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

Pulmonary fibrosis can be observed as an end state in a number of chronic inflammatory pulmonary diseases. Although the mechanisms by which lung fibrosis develops are not fully ascertained, recent findings suggest that oxidative stress may play an important role in the pathogenesis of tissue fibrosis affecting apoptosis of both structural and inflammatory cells and altering the cytokine microenvironment balance. Damage and alteration of alveolar epithelial cells is one of the hallmarks of interstitial lung fibrosis. Recently, it has been demonstrated that the presence of oxidative stress may lead to the damage, activation and/or apoptosis of alveolar epithelial cells either directly, through an imbalanced intracellular redox equilibrium, or indirectly, by activating redox-sensitive effector pathways, such as transcription factors and angiotensin converting enzyme, increasing the conversion of angiotensinogen into angiotensin II that can be considered a mediator of oxidative stress, capable of inducing apoptosis. Furthermore, it has been demonstrated that angiotensin II acts as a proinflammatory cytokine and is effective in activating fibroblasts through the release of transforming growth factor (TGF-beta). As well as activation, differentiation, proliferation and apoptosis of fibroblasts seem related to the oxidant/antioxidant balance, and the maintenance of a high intracellular level of reduced glutathione (GSH) is considered crucial in providing a reducing environment within the cell, able to protect against oxidative stress. In those conditions where oxidants, either inhaled or produced by inflammatory cell, increase, the ratio between GSH and oxidized glutathione (GSSH) may lower, influencing a variety of cellular redox-sensitive signaling processes such as the activation of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) that lead to a transcriptional up-regulation of a number of genes involved in inflammation and/or fibrogenesis, including cytokines [interleukin (IL)-1,, tumor necrosis factor (TNF-alpha), IL-6] chemokines (IL-8), adhesion molecules (VCAM-1, ICAM-1) and growth factors (GM-CSF). In addition, several studies have shown that oxidative stress may also affect the immune response by inducing an up-regulation of HLA-DR as well as the expression of two costimulatory molecules such as CD40 and CD86, determining a persistent state of immune activation, and affecting the Th1/Th2 balance, modulating the T-cell effector response towards the Th2 phenotype. It is clear that a better understanding of the precise sequence of events that make the difference between normal tissue repair and fibrosis, including the role played by oxidative stress, will certainly improve our therapeutic approach to pulmonary fibrosis.
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PMID:Role of oxidative stress in pulmonary fibrosis. 1261 77

Twenty-five subjects (24 males and 1 female, mean age 57.4 years) who have been exposed to asbestos underwent chest radiography, high resolution computed tomography (HRCT) of the chest, lung function tests and bronchoalveolar lavage (BAL) for evaluation of cell components (total cell count, percentages of macrophages, lymphocytes, neutrophil and eosinophil granulocytes and the lymphocyte subpopulations CD3+, CD4+, CD8+, CD19+ and HLADR+), soluble factors (IL-8, IL-10, IL-12 and MCP-1 in the supernatant) and concentration of asbestos fibre. The subjects were subdivided according to the degree of their exposure, to the concentration of asbestos fibres in the BAL and to chest X-ray findings using the I.L.O. classification (0/0pl, 0/1 and 1/0 and above). According to the exposure index, we showed statistically significant (p < 0.05) higher lymphocytes percentage in the BAL of subjects with moderate exposure and significantly higher levels of IL-10 (p < 0.05) in the supernatant of subjects showing an absence of asbestos fibres in their BAL. In the group of subjects with a 0/0 and 0/1 radiological profile, the cellular component of the BAL was characterised by a higher percentage of lymphocytes (p < 0.02), whereas a trend toward an increase in the number of neutrophils was noted in subjects with obvious pulmonary fibrosis. The percentage of neutrophils was inversely correlated with some parameters of respiratory function such as vital capacity (p = 0.03) and the partial pressure of oxygen (p = 0.05) in the blood. Investigating the cytokines in the supernatant of the BAL, we found a trend toward lower concentration of IL-10 in the group showing the worst radiological picture (I.L.O. > or = 1/0), and a statistically significant negative correlation between this cytokine and pO2 (p = 0.048). Concerning the other cytokines and chemokines studied (MCP-1, IL-8 and IL-12), no significant differences were found to be associated with the radiological profiles. There were, however, positive correlations between the concentration of IL-8 and the percentage of neutrophils (p = 0.038) and between the concentration of MCP-1 and the percentage of lymphocytes (p = 0.006). A negative relationship between the concentrations of IL-12 and IL-10 has been also observed (p = 0.028). This research allows us to hypothesise that IL-10 may have a pathogenetic role in the evolution of asbestosis.
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PMID:Immunocytological and mineralogical study of bronchoalveolar lavage in a group of subjects exposed to asbestos. 1287 99

