Early preventive effects of a Cathepsin S inhibitor on inflammation in a rat model of endotoxin-induced uveitis.
Abstract
Objectives
Uveitis, an inflammation of the uveal tissue, can cause permanent vision loss. A previous study revealed elevated levels of cathepsin S in the tear proteomic analyses of patients with juvenile idiopathic arthritis-associated uveitis. This study investigates the effects of a cathepsin S inhibitor on inflammation in a rat model of uveitis.
Methods
Forty female rats were divided into five groups: Group I (healthy control), Group II (vehicle group), Group III (Z-FL-COCHO-treated group), Group IV (EIU group), and Group V (lipopolysaccharide [LPS] and Z-FL-COCHO-treated group). Uveitis was induced by injection of LPS and was expected to develop within 24 h. The cathepsin S inhibitor, Z-FL-COCHO (4 mg/kg), was administered intraperitoneally. Uveitis was evaluated through clinical and histological assessments; inflammatory mediators were assessed by immunohistochemistry (BAFF), quantitative real-time PCR (BAFF, TNF-α, and NF-κB), and Western blot (BAFF-R, TNF-α, and NF-κB-p65).
Results
At 24 h, the median (IQR) clinical score was 0 (0-0) in Groups I, II, and III, 3.5 (3-4) in Group IV, and 0.5 (0-1) in Group V. Histological analysis showed normal morphology in Groups I, II, and III, whereas Group IV exhibited vascular congestion in retina, choroid, sclera and ciliary body. Group V showed reduced vascular congestion, decreased inflammation, and preserved ciliary body morphology. Inflammatory markers (BAFF and its receptor BAFF-R, TNF-α, and NF-κB) were significantly higher in Group IV than in Groups I, II, and III, but were reduced in Group V.
Conclusion
The results suggest that prophylactic administration of Z-FL-COCHO is associated with early preventive, anti-inflammatory effects in endotoxin-induced uveitis in rats. However, further investigations incorporating direct target engagement assays and positive comparators are required to fully elucidate its specific mechanism and to determine its comparative anti-inflammatory efficacy.