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Query: UNIPROT:P06889 (Mol)
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An early proliferative response of mesothelial and subpleural cells has been reported in animals after inhalation or intratracheal (I.T.) instillation to the lung of long asbestos fibers, which also induce pulmonary fibrosis. To determine whether this cell proliferation is directly related to asbestos exposure or is a nonspecific response to injury, we examined [3H]thymidine (3HT) uptake by cells at the pleura after exposing mice to 5 days of hyperoxia, to intravenous (I.V.) (3 mg) or I.T. (0.15 mg) bleomycin, to I.T. (1 mg) silica, and to I.T. (0.1 mg) crocidolite asbestos of mixed length. All exposures induced acute lung injury, as shown by high levels of protein in lavage fluid. After hyperoxia, the percentage of total lung cells labeled by 3HT in autoradiographs was high for only a few days, as repair took place with no increase in fibroblast growth and no subsequent development of fibrosis. Particle or bleomycin exposure induced a prolonged increase in 3HT uptake with enhanced fibroblast labeling over a 4- to 6-wk period. In each case, labeled subpleural cells, mainly fibroblasts, increased up to 10-fold in the first 2 to 4 wk. At the same time, 3HT uptake by mesothelial cells ranged from 1.4 to 3% compared with almost zero in controls and in oxygen-exposed mice after a few days upon return to air. These results indicate that mesothelial and subpleural cell proliferation occurs after various types of injury to the lung. The close temporal association between 3HT uptake by mesothelial cells and fibroblasts during the reparative phase suggests that mesothelial cells may respond to the same cytokines that trigger interstitial fibrosis.
Am J Respir Cell Mol Biol 1994 Mar
PMID:Mesothelial cell proliferation: a nonspecific response to lung injury associated with fibrosis. 750 11

In addition to its procoagulant properties, the serine protease thrombin increases endothelial permeability, stimulates granulocyte adherence, and serves as a fibroblast mitogen. We demonstrate that thrombin is mitogenic for human lung fibroblasts in vitro. The mitogenic effect of thrombin is associated with an increase in the expression of the ligand PDGF-AA and up-regulation of PDGF alpha-receptor. Since scleroderma (systemic sclerosis; SSc) is characterized by widespread microvascular injury and is frequently complicated by pulmonary fibrosis, we sought to determine the level of thrombin activity in bronchoalveolar lavage (BAL) fluid from SSc patients and normal controls. We report a significantly higher level of thrombin activity in BAL fluid from SSc patients compared with normal controls (P < 0.001). Taken together, the high levels of thrombin in BAL fluid and its demonstrated mitogenicity for lung fibroblasts suggest an important role for thrombin in the pathogenesis of SSc and perhaps other fibrotic lung diseases.
Am J Respir Cell Mol Biol 1994 Apr
PMID:Scleroderma bronchoalveolar lavage fluid contains thrombin, a mediator of human lung fibroblast proliferation via induction of platelet-derived growth factor alpha-receptor. 751 Sep 86

Activin A is a homodimeric protein structurally and functionally related to transforming growth factor beta (TGF-beta), and the expression of activin A is modulated by TGF-beta. Here, we demonstrate the expression of activin A in normal and bleomycin (BLM)-treated murine lungs. ICR mice were treated with BLM intraperitoneally for 10 days, whereas saline vehicle was injected into control mice. Intra-alveolar fibrotic changes were observed in the lung tissue obtained from the mice at day 14 after the final BLM administration. Immunohistochemical studies using a polyclonal antibody to activin A revealed the presence of activin A in the bronchiolar epithelium and smooth muscle cells of veins in both control and BLM-treated mice. In the BLM-treated mice at days 7 and 14, the marked infiltration of immunoreactive alveolar macrophages was observed in the area of fibrotic changes. Bioactivity of activin A measured by erythroid differentiation factor assay in the conditioned medium of alveolar macrophages obtained from BLM-treated mice at day 14 was significantly increased. These findings indicate that alveolar macrophages are a potent source of activin A after BLM treatment. The present study demonstrates for the first time the abundant expression of activin A in murine lung tissues after BLM administration, suggesting that activin A may play a role in the pathogenesis of BLM-induced pulmonary fibrosis.
Am J Respir Cell Mol Biol 1995 Jul
PMID:Expression of immunoreactive and bioactive activin A protein in adult murine lung after bleomycin treatment. 754 Dec 20

