leukotriene-b4 and Eye-Injuries

Age-related macular degeneration (AMD), a progressive chronic disease of the central retina, is associated with aging and is a leading cause of blindness worldwide. Here, we demonstrate that leukotriene B4 (LTB4) receptor 1 (BLT1) promotes laser-induced choroidal neovascularization (CNV) in a mouse model for wet-type AMD. CNV was significantly less in BLT1-deficient (BLT1-KO) mice compared with BLT1-WT controls. Expression of several proangiogenic and profibrotic factors was lower in BLT1-KO eyes than in BLT1-WT eyes. LTB4 production in the eyes was substantially increased in the early phase after laser injury. BLT1 was highly expressed in M2 macrophages in vitro and in vivo, and ocular BLT1+ M2 macrophages were increased in the aged eyes after laser injury. Furthermore, M2 macrophages were rapidly attracted by LTB4 and subsequently produced VEGF-A- through BLT1-mediated signaling. Consequently, intravitreal injection of M2 macrophages augmented CNV formation, which was attenuated by BLT1 deficiency. Thus, laser-induced injury to the retina triggered LTB4 production and attracted M2 macrophages via BLT1, leading to development of CNV. A selective BLT1 antagonist (CP105696) and 3 LTB4 inhibitors (zileuton, MK-886, and bestatin) reduced CNV in a dose-dependent manner. CP105696 also inhibited the accumulation of BLT1+ M2 macrophages in the laser-injured eyes of aged mice. Together, these results indicate that the LTB4-BLT1 axis is a potentially novel therapeutic target for CNV of wet-type AMD.

Topics: Animals; Benzopyrans; Carboxylic Acids; Choroidal Neovascularization; Disease Models, Animal; Eye; Eye Injuries; Hydroxyurea; Indoles; Lasers; Leucine; Leukotriene B4; Macrophages; Macular Degeneration; Male; Mice; Mice, Knockout; Neovascularization, Pathologic; Receptors, Leukotriene B4; Signal Transduction

Using radioimmunoassay technique, levels of leukotriene B4 and C4 (LTB4 and LTC4) in the aqueous humor of rabbit eyes were measured following experimental nonpenetrating ocular trauma. Slit lamp examination showed a time-dependent increase of flare, cells, and fibrin in the anterior chamber of the traumatized eyes. Polymorphonuclear (PMN) leukocyte influx into the aqueous humor was not seen at 6 hours but increased significantly in traumatized eyes after 12 hours. No inflammatory cells were observed in control eyes. Histopathologic studies demonstrated injuries of the ciliary body, ruptures of the retina and choroid, with intraocular hemorrhage. LTB4 values peaked at 6 hours, prior to PMN cell infiltration and remained significantly higher than controls, which remained undetectable at all intervals after injury. LTC4 values also peaked by 6 hours in the traumatized eyes. These data demonstrate that elevations in LTB4 and LTC4 are associated with blunt trauma, and this precedes PMN cell infiltration. Leukotrienes may play a role in the early inflammatory response following concussive ocular injuries.

Topics: Animals; Aqueous Humor; Eicosanoic Acids; Eye Injuries; Inflammation; Leukotriene B4; Male; Rabbits; Radioimmunoassay; SRS-A; Wounds, Nonpenetrating