- Email: [email protected]
Vitamin A and wound healing
Im
I
Vitamin A and wound healing Thomas K. Hunt, M.D. San Francisco, CA Retinoids have long been associated with wound healing, but objective data, until recently, have been scarce. Vitamin A deficiency retards repair. SecondIy, retinoids restore steroid-retarded repair toward normal. Because vitamin A tends to suppress fibroblasts in cell culture and stimulate steroid-treated macrophages to initiate reparative behavior in tissue, we favor the hypothesis that retinoids are particularly important in macrophagic inflammation, which plays a central role in the control of wound healing. Probably all patients who take ahti-inflammatory steroids should control their retinoid intake, but how they should control it is as yet unknown. (J AM ACADDERMATOL15:817-821, 1986.)
For over 60 years, vitamin A has been linked with wound healing, especially epithelial repair.' Nevertheless, little objective information was available until 1968, when Ehrlich discovered that vitamin A specifically stimulates wound healing that has been retarded by anti-inflammatory steroid h o r m o n e s ? Soon after that, Herrmann and Woodward 3 showed that wound healing could be stimulated in normal animals through either local or systemic administration of vitamin A. Wound healing is an amalgam of otherwise independent processes. Coagulation, inflammation, epithelialization, fibroplasia, collagen and proteoglycan synthesis, angiogenesis, and contraction contribute to the process. Although vitamin A deficiency is associated with disorders of epithelia !ization, its excess is linked to increased epithelial growth and connective tissue disorders? Vitamin A also affects fibroplasia, collagen synthesis, and angiogenesis in certain circumstances and is involved in inflammatory processes, with specific effeCts on macrophages.~9 Yet contraction, a process that causes open wounds to diminish as if drawn by a purse string, seems unaffected. From the Department of Surgery, the University of California at San Francisco. Reprint requests to: Dr. Thomas K. Hunt, Professor of Surgery, University of California at San Francisco, 839-I-ISE, Third and Parnassus, San Francisco, CA 94143.
Normal repair Vitamin A alone stimulates various aspects of wound repair. Animals fed a normal diet deposit more collagen into implanted sponges and have stronger wounds after either local or systemic vitamin A. 3''~ These are equivalent observations, because strength depends on collagen deposition. Partial-thickness corneal wounds also epithelize faster with topical tretinoin. 15"s These observations pose a semantic dilemma: do retinoids "stimulate" or do they repair a deficit caused by inadequate retinoid supply? Current knowledge cannot isolate these alternatives, because it is difficult to distinguish true deficiency, which implies depletion of liver vitamin A, from low blood vitamin A levels, which result from a variety of causes. Although few comparative studies have been done, retinoic acid (tretinoin) appears to be the most wound-active retinoid. Retinol and 13-carotene are active, but are less effective than these substances. ~,18 Freiman et al* have noted that animals deprived of vitamin A heal poorly. Unpublished data developed by Ehrlich in my laboratory confirm that observation. *Freiman M, Seifter E, Connerton C, et al: Vitamin A deficiency and surgical stress. Surg Forum 21:81-82, 1970.
