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)

In the present study the fibrogenic potential of intact bleomycins as well as their acetyldipeptide and terminal polyamine constituents have been assessed. Administration of Blenoxane, bleomycin A2, or bleomycin B2 to rats produced histopathologic evidence of pulmonary fibrosis when tissues were examined 28 days following a single intratracheal dose. These compounds also produced a readily detectable increase in pulmonary collagen synthesis as evidenced by an approximate twofold increase over control values in the formation of [3H]hydroxyproline in an in vitro lung mince system. Lung collagen synthetic activity remained significantly elevated over control values for up to 2 weeks. However, neither the acetyldipeptides nor the polyamine constituents of bleomycin A2 and B2 produced detectable increases in lung collagen synthesis or in histopathologic evidence of pulmonary injury. Spermine and spermidine, the terminal amine components associated with bleomycin-A6 and with tallysomycin A, tallysomycin B, and bleomycin-A5, respectively, did produce significant pulmonary fibrotic injury in rats following intratracheal administration. Out of an extensive series of polyamines, bleomycin acetyldipeptides and intact bleomycin and tallysomycin analogs, only spermine and spermidine were found to produce hydrogen peroxide and acrolein upon incubation in vitro with amine oxidase, a common pulmonary enzyme. Conclusions regarding the relative toxicity of different bleomycin analogs based solely on the toxicity produced by administration of their terminal amine constituent must therefore be made with caution.
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PMID:Fibrogenic structure-activity study of the bleomycin molecule. 619 69

Lysyl oxidase (LOX) is a copper-dependent amine oxidase that plays a critical role in pulmonary fibrosis. Our previous study demonstrated that epithelial-to-mesenchymal transition (EMT) was strongly associated with paraquat (PQ) induced pulmonary fibrosis. This present study was aimed to evaluate the potential involvement of LOX on EMT in the process of pulmonary fibrosis induced by PQ. We established an in vivo rat model and an in vitro cell model induced by PQ treatment and found that LOX protein expression was significantly up-regulated and collagen deposition was enhanced in rats. The EMT process was strongly found in A549 and RLE-6TN cells after PQ exposure. After inactivating LOX with an inhibitor, pulmonary fibrosis was significantly reduced and EMT was also suppressed. Additionally, small interfering RNA (siRNA) targeting LOX was used to silence LOX expression to observe EMT in A549 cells. As a result, LOX could promote the progress of EMT, and inactivating LOX alleviated the EMT process in PQ-induced pulmonary fibrosis and mesenchymal-to-epithelial transition (MET) occurred after inactivating LOX in vitro and in vivo. In conclusion, LOX could promote the progress of EMT and inactivating LOX alleviated EMT in PQ-induced pulmonary fibrosis. Therefore, LOX could potentially be a new candidate therapeutic target for pulmonary fibrosis induced by PQ by regulating the balance between EMT and MET.
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PMID:Lysyl oxidase promotes epithelial-to-mesenchymal transition during paraquat-induced pulmonary fibrosis. 2667 Sep 53

Pulmonary fibrosis is one of the important causes of morbidity and mortality in fibroproliferative disorders such as systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF). Lysyl oxidase (LOX) is a copper-dependent amine oxidase whose primary function is the covalent crosslinking of collagens in the extracellular matrix (ECM). We investigated the role of LOX in the pathophysiology of SSc. LOX mRNA and protein levels were increased in lung fibroblasts of SSc patients compared to healthy controls and IPF patients. In vivo, bleomycin induced LOX mRNA expression in lung tissues, and LOX activity increased in the circulation of mice with pulmonary fibrosis, suggesting that circulating LOX parallels levels in lung tissues. Circulating levels of LOX were reduced upon amelioration of fibrosis with an anti-fibrotic peptide. LOX induced ECM production at the transcriptional levels in lung fibroblasts, in human lungs and human skin maintained in organ culture. In vivo, LOX synergistically exacerbated fibrosis in bleomycin-treated mice. Further, LOX increased the production of IL-6, and the increase was mediated by LOX-induced c-Fos expression, the nuclear localization of c-Fos, and its engagement with the IL-6 promoter region. Our findings demonstrate that LOX expression and activity correlated with fibrosis in vitro, ex vivo, and in vivo. LOX induced ECM production via upregulation of IL-6 and nuclear localization of c-Fos. Our findings suggest that measuring circulating LOX levels and activity can be used for monitoring response to anti-fibrotic therapy. Thus, LOX has a direct pathogenic role in SSc-associated fibrosis that is independent of its crosslinking function.
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PMID:Lysyl Oxidase Directly Contributes to Extracellular Matrix Production and Fibrosis in Systemic Sclerosis. 3302 36