Impaired Wound Healing in Streptozotocin Diabetes

Abstract

Goodson and Hunt showed that wound healing is impaired in streptozotocin (Sz) diabetic rats; we speculated that this impairment results from defective early inflammatory responses to wounding. Because we had shown that supplemental vitamin A stimulates the early inflammatory response to wounding in nondiabetic rats, we studied the effect of supplemental vitamin A on wound healing in rats with Sz-induced diabetes. Male Sprague-Dawley rats were fed a commercial rat chow containing twice the amount of vitamin A recommended by the NRC for healthy rats. The rats ate and drank (tap water) ad libitum. Two-thirds of the rats were injected (intravenously) with Sz 60 mg/kg body weight. All of these rats became diabetic (hyperglycemia greater than 350 mg/dl, hyperphagic, polydipsic, polyuric, glycosuric greater than 2%). Seven days later, half of the Sz-injected rats were continued on the chow (Group 2) while the other half (Group 3) were switched to the chow supplemented with 150,000 units of vitamin A/kg chow. The next day, all were wounded (7 cm skin incisions and s.c. polyvinyl alcohol sponge implants). Similarly wounded saline injected nondiabetic rats ingesting the unsupplemented chow served as controls (Group 1). The wounds of Group 2 rats healed poorly compared to Group 1 (breaking strength of skin incisions, 308 +/- 19 g vs 584 +/- 23 g, p less than 0.001; hydroxyproline of the sponge reparative tissue, 0.87 mg vs 2.40 mg/100 mg sponge p less than 0.001). Supplemental vitamin A (Group 3) did not affect the hyperglycemia, hyperphagia, polydipsia or glycosuria, but increased the breaking strengths of the incisions of the diabetic rats (468 +/- 40 g, p less than 0.001), and the sponge hydroxyproline (2.38 mg/100 mg sponge, p less than 0.001). In another experiment, in which the wounding and start of supplemental vitamin A were delayed until 28 days after streptozotocin administration (50 mg/kg body weight), similar results were obtained. Streptozotocin diabetes also caused a decrease in the cross-linking of reparative collagen as judged by the ratio of breaking strengths of skin incisions before and after formalin fixation. Supplemental vitamin A did not influence this defect. Sz also caused peripheral lymphocytopenia, adrenal hypertrophy and thymic involution which responded to the supplemental vitamin A. Based upon experimental data and theoretical considerations we conclude Sz diabetes causes two defects in wound healing: a) quantitatively (reduction in reparative collagen accumulation) and b) qualitative reduction in the degree of cross-linking of reparative wound collagen. The action of supplemental vitamin A in correcting the impaired wound healing, adrenal enlargement, thymic involution and lymphocytopenia of Sz-diabetic rats is independent of an effect on their disturbed carbohydrate metabolism.

MDI 301, a nonirritating retinoid, improves abrasion wound healing in damaged/atrophic skin

“…Several past studies have, in fact, demonstrated beneficial effects of retinoid use in wound healing. Although most of these studies have focused on wounds in the skin, [11][12][13][14][15][16][17] retinoid efficacy has also been demonstrated in healing of wounds in other tissues-bone, cornea, respiratory tract, upper digestive system, and gut. [18][19][20][21][22][23][24][25] Although retinoids have beneficial activities, skin irritation is commonly seen following topical application of RA.…”

“…Although most studies have focused on wounds in the skin, [11][12][13][14][15][16][17] retinoid efficacy has also been demonstrated in healing of wounds in other tissues (bone, cornea, respiratory tract, upper digestive system, and gut). 27 Likewise, skin irritation is also a complication with synthetic retinoidal agents currently on the market.…”

Folic Acid Promotes Wound Healing in Diabetic Mice by Suppression of Oxidative Stress

“…For induction of type 1 diabetes, the animals were injected intraperitoneally with streptozotocin (STZ; Sigma Chemical, St. Louis, MO) dissolved in sterile citrate buffer (0.05 mol/L sodium citrate, pH 4.5, 50 mg/kg). STZ was administered for 5 d, as previously described (16,17). Blood glucose was measured from the mouse tail vein using an ACCU-CHEK Aviva blood glucose monitor (Roche, Mannheim, Germany).…”

All-trans Retinoic Acid Improves Structure and Function of Diabetic Rat Skin in Organ Culture

“…A number of experimental approaches have been proposed for the treatment of wounds in patients with diabetes, including the use of vitamin A. It was shown in a 1979 study by Seifter et al (21) that diabetic rats feed a diet high in vitamin A repaired incision wounds more rapidly than control rats. The authors concluded that proinflammatory retinoid activity contributed to wound repair in the vitamin A-fed rats.…”

“…It seems reasonable to speculate that similar effects might occur in diabetic skin and that these effects might lead to reduced incidence of wound formation and to improved healing when wounding occurs. To begin examining this possibility, we established organ cultures from the skin of streptozotocin-diabetic (STZ-D) rats (21) and from control rat skin. Organ cultures of diabetic skin were maintained under control conditions or treated with concentrations of RA that are known to improve histological structure and biochemical function in human skin (24 -30).…”