817
818
Journal of the American Academy of Dermatology
Hunt
Retinoids and steroid-retarded repair Ehrlich's earliest study demonstrated that retinoids specifically stimulate wound healing retarded by anti-inflammatory steroids. In fact, they stimulate steroid-retarded wounds far more than normal wounds. Vitamin A analogs restore steroid-depressed collagen deposition in implanted sponges, increase tensile strength of incisional wounds, and hasten epithelialization of wounds in various tissues, including corneas. These enhancing qualities move healing indices toward, but not necessarily to, normal. 2"1926 Curiously, contraction is dramatically retarded by anti-inflammatory steroids, but is not restored by vitamin A. ~This anomaly permits a gratifying degree of control over this repair component with local steroids and vitamin A. Thus if we choose to do so, we can make open wounds heal solely by epithelialization. The retardant effect of steroids on both inflammation and repair is shared by vitamin E and aspirin; the effect of each is countered by vitamin A analogs. 27.2s Other inhibitors of prostaglandin production probably also retard wound healing, but have not been tested in a system with vitamin A. Anabolic steroids share vitamin A's effect in countering the effects of steroids. 2~'29 Current experimental data on vitamin A lack uniformity. Two groups of investigations have found that vitamin A fails to reverse the effects of methylprednisolone.3~ In a sense, this may be inevitable because methylprednisolone has an extraordinary affinity for cytosolic steroid receptors. Nonetheless, this contradictory evidence is difficult to interpret in view of the fact that, with the use of cortisol, these investigators, among all who have tested, were unable to retard wound repair in rats. For that reason the admonition of one group that vitamin A be "reconsidered" for use in steroid-retarded repair seems hasty. Although we are not aware of an objective, randomized study to confirm the effect in humans, stimulation of steroid-retarded repair appears to have major clinical usefulness. 21 Stein and Keiser25 have shown objectively that steroids retard wound healing in humans. Using the same model in animals, they showed that vitamin A restores steroidretarded wound healing. Our own clinical experience in surgical patients, while not randomized, has shown sufficient dramatic stimulation of
chronically static, otherwise nonhealing wounds to confirm clinical usefulness. 21 Retinoids also stimulate healing retarded by other factors. Levenson and Seifter, who have probably contributed more than any others to an understanding of vitamin A's role in wound healing, have shown that vitamin A enhances healing retarded by stress, diabetes, and radiation. *'33'34 Their work has focused on systemic therapy, but in almost every case that involved local therapy, the effects duplicated or bettered those after systemic therapy. The common denominator of these healing effects seems to be the stimulatory action of anabolic steroids and retinoids on inflammation. In search of a rationale Numerous studies indicate that retinoids, like steroids, usually suppress replication of fibroblasts in cell culture systems, as well as suppress collagen and proteoglycan synthesis. 35-4~ In view of this, it seems apparent that retinoids do not directly affect fibroblasts in wounds. On the other hand, retinoids, for the most part, enhance inflammatory reactions. Consequently, it seems useful to examine the role of inflammation in wound healing and the effects of steroids on inflammation. Cumulative data demonstrate that macrophages play a dominant role in controlling repair. Without them, all components of repair suffer. 42'4~ Steroids suppress inflammation, including the appearance of macrophages in injured areas. 43 However, repair is retarded only when steroid therapy is started at the time of injury or in the first 3 or 4 days thereafter. 44 At this time the inflammatory reaction can be forestalled. The effect on contraction is the only exception to this rule. Contraction can be stopped by anti-inflammatory steroids at any stage. This discrepancy remains unexplained. Typically, the dosage of steroids necessary to prevent inflammation is far lower than the amount needed to suppress established inflammation. Macrophages secrete a fibroblast growth factor and an angiogenesis factor, t '45 Macrophages taken from wounds cause angiogenesis, fibroplasia, and *Freiman M, Seifter E, Connerton C, et al: Vitamin A deficiency and surgical stress. Surg Forum 21:81-82, 1970. tBanda MJ, Knighton DR, Jensen JA, et al: Regulation of angiogenesis by macrophages. Proceedings, Fourth Leiden Conference on Monuelear Phagocytes. Leiden, The Netherlands, in press, 1986.
Volume 15 Number 4, Part 2 October, 1986
scarring when transplanted autologously into cornea. However, macrophages taken from blood or uninflamed peritoneum cause no reaction. If one exposes wound macrophages to steroids during the transplantation, corneal effects are prevented. 46 Methylprednisolone has not been tested in this system. Washing the steroid-treated, wound-derived macrophages or concomitantly exposing them to vitamin A restores their ability to direct a healing reaction. The antagonism between steroids and retinoids, as well as some of the effects of retinoids alone, seems to be mediated in or on macrophages. The lysosomal theory that anti-inflammatory steroids stabilize membranes while vitamin A destabilizes them motivated Ehrlich to perform his original experiments. This construct is evolving and will probably emerge changed. But because it led us to the original discovery, we are reluctant to lose sight of it. Retinoids are particularly important in controlling membrane protein glycoconjugation, but steroids tend to have opposite e f f e c t s . 47 The data suggest a competition between vitamin A and steroids for the steroid receptor. The methylprednisolone data tend to support this theory, because this steroid has the highest known affinity for receptors and may possibly be overwhelmed only by very large doses of retinoids (at a level that might suppress fibroblast activity). Unfortunately, there exist no direct data of such a competitive interaction. Plainly, more remains to be done to clarify the mechanism. In particular, retinoids have such protean effects on cell biology that it seems unwise to assume a single mechanism. The singular effect of retinoids on epidermal cell proliferation, however, may account for a large portion of their effects on repair.
