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Biomedical subjects

M W Dunn

Publications and source records attributed to M W Dunn.

9 recordsLinked to original sources
PubMed1992

Induction of corneal epithelial cytochrome P-450 arachidonate metabolism by contact lens wear.

Two biologically active cytochrome P-450 arachidonate metabolites previously were characterized: 12(R)-hydroxy-5,8,10,14-eicosatetraenoic acid (12(R)-HETE) and 12(R)-hydroxy-5,8,14-eicosatrienoic acid (12(R)-DH-HETE), which are endogenously formed in the corneal epithelium. The functional activity of these novel metabolites mimics changes observed in hypoxic corneas. Therefore, the effect of hypoxic stress was examined on metabolite formation in rabbits fitted with polymethylmethacrylate contact lenses. Although applied lenses fit tightly to the rabbit cornea, mechanical irritation also may contribute to the ocular response. Contact lens-induced hypoxic stress stimulated endogenous formation of both 12(R)-HETE (a sodium, potassium adenosine triphosphatase inhibitor) and 12(R)-DH-HETE (a vasodilatory, chemotactic, and angiogenic factor) in a time-dependent manner. After 4 hr of contact lens wear, a 21-fold increase in endogenous 12(R)-HETE formation concomitant with an increase in corneal thickness was observed. After prolonged contact lens wear (144 hr), a 23-fold increase in endogenous 12(R)-DH-HETE formation was found, corresponding with the appearance of a marked conjunctival inflammation characterized by corneal neovascularization. The increased formation of these compounds was associated with time-dependent changes in corneal endothelial morphology. The ability of 12(R)-HETE and 12(R)-DH-HETE to mediate the clinical signs of corneal hypoxia suggest these metabolites may be potential mediators of contact lens complications that followed conditions of hypoxic stress and possibly mechanical irritation in this model.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1991

12(R)-hydroxyeicosatrienoic acid, a potent chemotactic and angiogenic factor produced by the cornea.

Human and bovine corneal epithelial cytochrome P450 convert arachidonic acid to compound D [12(R)-hydroxy-5,8,14(Z,Z,Z)-eicosatrienoic acid], a metabolite with inflammatory properties including vasodilatation and breakdown of the blood-aqueous barrier. Angiogenic properties of the endogenous compound D and the synthetic enantiomers DR and DS were examined using the corneal micropocket technique. The synthetic compound DR was as active as the endogenously formed compound D. Neovascularization of the cornea was found in all the implants containing as little as 0.5 micrograms of compound DR. In contrast, the stereoisomer DS at the same concentration (0.5 micrograms) was inactive. Since angiogenesis can be secondary to a local inflammatory response, we evaluated the effects of compound DR and its stereoisomer DS on human neutrophil chemotaxis by using a modified Boyden chamber technique. DR, but not DS, was found to be a potent chemotactic factor, exhibiting dose-dependent neutrophil chemotaxis with significant responses observed at doses as low as 10(-11) M, a concentration at which leukotriene B4 does not exhibit significant chemotactic activity. Therefore, compound D produced by the cornea may qualify as an intrinsic corneal angiogenic factor which, in association with other inflammatory mechanisms, account for the growth of new vessels in the cornea that appear in chronic inflammation or in the reparative stages of an acute process.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1990

Hormonal stimulation of 12(R)-HETE, a cytochrome P450 arachidonic acid metabolite in the rabbit cornea.

12(R)-HETE [12(R)-hydroxy-5, 8, 10, 14 eicosatetraenoic acid] is one of the major arachidonic acid metabolites produced by microsomal cytochrome P450 of the corneal epithelium. This metabolite is a potent inhibitor of Na(+)-K(+)-ATPase activity in several tissues. We investigated endogenous production of 12(R)-HETE in the rabbit corneal epithelium. Incubation of corneal epithelial sheets (prelabeled with 14C-arachidonic acid) with arginine vasopressin resulted in the production of radioactive 12(R)-HETE suggesting its formation from endogenously labeled-arachidonic acid. The maximal response was obtained with 1 microM arginine vasopressin and represents a 15-fold increase in 12(R)-HETE formation compared with that of control tissues. Stimulation of 14C-arachidonic acid release with a detergent, digitonin, also resulted in endogenous 12(R)-HETE formation. Analysis of the incubation media following digitonin treatment of prelabeled corneal epithelial sheets revealed that 12(R)-HETE production was maximal at 20 microM digitonin, a 17-fold increase over control values. This study is the first to describe hormonal and traumatic stimulation of 12(R)-HETE formation from endogenously labeled arachidonic acid in intact corneal tissues. This study demonstrates that the formation of this Na(+)-K(+)-ATPase inhibitor can be modulated by physiological and pathophysiological regulation.

