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

We studied the role of macrophages in the process of pulmonary fibrosis, focusing on gene expressions of cytokines. TGF-alpha is a factor which stimulates fibroblasts or endothelial cells to proliferate, by combining to receptors of EGF competitively with EGF in vitro. Total RNA was extracted from alveolar macrophages recovered by bronchoalveolar lavage from patients with idiopathic pulmonary fibrosis or normal healthy volunteers, and the expression of TGF-alpha mRNA was evaluated by Northern analysis. There was no detectable TGF-alpha mRNA in alveolar macrophages from normal healthy volunteers; however, in patients with idiopathic pulmonary fibrosis, a considerable level of mRNA of TGF-alpha could be detected. Using an experimental rat model of alveolitis induced by bleomycin, the expression of TNF-alpha mRNA in alveolar macrophages recovered by BAL was evaluated by Northern analysis. Alveolar macrophages from bleomycin-treated rats expressed a significant level of TNF-alpha mRNA. Both TGF-alpha and TNF-alpha have proliferative activity on fibroblasts, and may have an important role in the process of fibrosis of the lung.
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PMID:[Cytokine gene expression in interstitial lung diseases]. 143 13

A major role of TNF in pulmonary fibrosis is supported by the following evidences obtained from pulmonary fibrosis induced in mice by bleomycin or silica particles; 1) these diseases are associated with a marked and lasting increase of the TNF mRNA within the lung, 2) they can be prevented by a treatment with anti TNF antibody or aggravated by a perfusion of mouse recombinant TNF, 3) an infusion of TNF-alpha can reproduce the alterations observed during pulmonary fibrosis such as growth of fibroblasts, collagen deposition, cell necrosis.
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PMID:Is "tumor necrosis factor" the major effector of pulmonary fibrosis? 171 90

The hapten-immune model for pulmonary fibrosis shows that a specific T-cell-mediated immune response is essential for the induction of a nonresolving fibrosis. Here, we report results from studies that identify soluble factors released by activated T lymphocytes that might mediate long-lasting fibrosis. Pulmonary fibrosis was induced by priming hamsters for contact hypersensitivity responses with an epicutaneous application of 2,4,6-trinitro-1-chlorobenzene (TNCB) in carrier and challenging intratracheally (IT) 5 days later with a single dose of the soluble form of the immunizing hapten. Bronchoalveolar lavage fluid was harvested at various time points after IT challenge and assayed for tumor necrosis factor (TNF) and interleukin-2 (IL-2) bioactivity. After IT challenge with the sensitizing hapten, only the immune animals contained IL-2 activity in the bronchoalveolar lavage fluid. TNF activity was detected in lungs of both immune and nonimmune animals. Interestingly, the TNF activity was significantly higher (P less than 0.05) in nonimmune challenged than in immune challenged animals on day 5. Molecular hybridization studies showed that a similar amount of TNF-alpha mRNA was expressed in adherent cells from both groups. The nonadherent subpopulation of mononuclear cells harvested from challenged-immune animals expressed TNF-beta (lymphotoxin) mRNA. These data show, for the first time, an association of lymphotoxin with the appearance of pulmonary fibrotic disease in an animal model for pulmonary fibrosis. These observations are consistent with the postulates that lymphotoxin and IL-2 participate in the immunopathogenesis of hapten-immune induced pulmonary fibrosis and that TNF-alpha is associated with the healing of the fibrotic process initiated by toxic lung injury.
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PMID:Persistent interleukin-2 activity and molecular evidence for expression of lymphotoxin in the hapten-immune model for pulmonary interstitial fibrosis. 172 91

Intratracheal instillation of bleomycin (0.08 U) or silica (2 mg) to mice leads, after 15 days, to a patchy pulmonary fibrosis associated with a significant increase of the lung hydroxyproline. Since tumour necrosis factor (TNF) seems to be an important mediator in pulmonary fibrosis, we wondered whether this fibrosis might be prevented by a new TNF-alpha antagonist. Infusion of a 55 kD human recombinant soluble TNF receptor rsTNFR-beta, at a rate of 20 micrograms.day-1, prevented the bleomycin/silica induced increase of lung hydroxyproline content, as measured 15 days after instillation. Infusion of rsTNFR-beta was also effective in the treatment of an established fibrosis, i.e. administered 25 or more days after instillation of bleomycin or silica, since it reduced lung collagen content. Recombinant soluble TNFR-beta had no significant influence on the number of cells, mostly macrophages, recovered by bronchoalveolar lavage. The examination of histological sections indicated that the rsTNFR-beta reduced the proportion of areas of damaged lung and, in silicosis, the formation of nodules with a rich collagen content. This study suggests that rsTNFR-beta might be useful in the therapy of pulmonary fibrosis.
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PMID:Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. 801 95

