Identification of therapeutic targets for treating fibrotic diseases and cancer remains challenging. Our study aimed to investigate the effects of TGF-β1 and TGF-β3 on myofibroblast differentiation and extracellular matrix deposition in different types of fibroblasts, including normal/dermal, cancer-associated, and scar-derived fibroblasts. When comparing the phenotype and signaling pathways activation we observed extreme heterogeneity of studied markers across different fibroblast populations, even within those isolated from the same tissue. Specifically, the presence of myofibroblast and deposition of extracellular matrix were dependent on the origin of the fibroblasts and the type of treatment they received (TGF-β1 vs. TGF-β3). In parallel, we detected activation of canonical signaling (pSMAD2/3) across all studied fibroblasts, albeit to various extents. Treatment with TGF-β1 and TGF-β3 resulted in the activation of canonical and several non-canonical pathways, including AKT, ERK, and ROCK. Among studied cells, cancer-associated fibroblasts displayed the most heterogenic response to TGF-β1/3 treatments. In general, TGF-β1 demonstrated a more potent activation of signaling pathways compared to TGF-β3, whereas TGF-β3 exhibited rather an inhibitory effect in keloid- and hypertrophic scar-derived fibroblasts suggesting its clinical potential for scar treatment. In summary, our study has implications for comprehending the role of TGF-β signaling in fibroblast biology, fibrotic diseases, and cancer. Future research should focus on unraveling the mechanisms beyond differential fibroblast responses to TGF-β isomers considering inherent fibroblast heterogeneity.
- MeSH
- fibroblasty metabolismus MeSH
- hojení ran MeSH
- jizva hypertrofická * metabolismus patologie MeSH
- karcinogeneze metabolismus patologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- nádorová transformace buněk metabolismus MeSH
- protein - isoformy metabolismus MeSH
- transformující růstový faktor beta metabolismus MeSH
- transformující růstový faktor beta1 * farmakologie metabolismus MeSH
- transformující růstový faktor beta3 metabolismus farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: In sarcoidosis, the direction and intensity of immunological reactions involved in disease pathophysiology is affected by variation in the genes coding for effector and regulatory molecules with immune functions. This study, therefore, investigates polymorphic variants in genes involved in inflammation, immune reactions, and granuloma formation in context of their plausible association with sarcoidosis, with specific focus on Greek population. METHODS: A total of 18 single-nucleotide polymorphisms (SNPs) were genotyped in Greek patients with pulmonary sarcoidosis (n = 103) and in healthy Greek control subjects (n = 100) using multiplexed MassARRAY (MassARRAY ®) iPLEX assay based on MALDI-TOF mass spectrometry. RESULTS: TGF-β3 rs3917200*G variant was associated with sarcoidosis (OR: 3.04 [95% CI: 1.98-4.69], p = 2.76*10-7). Further, ANXA11 rs1049550*A variant was associated with sarcoidosis (OR: 0.59 [0.39-0.89], p = 0.01). CONCLUSIONS: This first study of genetic variation of immune-related genes in Greek patients with sarcoidosis brings to attention a novel disease 'susceptibility' factor: TGF-β3 rs3917200*G allele. It also confirms previously reported 'protective' association between sarcoidosis and functional variant ANXA11 rs1049550*A. Further work is required to validate these findings and to expand investigation of their plausible relationship with clinical course of the disease.
- MeSH
- alely MeSH
- annexiny genetika MeSH
- běloši genetika MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- genotypizační techniky MeSH
- jednonukleotidový polymorfismus * MeSH
- lidé středního věku MeSH
- lidé MeSH
- plicní sarkoidóza genetika metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- transformující růstový faktor beta3 genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Řecko MeSH
Plicní fibróza a emfyzém byly donedávna popisovány jako dvě zcela odlišné entity, které nemají patogeneticky nic společného. V posledních 20 letech byl však opakovaně popsán kombinovaný syndrom fibrózy a emfyzému (CPFE), kde jsou zastoupeny oba dva patologické obrazy současně a vytvářejí tak klinický, funkční a morfologický fenotyp odpovídající kombinaci obou nemocí. Pravděpodobným společným jmenovatelem v patogenezi těchto nemocí je cytokin ovlivňující hojení a fibrogenezi – transformující růstový faktor beta (TGF-ß). TGF-ß zřejmě ovlivňuje i mechanismu přechodu epiteliálních buněk v buňky mesenchymové (EMT) a komunikaci mezi těmito buňkami (EMC), což jsou hlavní mechanismy vzniku difúzních změn plicního intersticia, ať už ve smyslu fibrózy, nebo emfyzému. Klinicky existuje několik forem CPFE dle poměru a rozložení fibrózních a emfyzémových změn. Prognóza nemocných je nedobrá navzdory léčbě, i když je pravděpodobně lepší než u pacientů s idiopatickou plicní fibrózou.
Pulmonary fibrosis and emphysema have been considered as two entirely different groups of diseases. In spite of this, combined pulmonary fibrosis and emphysema (CPFE) syndrome, where the two pathologic phenotypes (fibrosis and emphysema) are described in one patient, has been repeatedly described in past 20 years. The clinical, functional and morphologic phenotype corresponds to both diseases in combination. Probable common pathogenetic feature of emphysema and fibrosis is transforming growth factor beta (TGF-ß), the cytokine that plays a crucial role in process of healing and fibrogenesis. TGF-ß is likely to influence the mechanism of epithelial- mesenchymal transdifferentiation (EMT) and even epithelial- mesenchymal crosstalk (EMC), that are the main pathogenetic mechanisms of diffuse interstitial lung diseases, both fibrosis and emphysema. From the clinical point of view, few forms of CPFE exist, according to emphysema and fibrosis ratio and mutual position. CPFE patient’s prognosis is unfavourable despite treatment, but probably better then in isolated idiopathic pulmonary fibrosis.
- MeSH
- cytokiny MeSH
- financování organizované MeSH
- laboratorní medicína MeSH
- lidé MeSH
- plicní emfyzém komplikace MeSH
- plicní fibróza komplikace MeSH
- transformující růstový faktor beta3 MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH