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 proliferation of myofibroblasts is a central feature of pulmonary fibrosis. In this study we have used tyrosine kinase inhibitors of the tyrphostin class to specifically block autophosphorylation of the platelet-derived growth factor receptor (PDGF-R) or epidermal growth factor receptor (EGF-R). AG1296 specifically inhibited autophosphorylation of PDGF-R and blocked PDGF-stimulated [3H]thymidine uptake by rat lung myofibroblasts in vitro. AG1478 was demonstrated as a selective blocker of EGF-R autophosphorylation and inhibited EGF-stimulated DNA synthesis in vitro. In a rat model of pulmonary fibrosis caused by intratracheal instillation of vanadium pentoxide (V2O5), intraperitoneal delivery of 50 mg/kg AG1296 or AG1478 in dimethylsulfoxide 1 hour before V2O5 instillation and again 2 days after instillation reduced the number of epithelial and mesenchymal cells incorporating bromodeoxyuridine (Brdu) by approximately 50% at 3 and 6 days after instillation. V2O5 instillation increased lung hydroxyproline fivefold 15 days after instillation, and AG1296 was more than 90% effective in preventing the increase in hydroxyproline, whereas AG1478 caused a 50% to 60% decrease in V2O5-stimulated hydroxyproline accumulation. These data provide evidence that PDGF and EGF receptor ligands are potent mitogens for collagen-producing mesenchymal cells during pulmonary fibrogenesis, and targeting tyrosine kinase receptors could offer a strategy for the treatment of fibrotic lung diseases.
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PMID:Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. 1039 53

A number of investigators have reported augmented expression of PDGF in lungs with idiopathic pulmonary fibrosis (IPF) or with other types of pulmonary fibrosis. To accomplish such a regulation of PDGF activity, we constructed an expression plasmid of the extracellular domain of PDGF receptor beta chain (XR), which lacks intracellular tyrosine kinase domain and transmembrane portions, and estimated the therapeutic effects of XR gene transfer through the trachea on bleomycin-induced lung fibrosis of C57BL/6 mice using the hemagglutinating virus of Japan(HVJ)-liposome method. The XR gene transfer ameliorated the increases in the wet weight and hydroxyproline content and the histopathologic changes of the lung induced by bleomycin. These findings suggest that PDGF plays a crucial role in the pathogenesis of pulmonary fibrosis, and that XR gene transfer using the HVJ-liposome method may limit the progression of pulmonary fibrosis.
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PMID:In vivo gene transfer of an extracellular domain of platelet-derived growth factor beta receptor by the HVJ-liposome method ameliorates bleomycin-induced pulmonary fibrosis. 1055 98

To explore the mechanism of pulmonary fibrosis by bleomycin and its derivative, peplomycin (PLM), we examined the influence of PLM on signal transduction in human peripheral blood lymphocytes (HL), monocytes (HM) and fibroblasts (HF). Tyrosine phosphorylation of multiple proteins in HL and HM were induced by 0.001 to 0.05 microg/ml and by 0.01 to 0.5 microg/ml of PLM, respectively. In HF, 116-kDa protein was phosphorylated 0.2 to 5 microg/ml of PLM. When HL were treated with 0.01 microg/ml of PLM, phosphorylation of p56lck and activation of extracellular-signal related kinase-2 (ERK2) were induced. ERK2 was also activated in HM. Coordinately, the ratio of p21ras-binding GTP/GDP was increased by PLM. As well as interleukin-2, PLM induced tyrosine phosphorylation of JAK-3. In addition, PLM upregulated the nuclear translocation of nuclear factor-kappa B and the expression of c-myc-mRNA in HL, HM and HF. Furthermore, 0.01 to 0.001 microg/ml PLM enhanced the cytokine generation by HL and HM, and 1 to 5 microg/ml PLM increased cytokine generation and collagen synthesis by HF. These upregulatory effects of PLM were abrogated by pretreatment of the cells with a tyrosine kinase inhibitor. These results indicate that PLM upregulates signal transduction in a variety of cell types and the upregulation may induce pulmonary fibrosis.
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PMID:The upregulation by peplomycin of signal transduction in human cells. 1167 97