Platelet trapping was explored during the course of bleomycin induced pulmonary fibrosis by the injection of indium-111 labelled platelets and by light and electron microscopy (EM) of the alveolar capillaries. An i.v. injection of bleomycin markedly increased the localization of labelled platelets in the lung (but not in other organs) for about 3 weeks. On day 7 after bleomycin injection, a significant increase in the number of platelets in contact with the alveolar endothelium was seen with EM. Platelet trapping was strongly correlated (P < 0.005) with collagen deposition when examined in mouse strains genetically susceptible (CBA, C57BL/10, BL10 A.2R), or resistant (Balb/c, BL10.D2, BL10.A), to bleomycin induced fibrosis. In addition, several treatments known to decrease bleomycin induced collagen deposition and synthesis, namely administration of antibodies against CD11a, CD11b, TNF-alpha and IL-1ra, also decreased platelet trapping. As evaluated by EM, anti CD11a mAb significantly decreased the number of platelets in contact with the alveolar endothelium. This study indicates that bleomycin induced pulmonary fibrosis is strongly correlated with platelet trapping and that platelets probably interact, via their CD11a, with the CD54 born by the alveolar endothelium.
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PMID:Pulmonary platelet trapping induced by bleomycin: correlation with fibrosis and involvement of the beta 2 integrins. 752 44

The role of bombesin was investigated in the course of the pulmonary inflammation and fibrosis (PF) elicited by the intratracheal (IT) or intravenous (i.v.) administration of bleomycin in mice. Bleomycin-induced alveolitis was associated with an accumulation of cells, presumably macrophages, containing bombesin, as evidenced by immunohistochemistry. Administration of bombesin by an osmotic minipump implanted IP, at a rate of 6 micrograms/h, decreased the lung hydroxyproline evident 15 days after IV or IT administration of bleomycin. In contrast, antibombesin monoclonal antibody 2A11 (mAb) increased the lung hydroxyproline content after IT administration of bleomycin. In addition, the mortality of bleomycin-injected mice was increased by the anti-bombesin mAb. Bombesin administration induced an increase, and anti-bombesin mAb induced a decrease, in the number of macrophages recovered from the bronchoalveolar lavage. Administration of bombesin did not change the mRNA levels of TNF-alpha, TGF-beta, and PDGF, as seen on Northern blots made with the lung RNA. Pulmonary platelet trapping, which was increased by a bleomycin injection, was decreased by an infusion of bombesin as demonstrated by the distribution of 111In-labeled platelets. This study indicates that bombesin act as an inhibitor of the development of pulmonary fibrosis, possibly by decreasing pulmonary platelet trapping.
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PMID:Bombesin down modulates pulmonary fibrosis elicited in mice by bleomycin. 753 40

The murine TNF-alpha gene was expressed under the control of the human surfactant protein SP-C promoter in transgenic mice. A number of the SP-C TNF-alpha mice died at birth or after a few weeks with very severe lung lesions. Surviving mice transmitted a pulmonary disease to their offspring, the severity and evolution of which was related to the level of TNF-alpha mRNA in the lung; TNF-alpha RNA was detected in alveolar epithelium, presumably in type II epithelial cells. In a longitudinal study of two independent mouse lines, pulmonary pathology, at 1-2 mo of age, consisted of a leukocytic alveolitis with a predominance of T lymphocytes. Leukocyte infiltration was associated with endothelial changes and increased levels of mRNA for the endothelial adhesion molecule VCAM-1. In the following months, alveolar spaces enlarged in association with thickening of the alveolar walls due to an accumulation of desmin-containing fibroblasts, collagen fibers, and lymphocytes. Alveolar surfaces were lined by regenerating type II epithelial cells, and alveolar spaces contained desquamating epithelial cells in places. Platelet trapping in the damaged alveolar capillaries was observed. Pulmonary pathology in the SP-C TNF-alpha mice bears a striking resemblance to human idiopathic pulmonary fibrosis, in which increased expression of TNF-alpha in type II epithelial cells has also been noted. These mice provide a valuable animal model for understanding the pathogenesis of pulmonary fibrosis and exploring possible therapeutic approaches.
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PMID:Expression of a tumor necrosis factor-alpha transgene in murine lung causes lymphocytic and fibrosing alveolitis. A mouse model of progressive pulmonary fibrosis. 754 80

