Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0034069 (pulmonary fibrosis)
 7,050 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cells that possess the morphology and collagen synthetic capacity of fibroblasts were recovered by bronchofiberscopic subsegmental pulmonary lavage from patients with pulmonary fibrosis, from patients with miscellaneous nonfibrotic lung diseases and from healthy volunteers. Lavage cells were placed in tissue culture, observed for 2 to 6 weeks, and compared with human lavage pulmonary alveolar macrophages (PAM), WI-38 and IMR-90 human fetal lung fibroblasts, and adult lung tissue fibroblasts (CLAC-76). Lavage fibroblsts (LF) were identified as proliferating clones in monolayers of nonproliferating PAM and could be subcultured repeatedly. Fibroglasts were propagated from 28 of the 92 lavage specimens cultured. Time-lapse cinematography showed similar distributions of interdivision times for LF, CLAC-76 and WI-38, but the LF and CLAC-76 lines had slower mean migration rates than the fetal line. Light, scanning, and transmission electron microscopy of LF showed attenuated spindle-shaped cells with interdigitating filopodia, flat surfaces with few microvilli, and containing numerous cytoplasmic polyribosomes and rough endoplasmic reticulum. Extracellular fibrils with the appearance of collagen were seen. Collagen synthesis by LF was measured as 3.9% to 4.9% of the cell-associated protein sensitive to bacterial collagenase. This protein was rich in hydroxyproline, and had an electrophoretic migration pattern identical to known collagen. LF did not contain lysozyme although this enzyme was abundant in fresh and 1-week cultured PAM. Thus LF were similar to human fetal and adult lung tissue fibroblasts in their morphology, tissue culture characteristics, constitutive enzymes and collagen synthetic properties but were distinctly different from PAM.
 ...
PMID:Isolation and characterization of fibroblasts obtained by pulmonary lavage of human subjects. 51 Dec 8

Several experiments have demonstrated low collagenolytic activity during the development of pulmonary fibrosis. In order to determine if fibroblasts play a role in this alteration, procollagenase and tissue inhibitor of metalloproteinases (TIMP) were quantified in fibroblasts derived from 12 human lung specimens (normal = 6, idiopathic pulmonary fibrosis [IPF] = 6). Under basal conditions, three cell strains from normal and three from fibrotic lung specimens did not synthesize collagenase and a similar number of normal and IPF-derived fibroblast strains produced the enzyme. However, the rate of enzyme synthesis among normal and fibrotic collagenase producing fibroblasts exhibited significant differences. Thus, whereas normal fibroblasts produced more than 300 ng/ml, fibrotic lung fibroblasts secreted approximately half of this amount (115 +/- 67 ng/ml). Phorbol myristate acetate (PMA) enhanced collagenase production in all of the 12 lung fibroblast lines tested. In four IPF fibroblasts, PMA increased collagenase secretion close to those of normal stimulated lung fibroblasts; however, a lower induction was observed in cell strains from two fibrotic lung specimens. There was a wide variation in TIMP production both in normal and fibrotic lung fibroblasts, and no statistically significant difference was observed. Under basal conditions, TIMP levels ranged from 329 to 16,911 ng/ml in normal lung cells, and from 377 to 17,557 in fibrotic lung fibroblasts. PMA induced a severalfold increase in all cell lines. These results suggest that there are subpopulations of lung fibroblasts with different potential to produce collagenase and TIMP in vitro, and that the predominance of low collagenase-producing subsets may contribute to the development of fibrosis.
 ...
PMID:Production of collagenase and tissue inhibitor of metalloproteinases by fibroblasts derived from normal and fibrotic human lungs. 139 48

Determinants of pulmonary fibrosis induced by inhaled mineral dusts include quantity retained, particle size, and surface area, together with their physical form and the reactive surface groups presented to alveolar cells. The outstanding problem is to ascertain how these factors exert their deleterious effects. Both compact and fibrous minerals inflict membrane damage, for which chemical mechanisms still leave uncertainty. A major weakness of cytotoxicity studies, even when lipid peroxidation and reactive oxygen species are considered, lies in tacitly assuming that membrane damage suffices to account for fibrogenesis, whereas the parallel occurrence of such manifestations does not necessarily imply causation. The two-phase procedure established that particles, both compact and fibrous, induce release of a macrophage factor that provokes fibroblasts into collagen synthesis. The amino acid composition of the macrophage fibrogenic factor was characterized and its intracellular action explained. Fibrous particles introduce complexities respecting type, durability, and dimensions. Asbestotic fibrosis is believed to depend on long fibers, but scrutiny of the evidence from experimental and human sources reveals that a role for short fibers needs to be entertained. Using the two-phase system, short fibers proved fibrogenic. Other mechanisms, agonistic and antagonistic, may participate. Growth factors may affect the fibroblast population and collagen production, with cytokines such as interleukin-1 and tumor necrosis factor exerting control. Immune involvement is best regarded as an epiphenomenon. Downregulation of fibrogenesis may follow collagenase release from macrophages and fibroblasts, while augmented type II cell secretion of lipid can interfere with the macrophage-particle reaction.
 ...
PMID:Minerals, fibrosis, and the lung. 195 26