In the context of a large-scale molecular epidemiology study, the possible immunomodulatory effects of mineral fibres, in workers occupationally exposed to asbestos, rockwool and glass fibres, were examined. In each plant, 61, 98 and 80 exposed workers and 21, 43 or 36 control clerical subjects, respectively, were recruited. In the case of the asbestos-exposed subjects, an additional town-control group of 49 people was included. Evidence of pulmonary fibrosis was found in 42% of the asbestos-exposed workers, while evidence of pleural fibrosis was found in 24%. The asbestos-exposed cohort had significantly decreased forced vital capacity of lungs as well as forced expiratory volume per first second. Our findings indicate that exposure to all three types of fibres examined modulates to different degrees the immune response. Suppression of T-cell immunity and to a lesser extent, B-cell immunity was found in the case of workers from a former asbestos cement plant, while stimulation of T-cell response was observed in rockwool workers, and stimulation of T- and B-cell response was seen in glass fibre workers. Depression of the percentage of lymphocyte subpopulation of CD 16+56 (natural killer cells) in peripheral blood was found in glass fibre workers. Statistical analysis showed increased levels of proinflammatory cytokines (IL-6 asbestos; IL-8 all three fibres), expression of adhesion molecule L-selectin on granulocytes and monocytes (asbestos), levels of soluble adhesion molecules (SAMs) in sera (ICAM-1 all three fibres; E-selectin glass fibres), increased levels of immunoglobulin E (asbestos and rockwool) and elevated expression of activation markers on eosinophils (CD66b asbestos, glass fibres; CD69 asbestos). Significant correlations were observed between lymphocyte proliferation and markers of DNA damage and repair. Increased levels of proinflammatory cytokines, SAMs, immunoglobulin E and elevated expression of activation markers on eosinophils was found in people with symptoms of hypersensitivity and an elevated inflammatory status.
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PMID:Immunomodulatory effects of mineral fibres in occupationally exposed workers. 1528 38

To investigate the effect of signal transducers and activators of transcription 1 (STAT1) antisense oligonucleotides (ASON) on concentrations of TNF-alpha, IL-8, NO secreted by alveolar macrophages (AMs) in bleomycin-induced rat pulmonary fibrosis, five adult female Wistar rats were intratracheally instilled with bleomycin. After 7 days, the rats were killed by right ventricle of heart exsanguinations under ketamine anaesthesia and bronchoalveolar lavage (BAL) was performed to obtain AMs. AMs were divided into four groups, treated with STAT1 ASON, STAT1 sense oligonucleotides (SON), dexamethasone (DEX) and medium alone (control), respectively. AMs and media were collected after culture for 36 h. The mRNA and protein expressions of STAT1 and ICAM-1 in AMs were detected by RT-PCR and ELISA, respectively. The concentrations of TNF-alpha, IL-8, NO in cultured medium were detected. The STAT1 mRNA expression by AMs in the STAT1 ASON group was lower than those of AMs in the STAT1 SON group, the DEX group and the control group (p<0.05). Moreover, the STAT1 mRNA expression by AMs in the DEX group was also lower than those of AMs in the STAT1 SON group and the control group (p<0.05), but the STAT1 mRNA expression by AMs in the STAT1 SON group was not different from that of the control group (p>0.05). The protein expressions of STAT1 and ICAM-1 and the mRNA expression of ICAM-1 showed similar changes to the STAT1 mRNA expression by AMs. The concentrations of TNF-alpha, IL-8, NO in cultured medium from STAT1 ASON group were lower than those from STAT1 SON, DEX and the control groups (p<0.05). Moreover, the concentrations of TNF-alpha, IL-8, NO in cultured medium from DEX group were also lower than those from the control and STAT1 SON group (p<0.05), but no difference between STAT1 SON group and the control (p>0.05). The results suggest that STAT1 ASON could inhibit the secretion of TNF-alpha, IL-8, NO in AMs, and STAT1 could become a target of treating pulmonary fibrosis.
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PMID:STAT1 antisense oligonucleotides attenuate the proinflammatory cytokine release of alveolar macrophages in bleomycin-induced fibrosis. 1621 89