Clinical aspects Vitamin A deficiency is common. It is also clinically difficult to deal with, because true "deficiency," which implies that the ordinarily massive liver stores are depleted, is difficult to prove. But as with vitamin C, an asymptomatic deficiency can be transformed into a critical one by illness, injury, or other physical stress. How much the rate of vitamin A release from the liver contributes to poor wound healing is unknown. Nonetheless, vitamin A deficiency does slow wound repair, and severely
Vitamin A and wound healing
819
injured patients, especially burn victims, become deficient quickly. 47'4~ Severely stressed patients also develop stomach and duodenal ulcers. This propensity has been linked to vitamin A by several investigators, who have noted associated low retinoid levels and who have prevented such ulcers with prophylactic vitamin A. $,49-51 One obvious application of vitamin A to clinical medicine lies in steroid-retarded repair. Patients taking steroids develop peptic ulcers more frequently than normal. Here lies the beginning of a dilemma. Vitamin A would undoubtedly prevent or heal some fraction of these ulcers, but because the vitamin also restores suppressed immune mechanisms--and inflammation and fibrosis, too--might it not restimulate the disease for which the corticoids are being given? In this circumstance, at least on skin wounds, the topical administration of vitamin A seems to have distinct advantages, because healing can be titrated with minimal absorption. S tress ulcers and poor healing are also commonly seen in patients with diabetes and in patients undergoing cancer chemotherapy. Perhaps increased vitamin A intake would be a useful part of such therapy. It appears possible that wounds made by dermatologic surgeons, particularly those on the face, might be made more cosmetic if patients were allowed to heal by epithelialization alone. As noted, this can be achieved with a combination of steroids and vitamin A. In corneal transplant surgery, retinoids may well stimulate repair suppressed by corticoids. Perhaps both agents would be useful in filtration procedures done for glaucoma, where connective tissue healing tends to defeat the ophthalmologic surgeon. An important question remains: How should vitamin A be supplied to a patient who has started taking steroids? Should the patient incorporate a limited amount of vitamin A in the diet, use vitamin A supplements, or apply it topically to any wound likely to become a problem? Another way of asking the same question is, Can a tomato juice binge produce a relapse of a steroid-controlled dis*Hutcher N, Silverberg SG, Lee HM: The effect of vitamin A on the formation of steroid-induced gastric ulcers. Surg Forum 22:322-324, 1971.
820
Hunt
e a s e ? N o o n e k n o w s . F e w s e e m to c a r e , b u t t h e s e are probably important clinical questions.
