A central role for inflammation in the pathogenesis of diabetic retinopathy.
Diabetic retinopathy is a leading cause of adult vision loss and blindness. Much of the retinal damage that characterizes the disease results from retinal vascular leakage and nonperfusion. Diabetic retinal vascular leakage, capillary nonperfusion, and endothelial cell damage are temporary and spatially associated with retinal leukocyte stasis in early experimental diabetes. Retinal leukostasis increases within days of developing diabetes and correlates with the increased expression of retinal intercellular adhesion molecule-1 (ICAM-1) and CD18. Mice deficient in the genes encoding for the leukocyte adhesion molecules CD18 and ICAM-1 were studied in two models of diabetic retinopathy with respect to the long-term development of retinal vascular lesions. CD18-/- and ICAM-1-/- mice demonstrate significantly fewer adherent leukocytes in the retinal vasculature at 11 and 15 months after induction of diabetes with STZ. This condition is associated with fewer damaged endothelial cells and lesser vascular leakage. Galactosemia of up to 24 months causes pericyte and endothelial cell loss and formation of acellular capillaries. These changes are significantly reduced in CD18- and ICAM-1-deficient mice. Basement membrane thickening of the retinal vessels is increased in long-term galactosemic animals independent of the genetic strain. Here we show that chronic, low-grade subclinical inflammation is responsible for many of the signature vascular lesions of diabetic retinopathy. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-inflammatory treatment in diabetic retinopathy.
Joussen
Antonia M
AM
Department of Vitreoretinal Surgery and Angiogenesis Laboratory, Center of Ophthalmology, University of Cologne, Köln, Germany. JoussenA@aol.com
Poulaki
Vassiliki
V
Le
Minh Ly
ML
Koizumi
Kan
K
Esser
Christina
C
Janicki
Hanna
H
Schraermeyer
Ulrich
U
Kociok
Norbert
N
Fauser
Sascha
S
Kirchhof
Bernd
B
Kern
Timothy S
TS
Adamis
Anthony P
AP
D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism; D003930:Diabetic Retinopathy / Q000209:etiology* / Q000473:pathology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D005690:Galactose / Q000097:blood / Q000378:metabolism; D007249:Inflammation / Q000150:complications* / Q000473:pathology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012160:Retina / Q000378:metabolism / Q000473:pathology; D013997:Time Factors
D018821:CD18 Antigens; D018799:Intercellular Adhesion Molecule-1; D005690:Galactose