Evidence suggests that transforming growth factor beta (TGF-beta) may play a central role in a variety of fibroproliferative disorders via the induction of extracellular matrix accumulation. The three mammalian TGF-beta isoforms are present in the normal lung, but very little is known about their expression during lung injury and repair. To more fully understand the role of TGF-beta in lung repair, we investigated the expression of the TGF-beta 1, TGF-beta 2, and TGF-beta 3 isoforms in a bleomycin-induced model of pulmonary fibrosis using immunohistochemical and in situ hybridization techniques. We found expression of the three TGF-beta isoforms, in an identical pattern, widely distributed throughout the normal rat lung: in airways, blood vessels, lung parenchyma, and alveolar macrophages. In general, the distribution of TGF-beta mRNA and protein coincided; however, bronchial epithelial cells were a notable exception, exhibiting immunoreactivity but no mRNA expression. During the "inflammatory" phase (days 1 and 3) of bleomycin-induced injury there was an increase in the mRNA and protein expression of all three TGF-beta isoforms in the injured areas, most prominently in parenchymal cells and alveolar macrophages. There was a further increase in TGF-beta isoform expression in the areas of developing fibrosis during the later reparative phase (days 7 and 14), and the bronchial epithelium, previously not expressing TGF-beta mRNA, showed strong expression of mRNA for the three isoforms concomitant with increased immunoreactivity. These findings implicate the three mammalian TGF-beta isoforms in the dysregulated repair process that results in pulmonary fibrosis. Furthermore, the pattern of TGF-beta mRNA and protein expression by the bronchial epithelium suggests that a transition may occur at this site from a paracrine mode of action in the normal lung to an autocrine mode of action during the "reparative" phase of fibrosis.
Am J Respir Cell Mol Biol 1995 Jul
PMID:Increased expression of transforming growth factor beta isoforms (beta 1, beta 2, beta 3) in bleomycin-induced pulmonary fibrosis. 754 Dec 21

Fibroblasts are the primary proliferating cell type in pulmonary fibrosis. We previously showed that inorganic, fibrogenic particles alter the platelet-derived growth factor (PDGF) receptor system on rat lung fibroblasts (Bonner, J. C., et al. 1993, J. Clin. Invest 92:425-430). In lung fibroblasts, PDGF is the most potent proliferative cytokine, and the responses to PDGF isoforms depend on the relative amounts of two PDGF receptors (PDGF-R alpha and PDGF-R beta). Interleukin 1 beta (IL-1 beta) production by lung macrophages is increased following exposure to fibrogenic particles. We have examined the role of IL-1 beta in regulating the lung fibroblast PDGF receptor system. IL-1 beta induced a 10-fold increase in the number of binding sites for [125I]PDGF-AA, caused a 2-fold increase in affinity of [125I]PDGF-AB, but it had no effect on [125I]PDGF-BB binding. PDGF-R alpha gene expression was increased 5-fold after 4 h of IL-1 beta treatment. IL-1 beta increased the proliferative and chemotactic response to PDGF isoforms in the following order of potency: AA > AB > BB. IL-1 beta was tested for its ability to cause increased [125I]PDGF-AA binding when complexed to its binding protein, alpha 2-macroglobulin (alpha 2M). IL-1 beta bound covalently to fast methyl-amine-activated alpha 2M (alpha 2M-MA). IL-1 beta-alpha 2M-MA or alpha 2M-MA alone possessed minimal activity for inducing an increase in [125I]PDGF-AA binding. However, treatment of the IL-1 beta-alpha 2M complex with thioredoxin, which released bioactive IL-1 beta that was covalently bound to alpha 2M, maximally increased [125I]PDGF-AA binding to the same extent as free IL-1 beta. These results indicate that the fibroblast response to PDGF isoforms is modulated by a complex interaction involving IL-1 beta, alpha 2M, and thioredoxin, all of which are produced in vivo by activated macrophages.
Am J Respir Cell Mol Biol 1995 Oct
PMID:Interleukin 1 beta (IL-1 beta) and the IL-1 beta-alpha 2-macroglobulin complex upregulate the platelet-derived growth factor alpha-receptor on rat pulmonary fibroblasts. 754 76

