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)

The induction of pulmonary alveolar macrophage (PAM) tissue factor-dependent procoagulant activity is central to the deposition of inflammatory fibrin in the pulmonary alveolus. The presence of enhanced tissue factor activity is often associated with pulmonary fibrin deposition, an important pathogenetic event that can delay resolution of pulmonary inflammation and promote the induction of pulmonary fibrosis. Since tissue factor synthesis induction and activation pathways are potential therapeutic targets for modulation of alveolar macrophage tissue factor (procoagulant) activity, we examined the pathways through which endotoxin lipopolysaccharide (LPS) induces bovine PAM tissue factor-dependent procoagulant activity. PAM procoagulant activity was markedly enhanced to 10 times the levels of freshly isolated PAM after 8 h of culture in the presence of either the protein kinase C (PKC) agonist phorbol 12-myristate 13-acetate (PMA) or LPS. Both LPS-(P less than 0.002) and PMA-induced activity (P less than 0.007) was completely ablated by the PKC inhibitor 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H 7,100 microM) but was unaffected by the cyclic nucleotide-dependent protein kinase inhibitor N-(2-guanidinoethyl)-5-isoquinolinesulfonamide (HA-1004, 100 microM). The arachidonate cyclooxygenase pathway inhibitor phenylbutazone (10(-4) M) had modest effects that were not statistically significant. The unstimulated increase of procoagulant activity in 8-h cultures was unaffected by the same inhibitory modulations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endotoxin-mediated bovine alveolar macrophage procoagulant induction is dependent on protein kinase C activation. 209 May 87

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

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

Current evidence suggests that bleomycin toxicity may be attributable to its DNA degradative activity possibly via generation of free radicals and O2 metabolites as mediators. Since lipopolysaccharide (LPS) has been known to provide protection against O2 toxicity, which is correlated with increased activity of O2 metabolite-detoxifying enzymes, the effect of this agent on bleomycin-induced pulmonary fibrosis was examined. Endotracheal bleomycin administration caused increased lung collagen synthesis. A single intraperitoneal injection of LPS (500 micrograms/kg) at day zero significantly decreased these increases. Total bleomycin-induced lung collagen increase was also significantly reduced. LPS alone had no significant effect on total lung catalase activity. Glutathiione peroxidase activity, however, was significantly decreased by 15.8% compared to untreated animals at 2 days after LPS treatment and remained unchanged at other time points. In addition, superoxide dismutase activity was significantly elevated by 30% above untreated animals only at 14 days after LPS administration and remained unchanged at other time points. Endotracheal bleomycin administration alone caused significant reductions in catalase activity at 2 days and 2 weeks after treatment, whereas glutathione peroxidase activity increased above control untreated animals at 2 and 4 weeks, respectively. Superoxide dismutase activity was unaffected by bleomycin treatment. Pretreatment with LPS before bleomycin prevented these reductions or caused increases in the activities of these enzymes at 2 days. Glutathione peroxidase was increased and was significantly greater than those animals treated with bleomycin alone. Catalase also was higher in the LPS plus bleomycin group (by 22.2%, p less than 0.05) than the bleomycin group alone. Compared to the effects on lung collagen synthesis and content, LPS treatment resulted in much less dramatic changes in total lung antioxidant enzyme activities. This discrepancy between the intensity of LPS effects on lung O2 metabolite-detoxifying enzymes and that on pulmonary fibrosis implies that the LPS-ameliorating effect on pulmonary fibrosis could not be totally explained by increased ability to detoxify O2 metabolites. Rather, the data would favor the possibility that LPS inhibits bleomycin-induced pulmonary fibrosis either by its known immunosuppressive effects or some other unknown mechanism. The former would be in agreement with previous data which suggest that an intact immune response is necessary for complete expression of the fibrogenic response to bleomycin.
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PMID:Inhibition of bleomycin-induced pulmonary fibrosis by lipopolysaccharide. 620 76

