Effects of steroids and retinoids on wound healing.

HYPOTHESIS Anti-inflammatory corticosteroids significantly impair wound healing. Retinoids partially, but significantly, reverse this effect. Little is known about the mechanism of steroid retardation or retinoid reversal. We hypothesized that corticosteroids lower transforming growth factor-beta (TGF-beta) and insulin-like growth factor-I (IGF-I) levels and tissue deposition in wounds and that retinoids stimulate corticosteroid-impaired TGF-beta and IGF-I release and collagen production. DESIGN Randomized controlled trial. SETTING Wound healing research laboratory. PARTICIPANTS Animal study. INTERVENTIONS Four wire mesh wound cylinders were implanted subcutaneously into the backs of 72 male Sprague-Dawley rats. Wound healing was impaired by a single subcutaneous injection of 6 mg of methylprednisolone acetate (Depo-Medrol). Two preparations of retinoids were used in separate experiments: all-trans-retinoic acid and 9-cis-retinoic acid that were fed orally. MAIN OUTCOME MEASURES Hydroxyproline content was measured in the healing tissue and TGF-beta and IGF-I levels were analyzed in the wound fluid. RESULTS Methylprednisolone treatment significantly decreased TGF-beta and IGF-I levels in the wound fluid and hydroxyproline content in the tissue (P<.05). Oral all-trans- and 9-cis-retinoic acid partially reversed the TGF-beta and IGF-I decrease and significantly increased hydroxyproline content toward normal levels (P<.05). Oral all-trans-retinoic acid enhanced collagen deposition, TGF-beta and IGF-I levels over normal chow fed control animals (P<.05). CONCLUSIONS Steroids and retinoids have antagonistic effects on growth factors and collagen deposition in wound healing. These effects can be relevant for treatment options in a clinical setting.

[1]  M. Sporn,et al.  Transforming growth factor beta. , 1988, Advances in cancer research.

[2]  E. Fonkalsrud,et al.  Effects of chronic corticosteroids and vitamin A on the healing of intestinal anastomoses. , 1992, American journal of surgery.

[3]  N. Sandberg.  TIME RELATIONSHIP BETWEEN ADMINISTRATION OF CORTISONE AND WOUND HEALING IN RATS. , 1964, Acta chirurgica Scandinavica.

[4]  F. Ruscetti,et al.  Transforming growth factor beta 1 functions in monocytic differentiation of hematopoietic cells through autocrine and paracrine mechanisms. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[5]  M. Sporn,et al.  Mechanistic interrelationships between two superfamilies: the steroid/retinoid receptors and transforming growth factor-beta. , 1992, Cancer surveys.

[6]  M. Sporn,et al.  Cellular biology and biochem-istry of the retinoids , 1984 .

[7]  L. Wakefield,et al.  Identification of the start sites for the 1.9- and 1.4-kb rat transforming growth factor-beta1 transcripts and their effect on translational efficiency. , 1998, Gene.

[8]  D. Rifkin,et al.  Activation of latent transforming growth factor beta. , 1993, Advances in pharmacology.

[9]  S. Levenson,et al.  Effect of dietary supplementation with vitamin A on arterial healing in rats. , 1987, The Journal of surgical research.

[10]  T. K. Hunt,et al.  Effects of Vitamin A and Glucocorticoids upon Inflammation and Collagen Synthesis , 1973, Annals of surgery.

[11]  D. Cromack,et al.  Differential acceleration of healing of surgical incisions in the rabbit gastrointestinal tract by platelet-derived growth factor and transforming growth factor, type beta. , 1990, Surgery.

[12]  Pemrick Sm,et al.  The retinoid receptors. , 1994 .

[13]  H. Scher,et al.  Differences in the pharmacokinetic properties of orally administered all-trans-retinoic acid and 9-cis-retinoic acid in the plasma of nude mice. , 1994, Drug metabolism and disposition: the biological fate of chemicals.

[14]  T. K. Hunt,et al.  Effects of Cortisone and Vitamin A on Wound Healing , 1968, Annals of surgery.

