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Sandeep Kumar, Alex Jones, Shixian Wang, Zachary Berriochoa, Yingbin Fu; Inflammation plays an important role in the pathogenesis of Polypoidal Choroidal Vasculopathy . Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):4196.
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© ARVO (1962-2015); The Authors (2016-present)
Polypoidal choroidal vasculopathy (PCV) is a variant of wet Age-related macular degeneration (AMD). The etiology and pathogenesis of PCV are largely unknown. Recently, we have generated a PCV mouse model (Tg44) by expressing human HTRA1 in mouse RPE. In vivo imaging showed that Tg44 mice exhibit a rich spectrum of “clinical” features (e.g. polyps, branching vascular networks, late geographic hyperfluorescence, pigment epithelium detachment) that closely mimic human PCV. We have shown previously that HTRA1 mediated degradation of extracellular matrix proteins in the RPE-choroid region is responsible for PCV initiation. The purpose of this study is to examine the role of inflammation in PCV pathogenesis using our Tg44 mice.
We compared the degradation of a vessel wall protein (alpha smooth muscle actin, αSMA), activation of the complement and JNK pathways by western blot in RPE/choroid lysate of Tg44, Tg33 (express protease inactive HTRA1-S328A and WT mice. We also analyzed the levels of pro-inflammatory cytokines in RPE/choroid lysate of different mouse lines by multiplex assays. Immunohistochemistry (IHC), histology and electron microscopy (EM) were performed on isolated PCV lesions from Tg44 mice. Student’s t-test was used for statistical analysis.
By western blot, the level of αSMA was degraded 1.8 times (p<0.05) in Tg44 compare to that in both Tg33 and WT. IFNγ and IL6 levels in Tg44 with severe PCV were ~2 and ~3 times higher, respectively, than those of Tg44 (weak PCV) and WT (p<0.001) while there was no significant difference between Tg44 (weak PCV) and WT. IHC, histology and EM of severe PCV lesions in Tg44 showed infiltration of inflammatory cells (e.g. macrophages and neutrophils), deposition of exudative serum proteins, deposition of degraded collagen and αSMA, degeneration of elastic layers in Bruch’s membrane and choroid vessel wall, hyalinized vessels, degenerated photoreceptors and RPE. The level of pJNK1 in Tg44 was 2.83 and 3.73 times (p<0.05) higher than that in both Tg33 and WT, respectively. The level of C5b-9 membrane attack complex in Tg44 was 4.5 times (p<0.05) higher than that in WT.
The increase of inflammatory cytokines, infiltration of inflammatory cells in severe PCV lesion areas, activation of JNK and complement pathways in PCV tissues suggest that inflammation plays a key role in PCV progression.
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