D SScPAH patients is scarce, the results obtainedhere provide valuable exploratory
D SScPAH patients is scarce, the results obtainedhere provide valuable exploratory information. However, they underscore the need for sampling of suitable tissue specimens in these patient groups for future research, also into receptor functionality studies. The majority of the PVOD samples were biopsies, while the samples from the SScPAH and IPAH group were derived from autopsy material. We cannot exclude some influence on results, as there is no knowledge on post-mortem behaviour of the (p)PDGFR-b and PDFG-B. Another influencing factor might be the fact that the biopsy group does not necessarily represent end-stage disease, in contrast to the explanation- and autopsy samples. How do we interpret these results? The pattern of immunoreactivity of PDGFR-b and probably pPDGFR-b in SScPAH, IPAH and PVOD follows the distinctOverbeek et al. Arthritis Research Therapy 2011, 13:R61 http://arthritis-research.com/content/13/2/RPage 11 ofArterioles100 Prevalence ( )Small vesselsVeins0 SScPAH IPAH PVOD Control SScPAH IPAH PVOD Control0 SScPAH IPAH PVOD ControlFigure 8 Number of cases with positive immunostaining for epidermal growth factor receptor (EGFR) in the intima of pulmonary vessels. A: arterioles, B: Small vessels, C: veins) in SScPAH, IPAH, PVOD and normal controls. No staining was observed in the capillaries. Small vessels: those arterioles and/or venules that cannot be distinguished as such by their anatomical localisationpatterns of histomorphologic vasculopathy between these disease groups [20]. The PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/29072704 specific role of PDGFR in SScPAH vascular VorapaxarMedChemExpress Vorapaxar remodeling is further supported by either PDGF or PDGFR autoantibodies [44]. Such antibodies may induce signaling pathways, which eventually may lead to local intimal fibrosis. No differences in the small vessel- and post-capillary vasculature were seen between SScPAH and PVOD. As PVOD-like changes may be seen in SScPAH pulmonary vasculature [19,20] it can be speculated that SScPAH and PVOD share activation of PDGFR-b as a pathophysiologic determinant. The observation of PDGFR-b immunoreactivity, in both affected and non-affected vessels, might be interpreted as pointing towards longstanding pathogenetic involvement. pPDGFR-b and PDGF-B showed immunoreactivity in the pulmonary vasculature of the diseased patient group, with an increased prevalence as compared to controls. This supports the pathogenetic role of the PDGFR-b pathway in PAH. However, this study neither demonstrated clear parallels in staining patterns between PDGFR-b and pPDGFR-b nor PDGFB in the SScPAH group. This might be explained by transactivation of PDGFR-b, resulting in phosphorylation of the PDGFR-b [45]. The extent of involvement of the PDGFR-b- pPDGFR-b-signalling pathway in PAH pathogenesis and whether the role of this pathway is different in SScPAH as in IPAH, will need to be investigated in functional studies. PDGFR-b can be inhibited by imatinib, a TKR inhibitor that also has specificity for the Abl-related gene protein in the tyrosine fusion protein Bcr-Abl and c-kit. The effect of imatinib in SSc pathogenesis might be enhanced by its inhibitory effect on c-Abl, which is important for the induction of extracellular matrix components via TGF-b signaling [46,47]. TGF-b is amongthe most important pro-fibrotic SSc-mediators [67]. This, together with the findings in the present study support the rationale for PDGFR-b targeted therapy in SScPAH. The effects of such therapy might extend to EGFR via transactivation by PDGFR-.

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