Hepatocyte growth factor (HGF) was purified as a potent mitogen for rat hepatocytes in primary culture and is believed to be the most physiological hepatotrophic factor that triggers liver regeneration. HGF is one of the largest disulfide-linked cytokines, consisting of a 60-kDa heavy chain and a 35-kDa light chain. Human HGF is synthesized as a single polypeptide chain precursor of 728 amino acid residues that has an appreciable homology with plasminogen, and it is processed proteolytically to release an N-terminal signal peptide of 31 amino acids and to generate an active heterodimer after secretion. The novel serine protease HGF activator and urokinase-type plasminogen activator (u-PA) are responsible for the latter extracellular processing. HGF stimulates the proliferation of rat hepatocytes in primary culture at concentrations as low as 10 pM. It also stimulates the growth of various epithelial cells, endothelial cells, and some kinds of mesenchymal cells. HGF inhibits the proliferation of several tumor cell lines and induces apoptosis of some of them. It also has motogenic, morphogenic, anti-apoptotic, angiogenic, and immunoregulatory activities. The receptor of HGF is the product of c-met proto-oncogene with tyrosine kinase activity that mediates the transduction of multiple biological signals of HGF. During liver regeneration, HGF gene expression in the liver, spleen, and lung and HGF levels in the blood and liver increase prior to the induction of liver DNA synthesis. Liver regeneration is markedly inhibited by continuous administration of a neutralizing anti-HGF antibody. HGF production in cultured cells is induced by PKC-activating agents, cAMP-elevating agents, PKA-activating agents, growth factors, and inflammatory cytokines; and it is inhibited by TGF-beta, glucocorticoids, 1,25-dihydroxyvitamin D3, and retinoic acid. There are many reports on potential application of HGF as a therapeutic agent for organ diseases that are difficult to cure such as liver cirrhosis, chronic renal failure, pulmonary fibrosis, myocardial infarction, and arteriosclerosis obliterans utilizing its potent growth-stimulating activity for a wide variety of cells. ELISA kits for assays of serum and plasma HGF levels are clinically used to prognosticate the development of fulminant hepatic failure.
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PMID:[Function and regulation of production of hepatocyte growth factor (HGF)]. 1206 Nov 40

The inappropriate regeneration of sequentially injured epithelium is an important process leading to pulmonary fibrosis. Previous studies have shown that the epithelial expression of epidermal growth factor receptor (EGFR) is increased in fibrotic lung tissue, compared with normal lung tissue, suggesting that EGFR-mediated signaling is involved in epithelial regeneration in fibrotic lung diseases. We examined the effect of EGFR inhibition using ZD1839, a selective EGFR tyrosine kinase inhibitor (TKI), on bleomycin-induced pulmonary fibrosis in mice. ICR mice were administered a single intratracheal injection of bleomycin (5 units/kg) on day 1. ZD1839 (200 mg/kg) or vehicle alone were administered p.o. 1 h before this injection and on days 1-5 each week for 3 weeks. Lung tissue was harvested on day 21. Lung histology and collagen analysis performed on day 21 showed more severe fibrosis in the mice receiving both bleomycin and the EGFR-TKI than in the mice receiving bleomycin and the vehicle. An immunohistochemistry analysis showed that phosphorylated EGFR and proliferation cell nuclear antigen were highly expressed by the regenerated epithelial cells in the mice treated with bleomycin and the vehicle. In contrast, the expression of these antigens was attenuated in the mice treated with bleomycin and the EGFR-TKI. In vitro studies also demonstrated that the addition of ZD1839 at a concentration of < or =1 microM suppressed the proliferation of type II-like epithelial cells (A549) but not that of lung fibroblasts (IMR90). These results suggest that the inhibition of EGFR phosphorylation augments bleomycin-induced pulmonary fibrosis by reducing regenerative epithelial proliferation. Our data suggest that EGFR-TKIs should be used with caution in cancer patients with pulmonary fibrosis.
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PMID:Epidermal growth factor receptor tyrosine kinase inhibition augments a murine model of pulmonary fibrosis. 1294 34

Gefitinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, is an effective treatment for patients with non-small cell lung cancer (NSCLC). Some investigators have recently reported several patients complicated by acute lung injury after the initiation of gefitinib administration. In this report, we investigated the efficacy and adverse events during treatment with gefitinib. The subjects of this study were all of the 110 patients with NSCLC who were treated in our hospital and its eight branch hospitals. Patients received gefitinib at a dose of 250 mg once daily. The response rate was 30%. The frequently reported adverse events were skin disorders, gastrointestinal disturbances, liver dysfunction and acute lung injury. Five of the 12 patients who were considered to have suffered acute lung injury died of progressive respiratory failure. Of the nine patients who had pulmonary fibrosis before use of gefitinib, five developed acute lung injury during the treatment. Sera from three of the 12 patients were evaluated and all three showed increases of surfactant protein (SP)-A, SP-D and KL-6. We conclude that gefitinib was clinically useful. However, several patients suffered acute lung injury which could have been caused by gefitinib. A detection system including SP-A, SP-D and KL-6 as prime candidates as markers should be established as promptly as possible. Clinicians should be aware that treatment of NSCLC with gefitinib involves the risk of acute lung injury and therefore careful consideration should be given before deciding whether or not gefitinib is indicated for treatment. Further study is necessary to elucidate the mechanism of acute lung injury by gefitinib.
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PMID:Acute lung injury as an adverse event of gefitinib. 1516 19