REFERENCES I. Brandaleone I-I, Papper E: Effect of the local and oral administration of cod liver oil on the rate of wound healing in vitamin A-deficient and normal rats. Ann Surg 340114:791-798, 1941. 2. Ehrlich HP, Hunt TK: Effects of cortisone and vitamin A on wound healing. Ann Surg 167:324-328, 1968. 3. Herrmann JB, Woodward SC: An experimental study of wound healing accelerators. Am Surg 38:26-34, 1972. 4. Jarrett A, Spearman RIC: Vitamin A and the skin. Br J Dermatol 82:197-199, 1970. 5. Demetriou AA, Franco I, Bark S, et al: Effects of vitamin A and beta-carotene on intra-abdominal sepsis. Arch Surg 119:161-165, 1984. 6. Fusi S, Kupper TS, Green DR, et at: Reversal of postburn immunosuppression by the administration of vitamin A. Surgery 96:330-335, 1984. 7. Jurin M, Tannock IF: Influence of vitamin A on immunological response. Immunology 23:283-287, 1972. 8. Rhodes J, Oliver S: Retinoids as regulators of macrophage function. Immunology 40:467-472, 1980. 9. Cohen BE, Cohen IK: Vitamin A: Adjuvant and steroid antagonist in the immune response. J Immunol 111:13761380, 1973. 10. Garber LE, Erdman JW Jr: Effect of dietary retiny] acetate, beta-carotene and retinoic acid on wound healing in rats. J Nutr 112:1555-1564, 1982. 12. Lee KH, Fu CC, Spencer MR, et al: Mechanism of action of retinyl compounds on wound healing 1II: Effect of retinoic acid homologs on granuloma formation. J Pharm Sci 62:895-899, 1973. 12. Lee KH, Tong TG: Mechanism of action of retinyl compounds on wound healing I: Structural relationship of retinyl compounds and wound healing. J Pharm Sci 59:851-854, 1970. 13. Prutkin L: Wound healing and vitamin A acid. Acta Derm Venereol (Stockh) 52:489-492, 1972. 14. Bark S, Rettura G, Goldman D, et al: Effect of supplemental vitamin A on the healing of colon anastomosis. J Surg Res 36:470-474, 1984. 15. Hatchell DL, Ubels JL, Stekiel T, et al: Corneal epithelial wound healing in normal and diabetic rabbits treated with tretinoin. Arch Ophthalrnol 103:98-100, 1985. 16. Smolin G, Okumoto M, Friedlaender M: Tretinoin and corneal epithelial wound healing. Arch Ophthalmol 97:545-546, 1979. 17. Smolin G, Okumoto M: Vitamin A acid and corneal epithelial wound healing. Ann Ophthalmol 13:563-566, 1981. 18. Ubels JL, Edelhauser HF, Austin KH: Healing of experimental corneal wounds treated with topically applied retinoids. Am J Ophthalrnol 95:353-358, 1983. 19. Ehrlich HP, Tarver H: Effects of beta-carotene, vitamin A, and glucocorticoids on collagen synthesis in wounds. Proc Soe Exp Biol Meal 137:936-938, 1971. 20. Ehrlich PIP, Tarver H, Hunt TK: Effects of vitamin A and glucocorticoids upon inflammation and collagen synthesis. Ann Surg 177:222-227, 1973.
Journal of the American Academy of Dermatology 21. Hunt TK, Ehrlich HP, Garcia JA, et al: Effect of vitamin A on reversing the inhibitory effect of cortisone on healing of open wounds in animals and man. Ann Surg 170:633-641, 1969. 22. Manning JP, DiPasquale G: The effect of vitamin A and hydrocortisone on the normal alkaline phosphatase response to skin wounding in rats. J Invest Dermatol 49:225-229, 1967. 23. Mehra KS, Mikuni I, Kumar A: Effects of vitamin A and cortisone on healing of corneal penetrating wounds. Tokai J Exp Clin Med 7:319-323, 1982. 24. Mehra KS, Mikuni I, Kumar A: Effects of vitamin A and cortisone on healing of corneal superficial wounds. Tokai J Exp Clin Med 7-315-318, 1982. 25. Stein HD, Keiser HR: Collagen metabolism in granulating wounds. J Surg Res 11:277-283, 1971. 26. Wehr RF, Smith JG, Cutroneo K: Vitamin A antagonism ofcorticosteroid-induced collagen synthesis inhibition. J Invest Dermatol 62:542, 1974 (abstract). 27. Ehrlich HP, Tarver H, Hunt TK: Inhibitory effects of vitamin E on collagen synthesis and wound repair. Ann Surg 175:235-240, 1972. 