Angiogenesis is a feature of chronic lung diseases such as asthma and pulmonary fibrosis; however, the pathways controlling pathological angiogenesis during lung disease are not completely understood. Adenosine is a signaling molecule that has been implicated in the exacerbation of chronic lung disease and in the regulation of angiogenesis; however, the relationship between these factors has not been investigated. The current study utilized adenosine deaminase (ADA)-deficient mice to determine whether chronic elevations in adenosine in vivo result in pulmonary angiogenesis. Results demonstrate substantial angiogenesis in the tracheas of ADA-deficient mice in association with adenosine elevations. ADA replacement enzyme therapy resulted in a lowering of adenosine levels and reversal of tracheal angiogenesis, indicating that the increases in vessel number are dependent on adenosine elevations. Levels of the angiogenic chemokine CXCL1 (mouse functional homologue of human IL-8) were found to be elevated in an adenosine-dependent manner in the lungs of ADA-deficient mice. Neutralization of CXCL1 and its receptor, CXCR2, resulted in the inhibition of angiogenic activity, which suggests that CXCL1 signaling through the CXCR2 receptor mediated the observed increases in angiogenesis. Our findings suggest that adenosine plays an important role, via CXCL1, in the induction of pulmonary angiogenesis.
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PMID:Enhanced CXCL1 production and angiogenesis in adenosine-mediated lung disease. 1722 50

The objective of this article was to show the role of cytokines in the pathogenesis of pulmonary fibrosis due to sulfur mustard gas inhalation. Eighteen veterans with mustard gas-induced pulmonary fibrosis and 18 normal patients were used as controls. Bronchoalveolar larvage (BAL) and analyses of BAL fluids for cellular and cytokine levels were performed. There was a significant difference in granulocyte colony stimulating factor (G-CSF) level in the BAL fluid of patients and the controls (p < 0.0001). Granulocyte-macrophage colony stimulating pulmonary fibrosis (GM-CSF) BAL levels were significantly increased in patients with pulmonary fibrosis (PF) in comparison with controls (p < 0.0001). Patients with PF have highly significant increases in IL-8 level compared to controls (87.94 +/- 59.63 vs. 8.66 +/- 6.97 g/mL(1); p < 0.0001) as well. IL-8 and G-CSF levels in BAL fluid correlate only with the percentage and the absolute number of neutrophils of the BAL fluid in patients with PF (p = 0.02/p = 0.01; p = 0.01/p = 0.01; respectively). A significant correlation was found between GM-CSF BAL fluid level and the percentage and the absolute number of the BAL fluid eosinophils (p = 0.04 and p = 0.03). Neutrophils alveolitis, the presence of eosinophils, and higher concentrations of interleukin-8, G-CSF, and GM-CSF in BAL fluid are associated with the development of fibrosis in sulfur mustard victims.
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PMID:Increased granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) levels in BAL fluid from patients with sulfur mustard gas-induced pulmonary fibrosis. 1789 41

Peroxisome Proliferator-Activated Receptor gamma (PPARgamma) ligands have the potential for use as anti-inflammatory agents in chronic airway diseases. We hypothesized that cigarette smoke (CS)-mediated pro-inflammatory cytokine release would be downregulated in the monocyte-macrophage cell line (MonoMac6) by synthetic and natural PPARgamma ligands. Surprisingly, treatment of MonoMac6 cells with the natural PPARgamma ligand 15-deoxy-Delta12,14-prostaglandin J2 led to increased cytokine (IL-8) release in response to either TNF-alpha or CS extract (CSE). However, exposure to rosiglitazone, a synthetic agonist, led to decreased TNF-alpha, but not CSE, mediated cytokine release. Cytokine release correlated with nuclear PPARgamma localization; CSE reduced the amount of activated PPARgamma located in the nucleus and formed aldehyde adducts as PPARgamma protein carbonyls. Furthermore, it was shown that PPARgamma interacts with the RelA/p65 subunit of NF-kappaB under TNF-alpha exposure conditions, but this interaction was disrupted by CS exposure, suggesting that CS blocks this important anti-inflammatory pathway involving PPARgamma. Thus, these new data show that activation of PPARgamma with natural or synthetic ligands have differential inhibitory effects on CS-mediated pro-inflammatory mediator release. These data have implications in designing therapies for treatment of COPD and pulmonary fibrosis.
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PMID:Rosiglitazone and 15-deoxy-Delta12,14-prostaglandin J2, PPARgamma agonists, differentially regulate cigarette smoke-mediated pro-inflammatory cytokine release in monocytes/macrophages. 1797 Jun 47

