Tissue & cell · 2026
Early preventive effects of a Cathepsin S inhibitor on inflammation in a rat model of endotoxin-induced uveitis.
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Yılmaz Tuğan Büşra, Göçmez Semil Selcen, Duruksu Gökhan, Sönmez Hafize Emine, Çelebi Gülşen, Furat Selenay, Kasap Murat, Akpinar Gürler, Önder Tokuç Ecem, Bayrak Yunus Emre, Karabaş Levent, Halis Furkan Ömer, Tüfekçi Gözde, Şahin Nihal, Yüksel Nurşen, Yazır Yusufhan, Utkan Tijen
Аннотация
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.
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.