Pathophysiology of Cyclooxygenase Inhibition in Animal Models

Abstract

Cyclooxygenase (COX) catalyzes the conversion of arachidonic acid into prostaglandins (PGs), which play a significant role in health and disease in the gastrointestinal tract (GI) and in the renal, skeletal, and ocular systems. COX-1 is constitutively expressed and found in most normal tissues, whereas COX-2 can be expressed at low levels in normal tissues and is highly induced by pro-inflammatory mediators. Inhibitors of COX activity include: (1) conventional nonselective, nonsteroidal anti-inflammatory drugs (ns-NSAIDs) and (2) COX-2 selective nonsteroidal antiinflammatory drugs (COX-2 s-NSAIDs). Inhibition of COX-1 often elicits GI toxicity in animals and humans. Therefore, COX-2 s-NSAIDs were developed to provide a selective COX-2 agent, while minimizing the attendant COX-1-mediated GI toxicities. Rats and dogs overpredict COX inhibition for renal effects such as renal handling of electrolytes in humans. COX inhibitors are shown to have both beneficial and detrimental effects, such as on healing of ligament or tendon tears, on the skeletal system in animal models. Certain ophthalmic conditions such as glaucoma and keratitis are associated with increased COX-2 expression, suggesting a potential role in their pathophysiology.

TLR4-mediated Cox-2 expression increases intestinal ischemia/reperfusion-induced damage

“…Produced following Cox conversion of arachidonic acid to PGG2, PGE2 is a vasodilator, which causes edema in intestinal IR. Constitutively active, Cox-1 maintains mucosal homeostasis within the intestine, and Cox-2 is up-regulated during inflammation [14]. However, a deficiency of either Cox gene does not result in mucosal damage, suggesting redundancy between Cox-1 and Cox-2 activity [15].…”

Immunohistochemical localisation of renal cyclooxygenase-1 expression in non-steroidal anti-inflammatory drug-treated mice

“…NSAIDs cause renal toxicity following direct inhibition of COX isoforms. Humans and animals exhibit differences in susceptibility, which may be associated with differences in expression of one or both isoforms in the kidney (Radi, 2009). Rats and dogs exhibit greater susceptibility than humans to the development of renal papillary necrosis due to their sluggish blood supply (Khan and Alden, 2002;.…”

ISFM and AAFP Consensus Guidelines: Long-Term use of NSAIDs in Cats

“…[52][53][54][55] Very little feline-specific data are available, but there could be differences in susceptibility to adverse events as a result of such differences in cats.…”