Asbestos and benzo(a)pyrene diol epoxide (BPDE) are pulmonary carcinogens with synergistic interaction in causing lung cancer. We used Affymetrix microarrays to study gene modulation in vitro using normal human bronchial epithelial cells exposed to chrysotile asbestos and/or BPDE for 4 or 24 h. Linear models were used to compare treated cells to controls at each time point to identify statistically significant up- or downregulation of genes. Profiles of genes regulated by chrysotile were dominated by cytokines, growth factors, and DNA damage. Profiles of genes with BPDE and chrysotile regulation were correlated with proliferation, DNA damage recognition and nucleotide-excision repair, cytokines, and apoptosis. Chemokines, growth-regulated oncogene-alpha (Gro-alpha, CXCL-1), and IL-8, were significantly increased, and these had previously been observed in bronchoalveolar lavage from asbestos workers or in animal models. Interestingly, the Hermansky-Pudlak gene, which is mutated in an autosomal recessive form of pulmonary fibrosis, was downregulated threefold by BPDE at 4 h. This is an interesting example of gene (Hermansky-Pudlak syndrome) and environment (BPDE) interaction. Transcription factors, including activating transcription factor 3 and Cbp/p300-interacting transactivator, were upregulated by chrysotile. Real Time PCR for IL-8, ATF-3, GADD45B, CXC Ligand 1, and CTGF compared to GAPDH validated microarray findings at 24 h. These in vitro findings in NHBE cells model environment-gene interaction for asbestos and BPDE, highlighting effects of inflammation, fibrosis, proliferation, and DNA damage recognition and repair.
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PMID:Gene profiling of normal human bronchial epithelial cells in response to asbestos and benzo(a)pyrene diol epoxide (BPDE). 1819 26

Pulmonary fibrosis is characterized by chronic inflammation and excessive collagen deposition. Neutrophils are thought to be involved in the pathogenesis of lung fibrosis. We hypothesized that CXCR2-mediated neutrophil recruitment is essential for the cascade of events leading to bleomycin-induced pulmonary fibrosis. CXCL1/KC was detected as early as 6 hours after bleomycin instillation and returned to basal levels after Day 8. Neutrophils were detected in bronchoalveolar lavage and interstitium from 12 hours and peaked at Day 8 after instillation. Treatment with the CXCR2 receptor antagonist, DF2162, reduced airway neutrophil transmigration but led to an increase of neutrophils in lung parenchyma. There was a significant reduction in IL-13, IL-10, CCL5/RANTES, and active transforming growth factor (TGF)-beta(1) levels, but not on IFN-gamma and total TGF-beta(1,) and enhanced granulocyte macrophage-colony-stimulating factor production in DF2162-treated animals. Notably, treatment with the CXCR2 antagonist led to an improvement of the lung pathology and reduced collagen deposition. Using a therapeutic schedule, DF2162 administered from Days 8 to 16 after bleomycin reduced pulmonary fibrosis and levels of active TGF-beta(1) and IL-13. DF2162 treatment reduced bleomycin-induced expression of von Willebrand Factor, a marker of angiogenesis, in the lung. In vitro, DF2162 reduced the angiogenic activity of IL-8 on human umbilical vein endothelial cells. In conclusion, we show that CXCR2 plays an important role in mediating fibrosis after bleomycin instillation. The compound blocks angiogenesis and the production of pro-angiogenic cytokines, and decreases IL-8-induced endothelial cell activation. An effect on neutrophils does not appear to account for the major effects of the blockade of CXCR2 in the system.
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PMID:Role of the chemokine receptor CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis. 1883 37

Mast cells play an essential role in diverse physiological and pathological processes, such as atherosclerosis, malignancy, asthma, pulmonary fibrosis and arthritis, directly interact with bacteria, and appear to play a vital role in host defense against pathogens. Mast cells could be recruited in the inflammatory site, by MCP-1, RANTES and SCF, to selectively secrete proinflammatory molecules; these could include growth factors, histamine, which is mitogenic (H1) and an immunosuppressant (H2), neovascularization agents, such as heparin, IL-8, and VEGF, as well as proteases that could permit new blood vessel formation. Neurogenic inflammation involves vasodilation and plasma protein extravasation in response to neural stimulation. Upon stimulation, sensory neurons release Substance P and other neuropeptides and activate neurokinin-1 receptors leading to plasma protein extravasation from post-capillary venules. Substance P is a neuropeptide that is released from nerve endings in many tissues and plays an important role in immunological and inflammatory states, and it is also a mediator of tissue injury, asthma, arthritis, allergy and autoimmune diseases. SP-positive nerve fibers and mast cell contacts are increased by acute stress in mice leading to dermal mast cell degranulation. VEGF is produced by flammatory cells. IL-33 is the newest inflammatory member of the IL-1 cytokine family and we show here that SP can induce VEGF secretion from mast cells and IL-33 augments the effect of SP in VEGF transcription and translation protein.
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PMID:VEGF, substance P and stress, new aspects: a revisited study. 2084 71

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