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D. Skondra, N. J. O'Connor, A. Jung, A. Veerappan, M. I. Rosenblatt, D. J. D'Amico, R. B. Silver; Mast Cell and Fibroblast Infiltration in Laser-Induced Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2010;51(13):6172.
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Fibrosis and extracellular matrix (ECM) deposition is thought to play a role in the development of choroidal neovascularization (CNV), though the mechanism responsible for this is unknown. Mast cells (MC) are also associated with fibrosis but their role in CNV in not known. Based on our finding that MCs are a source of renin, the rate-limiting enzyme in angiotensin (ANG II) formation, we hypothesized that MC mediators promote fibrosis and dysfunctional ECM synthesis in CNV.
CNV was induced in C57BL/6 mice by laser photocoagulation and eyes were collected at days 3 and 5 post-laser. MC and fibroblast (FB) infiltration was evaluated by immunohistochemistry in cryosections. MCs were stained with avidin conjugated to fluorescein and FBs with an antibody against prolyl-4-hydroxylase, an enzyme involved in collagen production. To study MC mediators on FB proliferation and collagen synthesis, isolated rodent FBs were grown to confluence and exposed to ANG II or histamine. FB counts were performed with a hemacytometer and culture media were assayed for hydroxyproline and pepsin-soluble collagen.
MCs could be identified in the choroid but not in the retinal pigment epithelium layer nor in the retinal layers of non-lasered control eyes and of eyes 3 days post laser. MCs infiltrated the sites of laser injury and surrounding retina as early as day 5 after laser. MC infiltration seen at day 5 correlated with FB activation at the sites of laser injury. Exposure of isolated FBs to ANG II or histamine caused significant proliferation by 148% and 257% respectively (p<0.05). Proliferation was inhibited by the selective ANG II AT1R blocker, EXP3174 by 37% (p<0.05) or pyrilamine, a histamine H1R blocker by 60% (p<0.05). Exposure of FBs to ANG II or histamine increased collagen by 52% and 99% (p<0.001) and hydroxyproline by 90% and 80% respectively (p<0.05).
These data suggest that MCs may play a role in the early stages of laser induced CNV working in tandem with FBs to promote pathologic deposition of collagen.
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