An Eye on the Dog as the Scientist’s Best Friend for Translational Research in Ophthalmology: Focus on the Ocular Surface

Abstract

Preclinical animal studies provide valuable opportunities to better understand human diseases and contribute to major advances in medicine. This review provides a comprehensive overview of ocular parameters in humans and selected animals, with a focus on the ocular surface, detailing species differences in ocular surface anatomy, physiology, tear film dynamics and tear film composition. We describe major pitfalls that tremendously limit the translational potential of traditional laboratory animals (ie., rabbits, mice and rats) in ophthalmic research, and highlight the benefits of integrating companion dogs with clinical analogues to human diseases into preclinical pharmacology studies. This One Health approach can help accelerate and improve the framework in which ophthalmic research is translated to the human clinic. Studies can be conducted in canine subjects with naturally occurring or non-invasively induced ocular surface disorders (eg., dry eye disease, conjunctivitis), reviewed herein, and tear fluid can be easily retrieved from canine eyes for various bioanalytical purposes. In this review, we discuss common tear collection methods, including capillary tubes and Schirmer tear strips, and provide guidelines for tear sampling and extraction to improve the reliability of analyte quantification (drugs, proteins, others).

Impact of acute conjunctivitis on ocular surface homeostasis in dogs

“…6 However, tear drainage (assessed with TTR) did not differ significantly in dogs with or without experimentally induced conjunctivitis (present study), nor did it change in a recent report of dogs receiving artificial tears at a volume of 10-100 µL. 27 Discrepancies between rabbits and dogs are likely due to notable differences in blinking rates (0.05-0.19 blinks/min vs 14.2 blinks/min, respectively), 29 an important physiologic response that promotes spillage of excessive tearing onto the periocular skin. 27,29 The quality of tears, or tear film stability, was reduced in canine eyes with a model of acute conjunctivitis.…”

“…These results provide useful information for clinicians who manage canine patients with an acute injury to the ocular surface (eg, corneal ulcer, foreign body, or chemical burn with secondary conjunctivitis), and for basic scientists who utilize histamine-induced conjunctivitis as a model to investigate ocular pharmacology and therapeutics. 19,29 It is well established that corneal irritation causes reflex tearing across species, [30][31][32][33] with greater corneal nociceptive stimulation leading to greater tear production. 33 In contrast, little is known about the impact of conjunctival irritation on lacrimal secretion.…”

“…27 Discrepancies between rabbits and dogs are likely due to notable differences in blinking rates (0.05-0.19 blinks/min vs 14.2 blinks/min, respectively), 29 an important physiologic response that promotes spillage of excessive tearing onto the periocular skin. 27,29 The quality of tears, or tear film stability, was reduced in canine eyes with a model of acute conjunctivitis. Shortened TFBUT is an established feature of dogs, 11 cats, 30 and humans 9 with chronic conjunctivitis, as chronicity of inflammation reduces the density of goblet cells that secrete pre-ocular mucins, although this finding is not well documented in eyes with acute conjunctivitis.…”

“…The present study is limited to the short-term effects of experimentally induced conjunctivitis on ocular surface homeostasis, in a relatively small population of dogs of a single breed. Topical histamine provides a robust method to induce conjunctivitis in a rapid and minimally invasive manner in dogs 19,29 ; however, the duration of conjunctivitis is limited in time as the disease is self-resolving (average duration of 115 and 390 minutes with 1 and 375 mg/mL solutions, respectively). 19 One could consider repeating administration of topical histamine to prolong the duration of conjunctival swelling, as recently performed in a pharmacokinetic study of prednisone in dogs, 39 although the safety profile of consistent extended dosing with histamine is currently unknown.…”

Effect of topical nitric oxide donors 0.03% nitroglycerin and 0.1% hydralazine on intraocular pressure in healthy canine eyes

“…Normality of data was assessed with the Shapiro–Wilk test. A mixed model for repeated measures was fitted to the data using the R software version 3.6.0, as previously described (Sebbag et al., 2019 ; Sebbag et al., 2020 ; Sebbag & Mochel, 2020 ). In the model, IOP was the response variable; the group (drug or control), time (0–250 min) and group‐by‐time interaction were treated as fixed effects; and the animal and animal‐by‐group interaction were treated as random effects, using animal as block.…”