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.
 ...
PMID:Fibroblast-alveolar cell interactions in sarcoidosis and idiopathic pulmonary fibrosis: evidence for stimulatory and inhibitory cytokine production by alveolar cells. 219 8

We have investigated the synthesis and matrix deposition of interstitial and basement membrane collagens in a rat model of bleomycin-induced pulmonary fibrosis. Rats weighing 175 to 200 g were injected intratracheally with bleomycin sulfate (1.5 units) or saline. At 10 days, lungs from bleomycin-treated rats showed multifocal interstitial and intraalveolar fibrosis, a nearly 2-fold increase in total lung hydroxyproline, and a 3-fold increase in the incorporation of [3H]proline into bacterial collagenase-sensitive protein. For characterization of the newly synthesized collagens, lung slices were labeled for 4 h with [3H]proline, homogenized in 4.5 M NaCl, and extracted at 4 degrees C with 2 M guanidine-HCl and/or by reduction and alkylation. Extracts contained type IV procollagen, types I, III, and V collagen, and greater than 95% of the nondialyzable [3H]hydroxyproline. At 10 days, bleomycin-treated rats showed a nearly 2-fold decrease in the proportion of type IV in extracts of the 4.5 M salt residue, a greater than 3-fold increase in incorporation of proline into interstitial collagens, and an increase in the ratio of type I to type III collagen. Total incorporation of proline into type IV procollagen was not significantly increased. These results suggest that the period of maximal collagen synthetic activity observed at 1 to 2 wk after bleomycin administration is associated with a selective increase in the synthesis and accumulation of interstitial collagens.
 ...
PMID:Biosynthesis of interstitial and basement membrane collagens in pulmonary fibrosis. 243 38

To study the nature and extent of mast cell heterogeneity within a single species, we have developed methodologies to isolate rat lung mast cells (LMC) and have compared these to peritoneal mast cells (PMC) and intestinal mucosal mast cells (IMMC). In normal and athymic nude (rnu/rnu) rats, a single intratracheal administration of bleomycin (5 U/kg) leads to pulmonary fibrosis accompanied by parenchymal hyperplasia of mast cells that are histochemically like PMC rather than IMMC. Using collagenase digestion of fibrotic rat lungs (30-80 days after bleomycin treatment), we recovered an average of 58.1 x 10(6) viable cells per rat, containing 2.5% mast cells. Control experiments in which PMC were subjected to the isolation procedure used for LMC showed that there was no qualitative effect on PMC, but that a reduction of 26-60% in responsiveness to secretagogues occurred. Isolated LMC secreted histamine in response to 48/80, A23187, substance P, VIP and somatostatin and bradykinin, but at lower levels than PMC. The anti-allergic compound theophylline, which does not inhibit antigen-induced histamine secretion by IMMC, was effective against both LMC and PMC. Taken together, the thymus independence of pulmonary mast cell hyperplasia, the histochemical characteristics and the responsiveness to secretagogues and anti-allergic compounds indicate that the majority of dispersed LMC are similar to PMC rather than to IMMC. Whether LMC should be considered analogous to PMC or, because of their size, histamine content and responsiveness to many secretagogues, intermediate between PMC and IMMC, remains to be determined through additional studies.
 ...
PMID:Isolation and characterization of lung mast cells from rats with bleomycin-induced pulmonary fibrosis. 246 79

Collagen accumulation is a major feature of pulmonary fibrosis and other fibrotic lesions. We have studied the synthesis of collagens in fibroblasts cultured from normal and fibrotic human lung specimens and evaluated how it is affected by transforming growth factor-beta (TGF-beta). Fibroblasts were obtained from normal and fibrotic adult human lungs (n = 11; normal = 6, idiopathic pulmonary fibrosis = 5). They were exposed to TGF-beta and pulse-labeled with [3H]proline and [3H]glycine. Collagen production was measured as bacterial collagenase-susceptible radioactivity, and collagen mRNA levels were determined by a solution hybridization assay using labeled procollagen alpha 1[I] cDNA clone HF677 as probe. Synthesis of collagen types I, III, and V were assessed after separating them by DEAE-cellulose chromatography and SDS-polyacrylamide gel electrophoresis. The results showed that both normal and fibrotic lung fibroblasts synthesized similar amounts of collagen. Type I was the major collagen species synthesized by both normal and fibrotic cell types, and the relative proportion of type I, III, and V collagens was similar in both cell types. TGF-beta caused a two to fourfold increase in stimulation of collagen production and collagen mRNA levels, and no differences were detected in the response of normal and fibrotic lung fibroblasts. All collagen types were stimulated by the TGF-beta. TGF-beta did not increase fibroblast proliferation and the majority of normal and fibrotic lung cells exposed to TGF-beta remained in G1 phase of the cell cycle. We conclude that fibroblasts of normal and fibrotic human synthesize similar amounts of collagens.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Collagen synthesis by normal and fibrotic human lung fibroblasts and the effect of transforming growth factor-beta. 275 Nov 76