12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
PubMed1979

Demonstration of a protease inhibitor in the cornea.

Sequential extraction of bovine corneal homogenates with aqueous 0.154M NaCl, 0.5M NaCl and 3M guanidine HCl revealed the presence, in the two sodium chloride extracts, of trypsin inhibitory factors. Upon gel-filtration chromatography of the o.5M NaCl soluble corneal material on Sephadex G-75, two peaks with trypsin inhibitory activity were resolved. One peak was eluted in the void volume, whereas a second peak had mobility corresponding to a molecular weight fraction much lower than, and therefore distinct from, alpha 1-antitrypsin inhibitor. The possible implication of this inhibitory factor in the pathogenesis of corneal ulceration is briefly discussed.

Amidohydrolases↗
PubMed1979

Nuclear translocation of the cytoplasmic glucocorticoid receptor in the iris--ciliary body of the rabbit.

The cytoplasmic glucocorticoid receptor of the iris--ciliary body of the rabbit has been shown to translocate to the cell nucleus within 30 min of an injection of cortisol. Over the next 2 1/2 hr the amount of receptor returns to the control value. The threshold of the loss of receptor from the cytosol was found at 0.04 mg of cortisol per kilogram body weight, with a maximal loss being reached at a cortisol dose of 0.5 mg/kg B.W. The inactive glucocorticoid tetrahydrocortisol and the major sex steroids, dihydrotestosterone, estradiol, and progesterone, had little or no effect on this translocation, indicating the specificity of the cortisol effect. Thus this receptor appears to migrate to the cell nucleus in a manner similar to that found in other steroid-sensitive tissues and is consistent with the accepted mechanism whereby these hormones regulate differential gene expression in the nucleus.

Animals↗
PubMed1978

Receptors for glucocorticoids in the lens epithelium of the calf.

The calf lens epithelium contains a specific cytoplasmic receptor for glucocorticoids. This binding protein has a high affinity for dexamethasone (average dissociation constant, 8 x 10(-9) mole per liter), a low capacity (average, 550 femtomoles per milligram of protein), extreme heat sensitivity, and exhibits a pattern of competition similar to that of glucocorticoid receptors in other tissues. This provides direct biochemical evidence that these tissues may function as a target organ for glucocorticoids.

Animals↗
PubMed1978

Soluble gentamicin ophthalmic inserts as a drug delivery system.

A comparison was made of soluble 14C-gentamicin ophthalmic inserts with drop, ointment, and the subconjunctival routes of administration. The insert is a solid, solubilizable collagen polymer containing 14C-gentamicin. We compared the levels of 14C-gentamicin in the rabbit tear film and in multiple corneal and scleral biopsies to determine which route of administration gave the best results. The wafer route of administration gave the highest tear film and tissue concentration of drug. The tear film concentration by subconjunctival injection was surprisingly low. Soluble collagen inserts offer a new method of delivering high doses of gentamicin in infected corneal tissue in a convenient and atraumatic fashion.

Administration, Topical↗
PubMed1977

Soluble artifical tear inserts.

This article reports a new concept in the treatment of tear film abnormalities. Solubilization of an artifical tear insert provides a continuous flow of polymer into the tear film in place of intermittent drop therapy. The physiochemical properties of succinylated collagen were studied in vitro and compared favorably with presently available tear substitutes. The use of this polymer as a solid solubilizable insert was evaluated in normal patients. It was found to be comfortable, resulted in no blurring of vision, and prolonged the tear film breakup time.

Cellulose↗