title: Leukocytes regulate retinal capillary degeneration in the diabetic mouse via generation of leukotrienes.
abstract: Understanding the early pathogenesis of DR may uncover new therapeutic targets to prevent or slow the progression of this sight-threatening disorder. We investigated the role of leukocyte-mediated generation of LTs in regulation of retinal capillary degeneration and inflammation in the diabetic mouse. We generated (1) chimeric mice that lacked the ability to generate LTs by transplanting 5LO-/- bone marrow cells into ND.WT mice and into SD.WT mice and (2) "control" chimeric mice by transplanting WT bone marrow cells into 5LO-/- mice or into WT mice. Retinas from diabetic chimeric mice with WT marrow demonstrated capillary degeneration to the same extent as retinas from diabetic, nonchimeric WT mice. In contrast, retinas from diabetic chimeric mice with 5LO-/- marrow developed significantly less capillary degeneration and pericyte loss (P<0.05). In the retinas from chimeric mice with WT marrow, diabetes induced a rise in leukocyte adherence to the microvasculature, expression of the NF-κB p65 subunit, and ICAM1, superoxide generation, and retinal microvascular permeability, yet these characteristic responses were blunted by >50% in diabetic chimeras containing 5LO-/- leukocytes (P<0.05). Our data suggest the critical involvement of leukocytes and LTs in the regulation of inflammation and capillary degeneration in DR.
authors.affiliation: Rainbow Babies and Children's Hospital, 11100 Euclid Ave., Cleveland, OH 44106, USA.
authors.forename: Ramaprasad
authors.initials: R
authors.lastname: Talahalli
authors.forename: Simona
authors.initials: S
authors.lastname: Zarini
authors.forename: Jie
authors.initials: J
authors.lastname: Tang
authors.forename: Guangyuan
authors.initials: G
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Murphy
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Kern
authors.forename: Rose A
authors.initials: RA
authors.lastname: Gubitosi-Klug
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002196:Capillaries / Q000473:pathology; D003930:Diabetic Retinopathy / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D007962:Leukocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015289:Leukotrienes / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D012160:Retina / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D012171:Retinal Vessels / Q000473:pathology; D018183:Transplantation Chimera
chemical_list: D015289:Leukotrienes