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)

Protease-activated receptors (PAR), which are G protein-coupled receptors, have 4 members, PAR-1 to PAR-4. PARs are activated by proteolysis of a peptide bond at the N-terminal domain of the receptor. PARs are widely distributed throughout the airways. Their activity is modulated by airway proteases of endogenous and exogenous origin, which can either activate or disable the receptors. The regulation of PAR activity by proteases is important under pathological conditions when the activity of proteases is increased. Moreover, various inflammatory mediators, such as cytokines, growth factors, or prostanoids, alter the PAR expression level. Elevated PAR levels are observed in various lung disorders, and their significance in the development of pathological situations in the lung is currently intensively investigated. Consequences of PAR activation can be either beneficial or deleterious, depending on the PAR subtype. PAR-1 has been shown to be an important player in the development of pulmonary fibrosis. Thus, PAR-1 represents an exciting target for clinical intervention in fibrotic diseases. PAR-2 contributes to allergic airway inflammation. However, the question whether the impact of PAR-2 is beneficial or deleterious is still under intensive discussion. Therefore, precise information concerning the participation of PAR-2 in various lesions is required. Moreover, it is necessary to generate selective PAR- and organ-targeted approaches for treating the diseases. A thorough understanding of PAR-induced cellular events and the consequences of receptor blockade may help in the development of novel therapeutic strategies targeted to prevent lung destruction and to avoid deterioration of conditions of patients with inflammatory or fibrotic lung diseases.
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PMID:A novel therapeutic target in various lung diseases: airway proteases and protease-activated receptors. 1753 72

Extravascular activation of the coagulation cascade in the lung is commonly observed in pulmonary fibrosis. Coagulation proteases may exert profibrotic cellular effects via protease-activated receptors (PARs)-1 and -2. Here, we investigated the potential role of two other members of the PAR family, namely PAR-3 and PAR-4, in the pathobiology of lung fibrosis. Elevated expression of PAR-3, but not PAR-4, was detected in the lungs of idiopathic pulmonary fibrosis (IPF) patients and in bleomycin-induced lung fibrosis in mice. Increased PAR-3 expression in fibrotic lungs was mainly attributable to alveolar type II (ATII) cells. Stimulation of primary mouse ATII, MLE15 and A549 cells with thrombin (FIIa) - that may activate PAR-1, PAR-3 and PAR-4 - induced epithelial-mesenchymal transition (EMT), a process that has been suggested to be a possible mechanism underlying the expanded (myo)fibroblast pool in lung fibrosis. EMT was evidenced by morphological alterations, expression changes of epithelial and mesenchymal phenotype markers, and functional changes. Single knockdown of FIIa receptors, PAR-1, PAR-3, or PAR-4, had no major impact on FIIa-induced EMT. Simultaneous depletion of PAR-1 and PAR-3, however, almost completely inhibited this process, whereas only a partial effect on FIIa-mediated EMT was observed when PAR-1 and PAR-4, or PAR-3 and PAR-4 were knocked down. PAR-1 and PAR-3 co-localise within ATII cells with both being predominantely plasma membrane associated. In conclusion, our study indicates that PARs synergise to mediate FIIa-induced EMT and provides first evidence that PAR-3 via its ability to potentiate FIIa-triggered EMT could potentially contribute to the pathogenesis of pulmonary fibrosis.
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PMID:Protease-activated receptors (PAR)-1 and -3 drive epithelial-mesenchymal transition of alveolar epithelial cells - potential role in lung fibrosis. 2373 22