Interstitial pneumonia has been reported to be a side effect of treatment with interferon, and Sho-saiko-to (Xiao-Chai-Hu-Tang) may enhance this side effect. It is well known that activated neutrophils are important mediators of pulmonary fibrosis, so we studied the effects of interferon and Sho-saiko-to on neutrophil activation. Homogenized lung myeloperoxidase (MPO) activity was assayed after intraperitoneal injection of interferon with or without pretreatment with Sho-saiko-to. Although Sho-saiko-to alone did not change the lung MPO content, MPO in the lung was significantly increased by interferon administration. The increase was enhanced further by pretreatment with Sho-saiko-to. When the accumulated neutrophils are activated by some cytokines, such as TNF alpha or IL-1 beta from monocytes/macrophages, they may damage lung tissue. We therefore studied the effects of Sho-saiko-to and interferon on TNF alpha production in freshly isolated human monocytes. Sho-saiko-to increased the production of TNF alpha, but interferon did not. In addition, Sho-saiko-to significantly increased the production of TNF alpha by monocytes stimulated by lipopolysaccharide. Taken together, these data indicate that interferon causes neutrophils to accumulate in the lung. Sho-saiko-to alone may not injure lung tissue, but it increases the effect of interferon. When stimulated by some antigen, Sho-saiko-to may overstimulate the neutrophils. Granulocytes elastase and oxygen radicals released from activated neutrophils may damage lung tissue. The fibroblasts that repair the damaged tissue may increase the risk of pulmonary fibrosis.
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PMID:[A possible mechanism of interstitial pneumonia during interferon therapy with sho-saiko-to]. 754 Jun 98

Paraquat (PQ) is a herbicide which is highly pneumotoxic by generating reactive oxygen intermediates (ROI). Pro-inflammatory cytokines, particularly IL-1 and TNF, have been implicated in some ROI-mediated pathologies, including bleomycin toxicity and ischaemia/reperfusion injury. We have studied the effect of PQ on the expression of the neutrophil chemotactic cytokine, IL-8, by human peripheral blood mononuclear cells (PBMC). While almost no IL-8 mRNA was detected in unstimulated cells, PQ (100 microM) induced high mRNA expression with a maximum at 24 h of incubation. While PQ did stimulate the appearance of IL-8 mRNA, no significant production of IL-8 protein was detected. However, PQ potentiated the production of IL-8 in the presence of 1 ng/ml of endotoxin (lipopolysaccharide, LPS). This was paralleled by an increased production of chemotactic activity for neutrophils, indicating that the IL-8 was actually bioactive. Stimulation of IL-8 mRNA by PQ was suppressed by IL-4 and by free radical scavengers (dimethylsulfoxide, mannitol). Increased IL-8 expression by PQ was also observed in the human pulmonary epithelial cell line A549 indicating that the effect of PQ was not specific for PBMC. These findings suggest that IL-8 might be involved in the pulmonary effects of PQ and that its production might be stimulated following an oxidative insult, and might clarify the pathogenetic mechanisms of adult respiratory distress syndrome (ARDS) or oxidant-induced pulmonary fibrosis.
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PMID:The pneumotoxicant paraquat induces IL-8 mRNA in human mononuclear cells and pulmonary epithelial cells. 814 10

Bis-basic ethers of fluorene and fluoren-9-substituted derivatives such as tilorone have been reported to inhibit silica-induced fibrosis in rats. The potential antifibrotic potency of 2,7-bis(diethylamino)ethoxy fluorene (F-9-H,H), fluorenone (F-9-one), fluorenoxime (F-9-oxime), and fluorenol (F-9-ol) was F-9-oxime > F-9-one approximately F-9-H,H >> F-9-ol. Since the release of reactive oxygen species and growth factors from alveolar macrophages (AM) in response to silica exposure has been linked to the development of pulmonary fibrosis, the present study was carried out to determine the inhibitory effects of these compounds on rat AM activity in vitro. The following parameters were monitored: (1) cellular viability; (2) zymosan-induced respiratory burst activity (superoxide and hydrogen peroxide release, chemiluminescence, and oxygen consumption) of AM; (3) drug binding to AM; and (4) lipopolysaccharide (LPS)-stimulated interleukin-1 (IL-1) release from AM. The bis-basic ethers, at 40 microM, did not affect cell viability when incubated with AM for 30 min, but significantly inhibited zymosan-induced macrophage respiratory burst activity. The inhibitory effect of these agents was F-9-oxime > F-9-one approximately F-9-H,H >> F-9-ol. Binding of these drugs to AM was time and dose dependent, and exhibited the following binding affinity: F-9-oxime > F-9-one > F-9-H,H > F-9-ol. F-9-oxime was shown to inhibit LPS-stimulated IL-1 release by AM in a dose-dependent manner. This inhibition of IL-1 release by AM cannot be explained as a decrease in viability. In addition, these drugs were also shown to impair human fibroblast proliferation in response to serum stimuli without impairing cell viability. These results indicate a positive correlation between drug binding to AM or other cell types and their inhibitory effects on cellular activities including oxygen consumption, superoxide release, hydrogen peroxide secretion, chemiluminescence, IL-1 release, and proliferation. The ability of these bis-basic ethers to modify AM and fibroblast functions in vitro suggests that further investigation of their reported antifibrotic potency in vivo is warranted.
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PMID:Modification of alveolar macrophage function with bis-basic ethers of fluorene and fluoren-9-substituted derivatives. 855 93

