Effect of cyclosporine on conjunctival mucin in a canine keratoconjunctivitis sicca model.


Moore CP, McHugh JB, Thorne JG, Phillips TE. Effect of cyclosporine on conjunctival mucin in a canine keratoconjunctivitis sicca model. Invest Ophthalmol Vis Sci. 2001;42(3):653-659. / PMID: 11222523


To test the hypothesis that beneficial effects of Cyclosporin A (CsA; Sandimmune; Sandoz, Basel, Switzerland) in treating keratoconjunctivitis sicca (KCS) include an effect on the mucin-producing conjunctival goblet cells independent of CsA’s effect on lacrimation.

Keratoconjunctivitis sicca was induced bilaterally in six dogs after removal of orbital and nictitans lacrimal glands. Two weeks after induction of KCS, either 2% CsA or vehicle was applied twice daily to each surgically altered eye until 6 weeks after KCS induction. Eyes of three control dogs without surgically altered eyes were treated twice daily with vehicle only. Incisional biopsy specimens of ventral fornix conjunctiva were collected before gland removal (baseline) and at 2, 4, and 6 weeks after KCS induction. At each sampling time, eyes were photographed, and color images were subsequently graded for degree of conjunctivitis and characteristics of ocular discharge. Intracellular mucin stores in conjunctival epithelia were estimated using computer-assisted morphometry of biopsy specimen cross sections, and clinical and morphometric findings were correlated.

Lacrimal gland removal resulted in induction of KCS in dogs by 2 weeks, with mean Schirmer tear test (STT) values of 5 mm/min or less occurring in surgically altered eyes compared with STT values of 22.5 mm/min before surgery and 22.9 mm/min in unaltered control eyes at 2 weeks. In surgically altered eyes, STTs remained low during the 6-week study, independent of topical treatment. Intracellular mucin stores were quantified from conjunctival samples collected from each eye at baseline and 2, 4, and 6 weeks. At 4 and 6 weeks (after 2 and 4 weeks of topical treatment), intraepithelial mucin quantities were significantly greater (P: < 0.05) in CsA-treated KCS eyes (14.4 and 13.1 microm(2)/microm, respectively) compared with pretreatment KCS (7.4 microm(2)/microm) eyes and vehicle-treated KCS eyes (7.3 and 8.5 microm(2)/microm, respectively). KCS eyes treated with CsA had lower conjunctivitis and ocular discharge scores than did vehicle-treated KCS eyes.

CONCLUSIONS: Topical 2% CsA restored in vivo conjunctival mucin stores to control levels over a 4-week period, determined by computer-assisted morphometry of sequential conjunctival biopsy specimens from eyes of dogs with surgically induced KCS. Degree of conjunctivitis and severity of mucus discharge were decreased in KCS eyes treated with CsA. Because lacrimal tissues were removed from animals in this study, conjunctival responses occurred independent of lacrimogenic effect(s). These results indicate that restoration of conjunctival goblet cell mucin production, i.e., the balance between synthesis and secretion of mucin glycoproteins, may play an important role in the beneficial effect of CsA in treating KCS.



涙腺除去により犬では2週間までにKCSが誘発され,平均シルマー涙液試験(STT)値は、手術前22.5mm/minで2週目の対照眼で22.9mm/minであったのに対して、5mm/min以下であった。外科処置した眼では、6週間の試験期間中、局所治療とは無関係にSTTは低値のままあった。ベースラインおよび2、4および6週間後に各眼から採取した結膜試料から、細胞内ムチン貯蔵量を定量した。4および6週間(局所治療後2および4週間)で、上皮内ムチン量は、CsA処置KCS眼(それぞれ14.4および13.1μm(2)/μm)、前処置KCS眼(それぞれ7.4μm(2)/μm)および賦形剤処置KCS眼(それぞれ7.3および8.5μm(2)/μm)と比較して有意に大きかった(P: < 0.05)。CsAで治療したKCS眼は賦形剤で治療したKCS眼よりも結膜炎と眼脂スコアが低かった。

局所2%CsAは、外科的に誘発されたKCSのイヌの眼からの定期的な結膜生検標本のコンピュータ支援形態計測により決定されたin vivo結膜ムチン貯蔵を、局所2%CsAは4週間にわたって対照レベルに回復させた。CsAで治療したKCS眼では,結膜炎の程度と粘性眼脂の重症度が低下した。この試験では動物から涙腺組織を除去したため、結膜の反応は催涙作用とは無関係に生じた。これらの結果は,結膜杯細胞のムチン産生の回復,すなわちムチン糖タンパク質の合成と分泌のバランスがKCS治療におけるCsAの有益な効果に重要な役割を果たすことを示した。