by the thymocyte proliferation assay and probit analysis and expressed in terms of secretion from 1 million macrophages. Results showed that, on average, macrophages derived from patients secreted more interleukin 1 after stimulation with lipopolysaccharide compared to normal subjects. Mean secretion was significantly greater from macrophages of patients with acquired immunodeficiency syndrome and interstitial pulmonary fibrosis when stimulated with 10 micrograms/ml lipopolysaccharide. Of the 24 individuals studied, spontaneous interleukin 1 secretion was detected from unstimulated macrophages in only 1 patient and 1 normal volunteer. We conclude that alveolar macrophages lavaged from the lungs of patients with inflammatory lung disease have an increased capacity to secrete interleukin 1 on in vitro stimulation with lipopolysaccharide. Possible mechanisms for this increase are discussed.
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PMID:Interleukin 1 secretion from human alveolar macrophages in lung disease. 348 3


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