In this review we have surveyed recent investigations of early cellular events in pulmonary fibrosis both in animal models and in human diseases. Analysis of the interactions of the numerous cell types in the lung following injury is an almost overwhelmingly complex enterprise. In the animal models experimental design has a profound effect on results, making it difficult to compare studies when species, fibrogenic agent, dose, route of exposure, schedule of administration, time course, and analytical methods may not be equivalent. In human diseases we are rarely able to obtain data at precisely the same time point in the course of the disease even among patients in the same study, and possible confounding variables present are legion. Transcending these difficulties for the moment, can we draw any conclusions from our current knowledge of early cellular interactions in pulmonary fibrosis? What is striking is not that there are so many agents that can potentially induce pulmonary fibrosis, but that the lung has such capabilities for recovery. Although the major effector cells may all initially participate in damaging the lung and initiating fibrosis, there is evidence that they may also have the capacity to participate in subsequent repair. Macrophages may initially recruit fibroblasts and stimulate them to proliferate, only to suppress them subsequently. Macrophage production of prostaglandins can lead to suppression of macrophage, neutrophil and lymphocyte responses, thus attenuating tissue injury and the development of fibrosis. Neutrophils may initially release toxic metabolites and enzymes that damage parenchyma. However, there is evidence that they may later play a role in attenuating fibrosis, perhaps through collagenase secretion, or through as yet unknown mechanisms. Lymphocytes may initially participate in a number of damaging ways by secreting chemoattractants for other cells and participating in destructive autoimmune processes. However, there is evidence that subpopulations of T cells may dramatically shift during the course of fibrosis, leading to attenuation of the process. It may thus be useful to consider irreversible pulmonary fibrosis as the end result of a process in which the balance of normal injury/repair mechanisms is disrupted. There is clearly no single "fibrogenic event." Rather, there seem to be a number of places where disruption of balance/repair processes may begin. In diseases of unknown etiology such as sarcoidosis or IPF, loss of control may occur at the genetic level, leading to the destructive alveolitis that is the apparent precursor of fibrosis.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Early cellular events in pulmonary fibrosis. 352 17

Previous reports have suggested that immune mechanisms are involved in the induction of certain types of pulmonary fibrosis. In this study endotracheal bleomycin was used to induce pulmonary fibrosis in rats, and they were then examined for cellular sensitivity to homologous interstitial collagens isolated from lung. Results indicate that rats treated with bleomycin develop transient cellular sensitivity to homologous collagen. Immunity appears to be selective to type I collagen with minimal response to type III collagen. The kinetics of the development of autoimmunity paralleled the transient increase in collagen synthesis in response to bleomycin treatment. This response was abolished upon prior treatment of the challenging antigen with purified bacterial collagenase, but was resistant to trypsin digestion. This finding confirms the true collagenous nature of the stimulating antigen and eliminates the possibility of a noncollagenous contaminant as the effective agent in the antigen preparation. The data suggest that cellular sensitivity to homologous collagen in response to bleomycin treatment may play a role in the overall fibrotic response.
 ...
PMID:Cellular sensitivity to collagen in bleomycin-treated rats. 618 Nov 64

In the multiple-dose bleomycin-hamster model of pulmonary fibrosis, combined treatment with taurine and niacin blocks the increase in lung collagen deposition. We investigated the effects of taurine and niacin on lung lysyl oxidase and type I collagenase activities in this model. Hamsters were intratracheally instilled with three weekly doses of saline or bleomycin sulfate. Animals were fed either a diet containing 2.5% niacin and 2.5% taurine, or a control diet throughout the experiment. The four groups were saline-instilled with the control diet (BCD), bleomycin-instilled with the diet containing taurine and niacin (BTN), and saline-instilled with the diet containing taurine and niacin (STN). Animals were sacrificed at 1, 4, and 8 weeks after the last bleomycin instillation. Hydroxyproline per lung in the BCD group was significantly elevated by 38, 56, and 60% over the SCD group at 1, 4, and 8 weeks, respectively. Lysyl oxidase activity per lung in the BCD group was significantly elevated by 57.5 and 91.4% over the SCD controls at 1 and 4 week time periods, respectively. Type I collagenase activity per lung in the BCD group was significantly elevated by 65 and 80% over the SCD controls at 1 and 4 weeks, respectively. The combined treatment with taurine and niacin abolished the bleomycin-induced increases in the lung hydroxyproline content and lysyl oxidase and collagenase activities. It was postulated that one of the mechanisms for the antifibrotic effect of taurine and niacin may be the blockage of bleomycin-induced increases in the lung lysyl oxidase and collagenase activities.
 ...
PMID:Mechanism of antifibrotic effect of taurine and niacin in the multidose bleomycin-hamster model of lung fibrosis: inhibition of lysyl oxidase and collagenase. 856 34


1 2 3 Next >>