Abstract
Conjunctival inflammation disturbs the blood–tear barrier and thus affects the tear film stability and composition. We aimed to develop a non-invasive and reliable method to induce conjunctivitis in dogs, a large animal model for translational work on ocular surface disease in humans. Six beagle dogs underwent a randomized, vehicle-controlled, balanced crossover trial—on six separate days, one eye received topical artificial tears (vehicle), while the other eye received one of six concentrations of histamine solution (0.005–500 mg/ml). At sequential times after eyedrop administration, a conjunctivitis score was given to each eye based on the degree of palpebral and bulbar conjunctival hyperemia and chemosis, ocular pruritus, and discharge. Total protein content (TPC) and serum albumin were quantified in tear fluid at baseline and 20 min. Additionally, 13 dogs presenting for various ophthalmic diseases with associated conjunctivitis were examined. Experimentally induced conjunctivitis developed rapidly (<1 min) following topical histamine administration and lasted for 1–3 h (four lowest doses) to 6–8 h (two highest doses). The severity of conjunctivitis was dose-dependent. Histamine was overall well tolerated, although transient blepharitis, aqueous flare, and ocular hypertension occurred in a few dogs receiving histamine ≥375 mg/ml. TPC and serum albumin levels increased in tears of eyes receiving histamine ≥1.0 mg/ml, being significantly higher than vehicle and baseline in eyes receiving histamine ≥375 mg/ml. Lacrimal albumin levels were also increased in 13 dogs with naturally acquired conjunctivitis, up 2.7–14.9 fold compared to contralateral healthy eyes. Histamine-induced conjunctivitis represents a robust model for translational work on the ocular surface given the low cost, non-invasiveness, self-resolving nature, ability to adjust the duration and severity of the disease, and shared features with naturally occurring ocular diseases. Histamine solutions of 1, 10, and 375 mg/ml induce mild, moderate, and severe conjunctivitis in dogs, respectively. Leakage of serum albumin in tear fluid of eyes with conjunctivitis suggests a breakdown of the blood–tear barrier.
Highlights
Conjunctivitis, or inflammation of the vascularized mucous membrane lining the inside of the eyelids, anterior sclera, and the nictitating membrane, is a common ocular surface disease in both humans and veterinary patients (Azari and Barney, 2013; Maggs, 2018)
The ocular surface was examined from different angles to evaluate the canine conjunctiva in a comprehensive manner, including a view from the front (Figure 1A), side (Figure 1B), top (Figure 1C), and globe retropulsion with lower lid retraction (Figure 1D), which facilitated assessment of the palpebral conjunctiva and nictitating membrane
The present study establishes a robust in vivo model of conjunctivitis in dogs, a translational large animal model that provides a framework for ocular surface studies in clinically relevant subjects, investigating the impact on conjunctivitis on tear film dynamics, pharmacokinetics, metabolomics, and other relevant fields
Summary
Conjunctivitis, or inflammation of the vascularized mucous membrane lining the inside of the eyelids, anterior sclera, and (when present) the nictitating membrane, is a common ocular surface disease in both humans and veterinary patients (Azari and Barney, 2013; Maggs, 2018). In addition to wellrecognized etiologies (e.g., infectious, allergic, toxic/irritative, immune-mediated), conjunctivitis frequently develops as a bystander to most adnexal and ocular diseases, such as blepharitis, keratitis, uveitis, and glaucoma (Azari and Barney, 2013; Maggs, 2018). Conjunctivitis compromises the tear film homeostasis and thereby contributes indirectly to ocular surface damage. Conjunctivitis increases vascular permeability and results in leakage of plasma compounds into the tear film, as exemplified by human patients with conjunctivitis and dry eye who were noted to have significantly greater serum albumin in tears compared to healthy controls (Zavaro et al, 1980; van Bijsterveld and Janssen, 1981; Janssen and van Bijsterveld, 1986; Li et al, 2010), and dogs with spontaneous keratoconjunctivitis sicca for whom the clinical signs of conjunctivitis were positively correlated with tear levels of serum proteins (Fullard et al, 1995)
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