28. Lee KH: Studies on the mechanism of action of salieylates: III. Effect of vitamin A on the wound healing retardation action of aspirin. J Pharm Sci 57:1238-1240, 1968. 29, Ehrlich HP, Hunt TK: The effects of cortisone and anabolic steroids on the tensile strength of healing wounds. Ann Surg 170:203-206, 1969. 30. Golan J, Mitelman S, Baruchin A, et al" Vitamin A and corticosteroid interaction in wound healing in rats. Isr J Med Sci 16:572-575, 1980. 31. Salmela K: The effect of methylprednisolone and vitamin A on wound healing I. Acta Chir Scand 147:307-312. 1981. 32. Salmela K: The effect of methylprednisolone and vitamin A on wound healing II. Acta Chir Scand 147:313-315, 1981. 33. Seifter E, Rettura G, Padawer J, et al: Impaired wound healing in streptozotocin diabetes. Prevention by supplemental vitamin A. Ann Surg 194:42-50, 1981. 34. Gruber C, Kan D, Levenson SM: Influence of vitamin A on wound healing in rats with femoral fracture. Ann Surg 181:836-841, 1975. 35. Bauer EA, Seltzer JL, Eisen AZ: Inhibition of collagen degradative enzymes by retinoic acid in vitro. J AM ACAD DaruaA'rou 6:603-607, 1982. 36. Bauer EA, Seltzer JL, Eisen AZ: Retinoic acid inhibition of collagenase and gelatinase expression in human skin fibroblast cultures: Evidence for a dual mechanism. J Invest Dermatol 81:162-169, 1983. 37. Dahl IMS, Axelsson I: The inhibition by retinoic acid of the biosynthesis of proteoglycans in corneal cell cultures. Exp Eye Res 31:443-450, 1980. 38. Hein R, Mensing H, Muller PK, et al: Effect of vitamin A and its derivatives on collagen production and chemotactic response of fibroblasts. Br J Dermatol 111:3744, 1984. 39. Lacroix A, Anderson GDL, Lippman ME: Retinoids and cultured human fibroblasts. Exp Cell Res 130:339-344, 1980. 40. Oikarinen H, Oikarinen AI, Tan EML, et al: Modulation
Volume 15 Number 4, Part 2 October, 1986
41. 42.
43. 44.
45. 46.
of procollagen gene expression by retinoids. J Clin Invest 75:1545-1553, 1985. Nelson DL, Balian G: The effect of retinoie acid on collagen synthesis by human dermal flbroblasts. Coll Relat Res 4:119-128, 1984. Hunt TK, Knighton DR, Thakral KK, et al: Studies on inflammation and wound healing: Angiogenesis and collagen synthesis stimulated in vivo by resident and activated wound macrophages. Surgery 96:48-54, 1984. Leibovich SJ, Ross R: The role of macrophages in repair: A study with hydrocortisone and antimacrophage serum. Am J Pathol 78:71-91, 1975. Sandberg N: Time relationship between administration of cortisone and wound healing in rats. Acta Chit Stand 127:446-455, 1964. Leibovich S J, Ross R: A macrophage-dependent factor that stimulates the proliferation of fibroblasts in vitro. Am J Pathol 84:501-513, /976. Andrews WS, Flick JT, Hunt TK: Corneal neovascular-
Vitamin A and wound healing
47. 48. 49. 50. 51.
821
ization initiated by wound macrophages and inhibited by prednisolone. Microvasc Res 17:S126, 1979 (abstract). Elias PN, Fritsch PO, Lampe M, et ah Retinoid effects on epidermal structure, differentiation and permeability. Lab Invest 44:531-540, 1981. Rai K, Courtemanche AD: Vitamin A assay in burned patients. J Trauma 15:419-424, 1975. Cynober L, Desmoulins D, Lioret N, et ah Significance of vitamin A and retinol binding protein serum levels after burn injury. Clin Chim Acta 148:247-253, 1985. Chernov MS, Hale HW, Wood M: Prevention of stress ulcers. Am J Surg 122:674-677, 1971. Patty I, T'Amok F, Simon L, et al: A comparative dynamic study of the effectiveness of gastric cytoprotection by vitamin A, De-Nol, sueralfate and ulcer healing pirenzepine in patients with chronic gastric ulcer (a multiclinical and randomized study). Aeta Physiol Hung 64:379-384, 1984.