[15]  W. Lee,et al.  Measurement of insulin-like growth factor-II in physiological fluids and tissues. I. An improved extraction procedure and radioimmunoassay for human and rat fluids. , 1991, Endocrinology.

[16]  F. Ruscetti,et al.  Induction of transforming growth factor-beta 1 (TGF-beta 1), receptor expression and TGF-beta 1 protein production in retinoic acid-treated HL-60 cells: possible TGF-beta 1-mediated autocrine inhibition. , 1991, Blood.

[17]  T. K. Hunt,et al.  The effect of insulinlike growth factor I on wound healing variables and macrophages in rats. , 1994, Archives of surgery.

[18]  M. Sporn,et al.  Complex regulation of TGF beta expression by retinoic acid in the vitamin A-deficient rat. , 1991, Development.

[19]  R. Diegelmann,et al.  Quantitation of hydroxyproline isomers in acid hydrolysates by high-performance liquid chromatography. , 1984, Analytical biochemistry.

[20]  E. Amento,et al.  One systemic administration of transforming growth factor-beta 1 reverses age- or glucocorticoid-impaired wound healing. , 1993, The Journal of clinical investigation.

[21]  M. Sporn,et al.  Prevention of breast cancer in the rat with 9-cis-retinoic acid as a single agent and in combination with tamoxifen. , 1994, Cancer research.

[22]  D. Rifkin,et al.  An assay for transforming growth factor-beta using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. , 1994, Analytical biochemistry.

[23]  A. Roberts,et al.  Transforming growth factor-beta: activity and efficacy in animal models of wound healing. , 1995, Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society.

[24]  E. Seifter,et al.  Zone II flexor tendon repair: Effects of vitamins A, E, β-carotene , 1990 .

[25]  M. Sporn,et al.  Transforming Growth Factor‐β , 1990 .

[26]  M E Bolander,et al.  Transforming growth factor-beta and the initiation of chondrogenesis and osteogenesis in the rat femur , 1990, The Journal of cell biology.

[27]  K. Cutroneo,et al.  Glucocorticoid and retinoid regulation of alpha‐2 type I procollagen promoter activity , 1992, Journal of cellular biochemistry.

[28]  D. Danielpour.  Induction of transforming growth factor-beta autocrine activity by all-trans-retinoic acid and 1 alpha,25-dihydroxyvitamin D3 in NRP-152 rat prostatic epithelial cells. , 1996, Journal of cellular physiology.

[29]  D. Rifkin,et al.  Mechanism of retinoid‐induced activation of latent transforming growth factor‐β in bovine endothelial cells , 1993, Journal of cellular physiology.

[30]  E. Seifter,et al.  Influence of vitamin A on wound healing in rats with femoral fracture. , 1975, Annals of surgery.

[31]  L. Wakefield,et al.  Release and activation of platelet latent TGF–β in blood clots during dissolution with plasmin , 1995, Nature Medicine.

[32]  M. Sporn,et al.  The Transforming Growth Factor‐Betas: Past, Present, and Future , 1990, Annals of the New York Academy of Sciences.

[33]  D. Leroith,et al.  Retinoid modulation of insulin-like growth factor-binding proteins and inhibition of breast carcinoma proliferation. , 1991, Endocrinology.

[34]  D. Rifkin,et al.  Activation of Latent Transforming Growth Factor ß , 1993 .

[35]  D. Danielpour.  Induction of transforming growth factor‐β autocrine activity by all‐trans‐retinoic acid and 1α,25‐dihydroxyvitamin D3 in NRP‐152 rat prostatic epithelial cells , 1996 .

[36]  T. K. Hunt,et al.  Somatomedins: do they play a pivotal role in wound healing? , 1988, Progress in clinical and biological research.

[37]  Sporn Mb,et al.  MECHANISTIC INTERRELATIONSHIPS BETWEEN TWO SUPERFAMILIES : THE STEROID/RETINOID RECEPTORS AND TRANSFORMING GROWTH FACTOR-BETA , 1992 .

[38]  M. Sporn,et al.  The Transforming Growth Factor-βs , 1991 .

[39]  M. Sporn,et al.  Transforming growth factor-beta 1: histochemical localization with antibodies to different epitopes , 1989, The Journal of cell biology.