The transmembrane glycoprotein CD44 represents a family of molecules, all encoded by one gene. The variability of the isoforms is generated by alternative splicing of the nuclear RNA. Apart from the abundant standard form (CD44s), the variant isoforms (CD44v) are mostly restricted to epithelia. The present study demonstrates the expression of CD44s and CD44v isoforms in embryonic and fetal lungs and in normal and pathologically altered (pulmonary fibrosis after radio- or chemotherapy) human adult pulmonary tissues. Using double immunofluorescence and avidin biotin complex (ABC) techniques on paraffin sections, presence of CD44s and CD44v isoforms (CD44v4, CD44v6, CD44v9) has been analyzed. In normal lung tissue, CD44s is present at the cell surface of alveolar macrophages, in some interstitial cells and in epithelial cells. It is also present in epithelial and non-epithelial cells during lung development. CD44v isoforms containing exon v6 and v9 encoded epitopes are selectively detectable in normal epithelial cells with a strong basolateral distribution pattern in the entire population of type II pneumocytes and in basal cells of the bronchial epithelium. During development exon v9 encoded isoforms appear at the pseudoglandular stage, whereas CD44v6 has only been found at the saccular stage. Examination of 12 fibrotic lung samples has revealed major alterations in the CD44 expression in comparison to normal lung tissue. These changes include cytoplasmic deposits of CD44s in alveolar epithelial cells and reduced expression of the CD44v6 and CD44v9 isoforms in alveolar epithelial and bronchial epithelial cells. The results suggest that CD44v isoforms may be utilized by type II pneumocytes in epithelial-mesenchymal interactions and in the maintenance of the pulmonary histoarchitecture.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1995 Dec
PMID:Distinct expression patterns of CD44 isoforms during human lung development and in pulmonary fibrosis. 757 2

Using a well-characterized model of bleomycin-induced pulmonary fibrosis in the rat, we determined that there was a time-dependent elaboration of monocyte chemotactic activity in bronchoalveolar lavage fluid. Northern hybridization analysis revealed markedly increased expression of rat monocyte chemoattractant protein-1 (MCP-1) mRNA in alveolar macrophages (AMs) from rats following induction of pulmonary fibrosis. Monocyte chemotactic activity was also significantly increased in conditioned media from AMs retrieved from injured rat lungs. These data suggest that one important role of AMs in the pathogenesis of chronic inflammatory lung injury and pulmonary fibrosis is the regulation of monocyte recruitment and activation within the lung secondary to secretion of monocyte chemoattractants including MCP-1.
Am J Respir Cell Mol Biol 1993 Sep
PMID:Expression of monocyte chemoattractant protein-1 (MCP-1) by rat alveolar macrophages during chronic lung injury. 769 Nov 8