Various molecules expressed on the surface of platelets have been shown to mediate the protective or deleterious role of these cells in immuno-inflammatory mechanisms. Increasing evidence points to the involvement of the cell adhesion molecules, gpIIb-IIIa, P-selectin, CD31, LFA-1, and CD36 in the interaction between platelets and endothelial cells as well as other cell types. The possible role of these molecules in the ability of platelets to support endothelium and to protect against tumour necrosis factor mediated cytolysis or parasitic invasion are reviewed. The involvement of platelets as effectors of tissue damage in cerebral malaria, lipopolysaccharide induced pathology, and pulmonary fibrosis is also discussed. This has then been extended to include the intercellular mechanisms underpinning their pathogenic role in metastasis, transplant rejection, stroke, brain hypoxia, and related conditions. A better understanding of the complex regulation and hierarchical organisation of these various platelet adhesion molecules may prove useful in the development of new approaches to the treatment of such diseases.
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PMID:Role of platelet adhesion in homeostasis and immunopathology. 935 Mar

To evaluate the contribution of reactive nitrogen species to inflammation by asbestos, Fischer 344 rats were exposed to crocidolite or chrysotile asbestos by inhalation to determine whether increases occurred in nitric oxide (NO.) metabolites from alveolar macrophages (AMs). AMs from animals inhaling asbestos showed significant elevations (p < .05) in nitrite/nitrate levels which were ameliorated by NG-monomethyl-L-arginine (NMMA), an inhibitor of inducible nitric oxide synthase (iNOS) activity. Temporal patterns of NO. generation from AMs correlated with neutrophil influx in bronchoalveolar lavage samples after asbestos inhalation or bleomycin instillation, another model of pulmonary fibrosis. To determine the molecular mechanisms and specificity of iNOS promoter activation by asbestos, RAW 264.7 cells, a murine macrophage-like line, and AMs isolated from control rats were exposed to crocidolite asbestos in vitro. These cells showed increases in steady-state levels of iNOS mRNA in response to asbestos and more dramatic increases in both iNOS mRNA and immunoreactive protein after addition of lipopolysaccharide (LPS). After transfection of an iNOS promoter/luciferase reporter construct, RAW 264.7 cells exposed to LPS, crocidolite asbestos and its nonfibrous analog, riebeckite, revealed increases in luciferase activity whereas cristobalite silica had no effects. Studies suggest that NO. generation may be important in cell injury and inflammation by asbestos.
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PMID:Mechanisms of asbestos-induced nitric oxide production by rat alveolar macrophages in inhalation and in vitro models. 958 8

Although alveolar reorganization after acute lung injury depends on regeneration of alveolar epithelial cells, there is little knowledge of regulation of pulmonary healing process. Transcription factors may play key roles in this regulation. To investigate whether the CCAAT enhancer binding protein (C/EBP) family, alpha, beta, and delta, were involved in alveolar reorganization after injury, we examined expression of C/EBP proteins and mRNAs in lung injuries induced by lipopolysaccharide (LPS) or bleomycin (Bleo) and in cell proliferation by keratinocyte growth factor (KGF). By immunohistochemistry, we demonstrated that C/EBP alpha and C/EBP beta were expressed in alveolar type II cells and alveolar macrophages, but C/EBP delta was expressed restrictedly in some of alveolar type II cells in a spatial pattern in the control lungs. Further, these three C/EBP family members were differentially expressed in alveolar cell proliferation and in acute lung injury, in which, interestingly, C/EBP alpha and C/EBP delta were reciprocally expressed in alveolar type II cell proliferation and in pulmonary fibrosis. However, expressions of their mRNAs by in situ hybridization were dramatically increased in the affected lesions of the lungs by LPS and Bleo, and Northern blot analysis showed an increased abundance of the mRNA for C/EBP beta in LPS-treated lungs and for C/EBP delta in Bleo-treated lungs, compared with those in the control lungs. Thus, differential expression of the C/EBP family may be required to maintain and reorganize the basic integrity of alveolar structure during pathological states, which suggests an important role for the C/EBP family in maintaining normal alveolar architecture and function and in repairing the damaged epithelium after injury.
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PMID:Differential expression of CCAAT enhancer binding protein family in rat alveolar epithelial cell proliferation and in acute lung injury. 1047 Apr 96


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