Tissue-specific dysregulation of cortisol metabolism in equine laminitis.
BACKGROUND
The role of glucocorticoids (GCs) in the pathogenesis of laminitis is incompletely understood. Local tissue activity of GC is regulated by the steroid converting enzyme, 11beta-hydroxysteroid dehydrogenase-1 (11beta-HSD-1). Changes in integumentary (skin and hoof lamellar) 11beta-HSD activity occurring during laminitis could affect the extent to which GCs are involved in its development.


OBJECTIVE
That changes in integumentary 11beta-HSD-1 activity associated with the laminitic condition would lead to elevated local tissue levels of GCs, which could subsequently contribute, through paracrine and autocrine mechanisms, to the further development of laminitis; and that similar changes in 11beta-HSD-1 activity would be evident in both skin and hoof lamellar tissue.


METHODS
Activity of 11beta-HSD-1 was determined in skin and hoof lamellar tissue specimens obtained from normal and laminitic horses using a radiometric assay. Skin samples were obtained from 10 normal horses and from 10 horses before and after induction of acute laminitis following administration of starch via nasogastric tube. Hoof lamellar samples were obtained from 10 normal horses, 10 horses following induction of acute laminitis and 4 chronically-foundered horses. Bidirectional 11beta-HSD-1 activity was measured in both skin and lamellar tissues.


RESULTS
11-ketoreductase activity exceeded 11beta-dehydrogenase activity in both skin and lamellar tissues. Cutaneous activity was higher than lamellar 11beta-HSD-1 activity in all groups. Both ketoreductase and dehydrogenase activity increased in skin and lamellae following experimental induction of acute laminitis, but the increase in ketoreductase activity was substantially greater than that for dehydrogenase in the lamellae. Induction of acute laminitis was attended by increases of 227 and 220% in cutaneous dehydrogenase and ketoreductase activity, respectively, and 173 and 398% in lamellar dehydrogenase and ketoreductase activity, respectively (P<0.05).


CONCLUSIONS
The 11-ketoreductase moiety of 11beta-HSD-1 plays a role in equine skin and hoof lamellae regarding the regulation of local glucocorticoid activity. Increased 11-ketoreductase activity will lead to increased local tissue GC activity by virtue of conversion of cortisone to cortisol.


CONCLUSIONS
The laminitic condition is attended by integumentary biochemical changes that enhance the local concentration of cortisol, especially in the hoof lamellar interface. Through multiple and diverse actions, increased local GC activity contributes to the pathogenesis and morbidity associated with laminitis. Pharmacological manipulation of 11beta-HSD-1 deserves further investigation regarding the prevention and treatment of laminitis.
Johnson
P J
PJ
Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri at Columbia, Missouri 65211, USA.
Ganjam
V K
VK
Slight
S H
SH
Kreeger
J M
JM
Messer
N T
NT
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000378:metabolism*; D000208:Acute Disease; D000818:Animals; D002908:Chronic Disease; D005260:Female; D005534:Foot Diseases / Q000378:metabolism / Q000662:veterinary*; D005938:Glucocorticoids / Q000378:metabolism; D006724:Hoof and Claw; D006734:Horse Diseases / Q000378:metabolism*; D006736:Horses; D006854:Hydrocortisone / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism / Q000662:veterinary; D007794:Lameness, Animal / Q000209:etiology / Q000378:metabolism; D008297:Male; D012867:Skin / Q000201:enzymology
D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone