Topical modulation of interleukin-1 activity in corneal neovascularization.
OBJECTIVE
To determine whether inflammatory corneal neovascularization (CNV) is associated with interleukin-1 (IL-1) activity and if so, to assess the efficacy of topical interleukin-1 receptor antagonist (IL-1ra) to suppress CNV.


METHODS
Inflammatory CNV was induced on day 0 by placement of paracentral intrastromal sutures in BALB/c murine eyes. Quantification of IL-1alpha and -beta cytokine levels was done by a sandwich enzyme-linked immunosorbent assay (ELISA) on the supernatants of incubated corneas excised at specified time points after induction of CNV (n = 6 per time point studied). To study suppression of CNV by IL-1ra, animals were divided into treatment subgroups that received topical 20 mg/ml of IL-1ra mixed in 0.2% sodium hyaluronate (n = 28) or placebo (vehicle) alone (n = 22) 3 times daily during days 0-35. Other groups of animals received placebo for 1 (n = 10) or 2 (n = 14) weeks before being switched and retained on IL-1ra. Neovascularization was assessed biomicroscopically and graded by using a standardized scheme.


RESULTS
Induction of CNV stimulus was associated with a significant surge in the expression of both IL-1alpha (p < 0.001) and IL-1beta (p < 0.001) as early as 2 h after the stimulus, which peaked at 24 h, before decreasing substantially in the case of IL-1beta and returning to basal levels by day 7. Topical application of IL-1ra led to a significant suppression of CNV for the duration of therapy only if initiated early after induction of the neovascular stimulus. Initiation of therapy 1 week after CNV induction was associated only with a transient suppression in the angiogenic response.


CONCLUSIONS
Our data strongly implicate IL-1 as a critical mediator in the early phase of CNV and suggest that IL-1ra can be an effective modality in suppressing CNV if initiated sufficiently early after the inflammatory neovascular stimulus.
Dana
M R
MR
Laboratory of Immunology, Schepens Eye Research Institute, Brigham and Women's Hospital, Boston, Massachusetts 02114, USA.
Zhu
S N
SN
Yamada
J
J
D000287:Administration, Topical; D000818:Animals; D016510:Corneal Neovascularization / Q000188:drug therapy / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005500:Follow-Up Studies; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D009883:Ophthalmic Solutions; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins; D012795:Sialoglycoproteins / Q000008:administration & dosage*
C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D009883:Ophthalmic Solutions; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins