Ketorolac eye drops reduce inflammation and delay re-epithelization in response to corneal alkali burn in rabbits, without affecting iNOS or MMP-9

Abstract

Purposes: To assess the effects of 0.5% ketorolac tromethamine without preservatives on the expression of iNOS and MMP-9 in alkali burn ulcers. Methods: Twelve eyes of 120-day-old male rabbits were treated (TG) every 6 h with 0.5% ketorolac tromethamine and 12 other eyes were treated with saline solution (CG), immediately after the occurrence of ulcers by 1 M sodium hydroxide (NaOH). Re-epithelialization was monitored using fluorescein every 6 h. After 24 h, six corneas (n=6) of each group were collected (M1). The others (n=6) were collected after reepithelialization (M2). At both moments, the inflammatory infiltrate and the conditions of the newly formed epithelium were histologically analyzed. iNOS and MMP-9 were evaluated by immunohistochemistry. Results: Mean epithelialization time in TG was 55 ± 0.84 h. In CG, it was 44 ± 1.06 h (p=0.001). At M1, corneas of TG had lower inflammatory exudation compared with (p <0.001). At M2, TG revealed discrete inflammatory exudation (p>0.05) and lower numbers of epithelial layers compared with CG. The mean iNOS in stromal cells did not differ in TG over both moments compared with CG (p>0.05) At M2, the central corneal region expressed more iNOS in both groups compared with the peripheral region. No significant differences were observed in iNOS scores of epithelial immunostaining between the groups and across M1 and M2 (p=0.69). Epithelial immunostaining scores for MMP-9 did not differ in TG compared with CG (p=0.69). The average immunostaining score of MMP-9 in stromal cells showed no differences between groups or moments. There was no correlation between immunostaining of iNOS and MMP-9 or between the amount of inflammatory cells and immunostaining of iNOS. Conclusions: Use of 0.5% keratolac tromethamine reduced inflammation and delayed reepithelialization in a cornea alkali burn model without impacting the expression of iNOS or MMP-9.Keywords: Corneal ulcer/chemically induced; Ketrolac tromethamine/administration; iNOS, MMP-9 RESUMOObjetivos: Avaliarem-se os efeitos do cetorolaco de trometamina 0,5%, sem conservante, sobre a expressão da iNOS e da MMP-9, em córneas com úlceras químicas. Métodos: Doze olhos de coelhos machos, 120 dias de idade, foram tratados (GT), a cada 6 horas, com o cetorolaco de trometamina 0,5% e outros 12 com solução salina (GC), imediatamente à ocorrência de úlceras por hidróxido de sódio (NaOH) 1 mol/L. A reepitelização foi monitorada por fluresceína a cada seis horas. Decorridas 24 horas, seis córneas (n=6) de cada grupo foram colhidas (primeiro momento). As demais (n=6) o foram após a sua reepitelização (segundo momento). Em ambos os momentos, avaliaram-se o infiltrado inflamatório e as condições do epitélio neoformado (HE). Por imuno-histoquímica, avaliou-se a imunomarcação de iNOS e de MMP-9. Resultados: A média do tempo de epitelização no GT foi de 55 ± 0,84 horas. No GC, ela foi de 44 ± 1,06 horas (p=0,001). Às 24 horas, as córneas do GT apresentaram menor exsudação inflamatória (p<0,01). No segundo momento, o GT mostrou discreta ...

Effects of topical ketorolac tromethamine on tear parameters, meibography, goblet cell density, and conjunctival oxidative stress in healthy dogs

“…However, another study reported that diclofenac, meloxicam, and celecoxib have variable antioxidant effects, decreasing blood levels of MDA and increasing blood levels of SOD in human patients with rheumatoid arthritis 31 . In the ophthalmology field, one study showed that the same FKT solution used herein reduced the inflammation and delayed the epithelialization of the cornea of rabbits without impacting the expression of the inducible isoform of nitric oxide or MMP‐9 47 …”

“…31 In the ophthalmology field, one study showed that the same FKT solution herein reduced the inflammation and delayed the epithelialization of the cornea of rabbits without impacting the expression of the inducible isoform of nitric oxide or MMP-9. 47 To our knowledge, this is the first study that reports the results of biomarkers of oxidative stress in the conjunctiva of dogs treated with TK. One study reported that during aging, SOD1-knockout mice develop a cumulative oxidative stress status that induces squamous metaplasia of the conjunctival epithelium, with a consequent reduction in TFBT.…”

Verätzungen und Verbrennungen des Auges

“…Weitere tierexperimentelle Studienvorwiegend an alkaliverätzten Hornhäutenbelegen u. a. hohe Aktivitäten lysosomaler Enzyme nach der Leukozyteninfiltration in die Hornhaut [33], führten zur Identifizierung weiterer Entzündungsmediatoren [34] und erbrachten den Nachweis des Zusammenhangs zwischen reduzierter Entzündungsreaktion, gedrosseltem Leukozyteneinstrom, beschleunigter Reepithelisierung und verringerter Fibrosierung des Gewebes [35]. In einer Vielzahl von Studien erwies sich im Tierexperiment, aber auch an humanen limbalen epithelialen Stammzellkulturen, die Wirksamkeit diverser lokal, aber auch systemisch applizierter steroidaler und nicht steroidaler Antiphlogistika sowie antiangionetischer Substanzen zur Therapie der Augenverätzung [11,20,[36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55]. Dieser Therapieansatz einer antientzündlichen und damit auch antiangiogenetischen Behandlung hat damit in der klinischen Praxis einen zentralen Stellenwert.…”

The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns?(Review)

“…MMP-12 may disintegrate certain components of the extracellular matrix (ECM) released following severe alkali burn, which may be involved in ECM remodeling ( 129 ). Inhibiting alkali burn-induced CNV by accelerating corneal wound healing and by reducing the production of angiogenic factors, inflammatory cytokines and MMPs may be a potential therapeutic strategy ( 29 , 125 , 130 – 133 ). PPAR-γ agonists are able to affect proliferation, differentiation, apoptosis and inflammation in different cell types.…”