I
Vitamin A and wound healing Thomas K. Hunt, M.D. San Francisco, CA Retinoids have long been associated with wound healing, but objective data, until recently, have been scarce. Vitamin A deficiency retards repair. SecondIy, retinoids restore steroid-retarded repair toward normal. Because vitamin A tends to suppress fibroblasts in cell culture and stimulate steroid-treated macrophages to initiate reparative behavior in tissue, we favor the hypothesis that retinoids are particularly important in macrophagic inflammation, which plays a central role in the control of wound healing. Probably all patients who take ahti-inflammatory steroids should control their retinoid intake, but how they should control it is as yet unknown. (J AM ACADDERMATOL15:817-821, 1986.)
For over 60 years, vitamin A has been linked with wound healing, especially epithelial repair.' Nevertheless, little objective information was available until 1968, when Ehrlich discovered that vitamin A specifically stimulates wound healing that has been retarded by anti-inflammatory steroid h o r m o n e s ? Soon after that, Herrmann and Woodward 3 showed that wound healing could be stimulated in normal animals through either local or systemic administration of vitamin A. Wound healing is an amalgam of otherwise independent processes. Coagulation, inflammation, epithelialization, fibroplasia, collagen and proteoglycan synthesis, angiogenesis, and contraction contribute to the process. Although vitamin A deficiency is associated with disorders of epithelia !ization, its excess is linked to increased epithelial growth and connective tissue disorders? Vitamin A also affects fibroplasia, collagen synthesis, and angiogenesis in certain circumstances and is involved in inflammatory processes, with specific effeCts on macrophages.~9 Yet contraction, a process that causes open wounds to diminish as if drawn by a purse string, seems unaffected. From the Department of Surgery, the University of California at San Francisco. Reprint requests to: Dr. Thomas K. Hunt, Professor of Surgery, University of California at San Francisco, 839-I-ISE, Third and Parnassus, San Francisco, CA 94143.
Normal repair Vitamin A alone stimulates various aspects of wound repair. Animals fed a normal diet deposit more collagen into implanted sponges and have stronger wounds after either local or systemic vitamin A. 3''~ These are equivalent observations, because strength depends on collagen deposition. Partial-thickness corneal wounds also epithelize faster with topical tretinoin. 15"s These observations pose a semantic dilemma: do retinoids "stimulate" or do they repair a deficit caused by inadequate retinoid supply? Current knowledge cannot isolate these alternatives, because it is difficult to distinguish true deficiency, which implies depletion of liver vitamin A, from low blood vitamin A levels, which result from a variety of causes. Although few comparative studies have been done, retinoic acid (tretinoin) appears to be the most wound-active retinoid. Retinol and 13-carotene are active, but are less effective than these substances. ~,18 Freiman et al* have noted that animals deprived of vitamin A heal poorly. Unpublished data developed by Ehrlich in my laboratory confirm that observation. *Freiman M, Seifter E, Connerton C, et al: Vitamin A deficiency and surgical stress. Surg Forum 21:81-82, 1970.