Idiopathic pulmonary fibrosis is a progressive and fatal fibrotic disease of the lungs with unclear etiology. Prior efforts to treat idiopathic pulmonary fibrosis that focused on anti-inflammatory therapy have not proven to be effective. Recent insight suggests that the pathogenesis is mediated through foci of dysregulated fibroblasts driven by profibrotic cytokine signaling. TGF-beta and PDGF are 2 of the most potent of these cytokines. In the current study, we investigated the role of TGF-beta-induced fibrosis mediated by activation of the Abelson (Abl) tyrosine kinase. Our data indicate that fibroblasts respond to TGF-beta by stimulating c-Abl kinase activity independently of Smad2/3 phosphorylation or PDGFR activation. Moreover, inhibition of c-Abl by imatinib prevented TGF-beta-induced ECM gene expression, morphologic transformation, and cell proliferation independently of any effect on Smad signaling. Further, using a mouse model of bleomycin-induced pulmonary fibrosis, we found a significant inhibition of lung fibrosis by imatinib. Thus, Abl family members represent common targets for the modulation of profibrotic cytokine signaling.
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PMID:Imatinib mesylate inhibits the profibrogenic activity of TGF-beta and prevents bleomycin-mediated lung fibrosis. 1552 Aug 63

Lung cancer often develops in individuals with pre-existing pulmonary and cardiac pathology. Many of these individuals with pre-existing pathology are also at risk of occupational lung disease. New and worsening symptoms can be secondary to pre-existing pathology, progressive cancer or treatment. Pulmonary toxicity, including interstitial lung disease, following radiotherapy and conventional cytotoxic chemotherapy (e.g. cyclophosphamide, bleomycin), has been recognised for many years. Pulmonary toxicity also occurs with the newer classes of cytotoxic agents, including the deoxycytidine analogue gemcitabine. A small percentage (0.88%) of patients treated with the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib have developed interstitial lung disease. This complication has been reported at a higher frequency in Japanese patients than in US patients (1.9% vs 0.34%, respectively) and in those with pre-existing pulmonary fibrosis. This review discusses the difficulties in both recognition and treatment of gefitinib-associated interstitial lung disease. Symptoms are vague, such as dyspnoea, cough and fever and can be difficult to differentiate from progressive disease, co-existing morbidity and new pulmonary pathology. Diagnosis is, therefore, by rigorous investigation to exclude all other differential diagnoses. Treatment, at present, is supportive and includes discontinuation of gefitinib, oxygen supplementation, high-dose corticosteroids and antibacterials.
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PMID:Interstitial lung disease in lung cancer: separating disease progression from treatment effects. 1569 Dec 21

Imatinib mesylate is a potent and specific tyrosine kinase inhibitor against c-ABL, BCR-ABL, and c-KIT, and has been demonstrated to be highly active in chronic myeloid leukemia and gastrointestinal stromal tumors. We examined the antifibrotic effects of imatinib using a bleomycin-induced lung fibrosis model in mice because imatinib also inhibits tyrosine kinase of platelet-derived growth factor receptors (PDGFRs). Imatinib inhibited the growth of primary murine lung fibroblasts and the autophosphorylation of PDGFR-beta induced by PDGF. Administration of imatinib significantly prevented bleomycin-induced pulmonary fibrosis in mice, partly by reducing the number of mesenchymal cells incorporating bromodeoxyuridine. Analysis of bronchoalveolar lavage cells demonstrated that imatinib did not suppress early inflammation on Days 7 and 14 caused by bleomycin. These results suggest that imatinib has the potential to prevent pulmonary fibrosis by inhibiting the proliferation of mesenchymal cells, and that imatinib might be useful for the treatment of pulmonary fibrosis in humans.
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PMID:Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice. 1573 62

Interstitial lung disease is a rare but serious complication of epidermal growth factor receptor tyrosine kinase inhibitor therapy. Although our understanding of this phenomenon remains incomplete, recently there have been significant insights made into the mechanisms of injury, incidence, risk factors, and its clinical manifestations. Japanese patients appear to be at a higher risk (1.6%-3.5%) than patients in the rest of the world (0.3%), and other risk factors, such as coincident interstitial lung disease, concurrent chemotherapy, previous radiation, preexisting pulmonary fibrosis, and male sex, have been identified. In the majority of cases, the histopathology, the acute and often dramatic clinical presentation, and the radiographic findings resemble acute respiratory distress syndrome. Aside from immediate cessation of the offending agent, the treatment is largely supportive, although corticosteroids appear to be of benefit. The mortality remains high at approximately 30%-50%. We present a review of the incidence, risk factors, clinical manifestations, diagnosis, management, and outcome of this disorder.
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PMID:Interstitial lung disease associated with epidermal growth factor receptor tyrosine kinase inhibitor therapy in non-small-cell lung carcinoma. 1723 88


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