We have investigated the mitogenic and chemotactic role of platelet-derived growth factor (PDGF) in pulmonary fibrogenesis induced by chrysotile asbestos. Since fibroblasts phagocytize asbestos in the lung interstitium, we have sought to learn whether the fibers alter the production of PDGF-like molecules by rat lung fibroblasts or induce mitogenesis of these fibroblasts in vitro. Conditioned medium as well as cell lysates from fibroblasts exposed to asbestos contained approximately 4-fold more PDGF than unexposed cells as detected by Western blot. Two distinct molecular weight forms of PDGF (36 and 18 kD) were detected by Western blotting. We postulate that these PDGF-like molecules are homologues of human PDGF-AA since we could not detect any PDGF in a sensitive enzyme immunoassay that recognized only PDGF-BB and PDGF-AB. Furthermore, PDGF-A chain mRNA was readily detected by Northern analysis, whereas PDGF-B chain mRNA was not detected by conventional Northern analysis. However, message amplification using a reverse transcriptase polymerase chain reaction allowed detection of the B-chain message. A significant dose-dependent mitogenic effect of asbestos was found by using both a cell proliferation assay and nuclear labeling with bromodeoxyuridine when fibroblasts were exposed under serum-free conditions. This mitogenesis induced directly by asbestos was blocked almost entirely with an anti-PDGF antibody that neutralized all three PDGF isoforms. Thus, these data support our hypothesis that an autocrine loop for PDGF-AA is operative in vitro following exposure to asbestos in lung fibroblasts, and we suggest that this signaling pathway could be significant in the pathogenesis of pulmonary fibrosis.
Am J Respir Cell Mol Biol 1995 Feb
PMID:Chrysotile asbestos stimulates platelet-derived growth factor-AA production by rat lung fibroblasts in vitro: evidence for an autocrine loop. 786 15

Increases in alveolar macrophage (AM) number occur during chronic inflammation and pulmonary fibrosis. Although the underlying mechanism(s) for such increases remain poorly understood, the overall process is known to involve the local proliferation of the AM. In the present study, we report that AM lavaged from the lungs of rats and mice proliferate in vitro when grown atop lung fibroblasts (LF) or when they are cultured in the presence of LF-conditioned media. Using murine AM and LF, we additionally show that the LF-derived mitogenic cytokines for the AM are macrophage colony-stimulating factor (M-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF). Our findings suggest that LF, via the production of M-CSF and GM-CSF, may play an important role in regulating the size of the AM population during chronic inflammatory/fibrogenic lung disorders, and that the complex cytokine network that results in pulmonary fibrogenesis may involve a "coupled reciprocity" between the lung's AM and LF.
Am J Respir Cell Mol Biol 1994 Oct
PMID:Stimulation of rat and murine alveolar macrophage proliferation by lung fibroblasts. 791 6

Pulmonary fibrosis is a major cause of morbidity and mortality in patients with systemic sclerosis (SSc). The pathogenesis of this condition is poorly understood, but one of the earliest pathologic features is endothelial and epithelial cell injury with subsequent regeneration. Endothelial and epithelial cells can release several mediators, including endothelin-1 (ET-1). In this study, we investigated the levels of ET-1 in bronchoalveolar lavage fluid (BALF) from patients with SSc and assessed the contribution of ET-1 to the fibroblast mitogenic activity induced by these fluids. A total of 26 patients were evaluated and divided into those with evidence of pulmonary fibrosis, assessed by thin-section computed tomography (group I, n = 16), and those with a normal scan (group II, n = 10). BALF from both groups of patients stimulated fibroblast proliferation. Values expressed as median (range) percentage increase above media controls were 25.5% (5.0 to 47.8%) and 27.6% (10.9 to 51.6%) for groups I and II, respectively (P < 0.02 in both cases). Mitogenic activity was inhibited by about 40% in the presence of either a neutralizing antibody to ET-1 or two synthetic ET-1 receptor ligands. Levels of ET-1 in BALF, expressed as medians (range) were 2.90 ng/mg albumin (0.68 to 5.75) in patients with SSc and 1.23 ng/mg albumin (0.84 to 2.0) in control patients (P < 0.02). Furthermore, ET-1 levels in BALF from patients in group II (3.83 ng/mg albumin, range 1.76 to 5.75) were elevated compared with those in group I (2.62 ng/mg albumin, range 0.68 to 3.81; P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1994 Oct
PMID:Increased levels of endothelin-1 in bronchoalveolar lavage fluid from patients with systemic sclerosis contribute to fibroblast mitogenic activity in vitro. 791 11


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