817
818
Journal of the American Academy of Dermatology
Hunt
Retinoids and steroid-retarded repair Ehrlich's earliest study demonstrated that retinoids specifically stimulate wound healing retarded by anti-inflammatory steroids. In fact, they stimulate steroid-retarded wounds far more than normal wounds. Vitamin A analogs restore steroid-depressed collagen deposition in implanted sponges, increase tensile strength of incisional wounds, and hasten epithelialization of wounds in various tissues, including corneas. These enhancing qualities move healing indices toward, but not necessarily to, normal. 2"1926 Curiously, contraction is dramatically retarded by anti-inflammatory steroids, but is not restored by vitamin A. ~This anomaly permits a gratifying degree of control over this repair component with local steroids and vitamin A. Thus if we choose to do so, we can make open wounds heal solely by epithelialization. The retardant effect of steroids on both inflammation and repair is shared by vitamin E and aspirin; the effect of each is countered by vitamin A analogs. 27.2s Other inhibitors of prostaglandin production probably also retard wound healing, but have not been tested in a system with vitamin A. Anabolic steroids share vitamin A's effect in countering the effects of steroids. 2~'29 Current experimental data on vitamin A lack uniformity. Two groups of investigations have found that vitamin A fails to reverse the effects of methylprednisolone.3~ In a sense, this may be inevitable because methylprednisolone has an extraordinary affinity for cytosolic steroid receptors. Nonetheless, this contradictory evidence is difficult to interpret in view of the fact that, with the use of cortisol, these investigators, among all who have tested, were unable to retard wound repair in rats. For that reason the admonition of one group that vitamin A be "reconsidered" for use in steroid-retarded repair seems hasty. Although we are not aware of an objective, randomized study to confirm the effect in humans, stimulation of steroid-retarded repair appears to have major clinical usefulness. 21 Stein and Keiser25 have shown objectively that steroids retard wound healing in humans. Using the same model in animals, they showed that vitamin A restores steroidretarded wound healing. Our own clinical experience in surgical patients, while not randomized, has shown sufficient dramatic stimulation of
chronically static, otherwise nonhealing wounds to confirm clinical usefulness. 21 Retinoids also stimulate healing retarded by other factors. Levenson and Seifter, who have probably contributed more than any others to an understanding of vitamin A's role in wound healing, have shown that vitamin A enhances healing retarded by stress, diabetes, and radiation. *'33'34 Their work has focused on systemic therapy, but in almost every case that involved local therapy, the effects duplicated or bettered those after systemic therapy. The common denominator of these healing effects seems to be the stimulatory action of anabolic steroids and retinoids on inflammation. In search of a rationale Numerous studies indicate that retinoids, like steroids, usually suppress replication of fibroblasts in cell culture systems, as well as suppress collagen and proteoglycan synthesis. 35-4~ In view of this, it seems apparent that retinoids do not directly affect fibroblasts in wounds. On the other hand, retinoids, for the most part, enhance inflammatory reactions. Consequently, it seems useful to examine the role of inflammation in wound healing and the effects of steroids on inflammation. Cumulative data demonstrate that macrophages play a dominant role in controlling repair. Without them, all components of repair suffer. 42'4~ Steroids suppress inflammation, including the appearance of macrophages in injured areas. 43 However, repair is retarded only when steroid therapy is started at the time of injury or in the first 3 or 4 days thereafter. 44 At this time the inflammatory reaction can be forestalled. The effect on contraction is the only exception to this rule. Contraction can be stopped by anti-inflammatory steroids at any stage. This discrepancy remains unexplained. Typically, the dosage of steroids necessary to prevent inflammation is far lower than the amount needed to suppress established inflammation. Macrophages secrete a fibroblast growth factor and an angiogenesis factor, t '45 Macrophages taken from wounds cause angiogenesis, fibroplasia, and *Freiman M, Seifter E, Connerton C, et al: Vitamin A deficiency and surgical stress. Surg Forum 21:81-82, 1970. tBanda MJ, Knighton DR, Jensen JA, et al: Regulation of angiogenesis by macrophages. Proceedings, Fourth Leiden Conference on Monuelear Phagocytes. Leiden, The Netherlands, in press, 1986.
Volume 15 Number 4, Part 2 October, 1986
scarring when transplanted autologously into cornea. However, macrophages taken from blood or uninflamed peritoneum cause no reaction. If one exposes wound macrophages to steroids during the transplantation, corneal effects are prevented. 46 Methylprednisolone has not been tested in this system. Washing the steroid-treated, wound-derived macrophages or concomitantly exposing them to vitamin A restores their ability to direct a healing reaction. The antagonism between steroids and retinoids, as well as some of the effects of retinoids alone, seems to be mediated in or on macrophages. The lysosomal theory that anti-inflammatory steroids stabilize membranes while vitamin A destabilizes them motivated Ehrlich to perform his original experiments. This construct is evolving and will probably emerge changed. But because it led us to the original discovery, we are reluctant to lose sight of it. Retinoids are particularly important in controlling membrane protein glycoconjugation, but steroids tend to have opposite e f f e c t s . 47 The data suggest a competition between vitamin A and steroids for the steroid receptor. The methylprednisolone data tend to support this theory, because this steroid has the highest known affinity for receptors and may possibly be overwhelmed only by very large doses of retinoids (at a level that might suppress fibroblast activity). Unfortunately, there exist no direct data of such a competitive interaction. Plainly, more remains to be done to clarify the mechanism. In particular, retinoids have such protean effects on cell biology that it seems unwise to assume a single mechanism. The singular effect of retinoids on epidermal cell proliferation, however, may account for a large portion of their effects on repair.