The lung macrophage is proposed to be involved in the development of asbestos-induced pulmonary fibrosis. Knowledge of the effects of long-term asbestos exposure on lung macrophage cytokine release should better define the role of the macrophage in fibrogenesis. This study examines the effects of acute in vitro asbestos exposure and chronic in vivo asbestos exposure on human alveolar macrophage cytokine release. As indicators of asbestos-induced macrophage activation, the cellular release of IL-1 beta, TNF-alpha, IL-6, GM-CSF, and PGE2 was measured during a 24-h in vitro culture. Alveolar macrophages from normal volunteers were cultured in vitro with chrysotile asbestos. Of the factors measured, only TNF-alpha was elevated in response to asbestos exposure. Alveolar macrophages from asbestos-exposed individuals were placed into one of two groups based on their exposure history. These two groups were matched for age, smoking history, and diagnosis; none met the criteria for asbestosis. Cells isolated from subjects that had been exposed to asbestos for more than 10 years secreted enhanced basal amounts of IL-1 beta, TNF-alpha, IL-6, and PGE2, while those who had been exposed for less than 10 years did not. The results indicate that while asbestos had minimal acute effects on cytokine production by the human alveolar macrophage, intense, chronic exposure to asbestos leads to the enhanced basal release of significant amounts of several cytokines that have activity for the fibroblast, even in the absence of overt fibrosis.
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PMID:Human alveolar macrophage cytokine release in response to in vitro and in vivo asbestos exposure. 844 Feb 2

Although the pathological patterns of interstitial pneumonia associated with collagen vascular disease (CVD-IP) resemble those of usual interstitial pneumonia in idiopathic interstitial pneumonia (IIP), the clinical features of CVD-IP and IIIP are quite different. We evaluated the differences between these conditions, with regard to the expression of genes in cells obtained by bronchoalveolar lavage. The reverse transcription-polymerase chain reaction was used to measure the levels of mRNA for IL-1 beta, TNF-alpha, IL-8, TGF-beta, PDGF-B, and IGF-1, and no significant differences were found between patients with CVD-IP and those with IIP. However, differential display analysis revealed a fragment that can be considered to have been derived from an unknown gene mRNA, and this was found only in patients with pulmonary fibrosis associated with progressive systemic sclerosis. Expression of specific genes may differentiate CVD-IP from IIP.
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PMID:[Pulmonary manifestation of collagen vascular diseases: role of cytokines in interstitial pneumonia associated with collagen vascular diseases]. 875 19

Despite abundant evidence documenting the importance of TNF-alpha in the pathogenesis of pulmonary fibrosis, its actual role has not been fully elucidated. Recent observations also indicate that eosinophils found in fibrotic lung express elevated levels of cytokines known to be important in lung fibrosis. These findings suggest a possible role for TNF-alpha in eosinophil recruitment and cytokine expression in this disease. To examine this hypothesis, pulmonary fibrosis was induced in mice by endotracheal bleomycin treatment, and separate groups of animals were also treated with either anti-TNF-alpha Ab or control serum. On days 7 and 14 post-bleomycin treatment, lungs were harvested and analyzed for fibrosis, cytokine expression, and eosinophil influx. Anti-TNF-alpha caused a significant reduction in lung fibrosis, as indicated by a reduction in hydroxyproline content, which was accompanied by suppression of lung TGF-beta1, IL-5, and JE mRNA expression. Examination of tissue sections revealed a significant reduction in lung eosinophils and overall cellularity by anti-TNF-alpha treatment without a significant effect on the number of lung macrophages. The number of IL-5-expressing cells was also significantly reduced by anti-TNF-alpha treatment. Since IL-5 is important in eosinophil differentiation, activation, and recruitment, these findings suggest a novel mechanism by which TNF-alpha could mediate pulmonary fibrosis via induction of IL-5-mediated eosinophil recruitment and fibrogenic cytokine production. Since these eosinophil-derived cytokines include JE/monocyte chemotactic factor-1 and TGF-beta1, this cytokine networking orchestrated by TNF-alpha could, in turn, amplify the inflammatory response and drive the progression to fibrosis and end-stage lung disease.
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PMID:TNF-alpha-mediated lung cytokine networking and eosinophil recruitment in pulmonary fibrosis. 899 16


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