Clinical aspects Vitamin A deficiency is common. It is also clinically difficult to deal with, because true "deficiency," which implies that the ordinarily massive liver stores are depleted, is difficult to prove. But as with vitamin C, an asymptomatic deficiency can be transformed into a critical one by illness, injury, or other physical stress. How much the rate of vitamin A release from the liver contributes to poor wound healing is unknown. Nonetheless, vitamin A deficiency does slow wound repair, and severely
Vitamin A and wound healing
819
injured patients, especially burn victims, become deficient quickly. 47'4~ Severely stressed patients also develop stomach and duodenal ulcers. This propensity has been linked to vitamin A by several investigators, who have noted associated low retinoid levels and who have prevented such ulcers with prophylactic vitamin A. $,49-51 One obvious application of vitamin A to clinical medicine lies in steroid-retarded repair. Patients taking steroids develop peptic ulcers more frequently than normal. Here lies the beginning of a dilemma. Vitamin A would undoubtedly prevent or heal some fraction of these ulcers, but because the vitamin also restores suppressed immune mechanisms--and inflammation and fibrosis, too--might it not restimulate the disease for which the corticoids are being given? In this circumstance, at least on skin wounds, the topical administration of vitamin A seems to have distinct advantages, because healing can be titrated with minimal absorption. S tress ulcers and poor healing are also commonly seen in patients with diabetes and in patients undergoing cancer chemotherapy. Perhaps increased vitamin A intake would be a useful part of such therapy. It appears possible that wounds made by dermatologic surgeons, particularly those on the face, might be made more cosmetic if patients were allowed to heal by epithelialization alone. As noted, this can be achieved with a combination of steroids and vitamin A. In corneal transplant surgery, retinoids may well stimulate repair suppressed by corticoids. Perhaps both agents would be useful in filtration procedures done for glaucoma, where connective tissue healing tends to defeat the ophthalmologic surgeon. An important question remains: How should vitamin A be supplied to a patient who has started taking steroids? Should the patient incorporate a limited amount of vitamin A in the diet, use vitamin A supplements, or apply it topically to any wound likely to become a problem? Another way of asking the same question is, Can a tomato juice binge produce a relapse of a steroid-controlled dis*Hutcher N, Silverberg SG, Lee HM: The effect of vitamin A on the formation of steroid-induced gastric ulcers. Surg Forum 22:322-324, 1971.
820
Hunt
e a s e ? N o o n e k n o w s . F e w s e e m to c a r e , b u t t h e s e are probably important clinical questions.
REFERENCES I. Brandaleone I-I, Papper E: Effect of the local and oral administration of cod liver oil on the rate of wound healing in vitamin A-deficient and normal rats. Ann Surg 340114:791-798, 1941. 2. Ehrlich HP, Hunt TK: Effects of cortisone and vitamin A on wound healing. Ann Surg 167:324-328, 1968. 3. Herrmann JB, Woodward SC: An experimental study of wound healing accelerators. Am Surg 38:26-34, 1972. 4. Jarrett A, Spearman RIC: Vitamin A and the skin. Br J Dermatol 82:197-199, 1970. 5. Demetriou AA, Franco I, Bark S, et al: Effects of vitamin A and beta-carotene on intra-abdominal sepsis. Arch Surg 119:161-165, 1984. 6. Fusi S, Kupper TS, Green DR, et at: Reversal of postburn immunosuppression by the administration of vitamin A. Surgery 96:330-335, 1984. 7. Jurin M, Tannock IF: Influence of vitamin A on immunological response. Immunology 23:283-287, 1972. 8. Rhodes J, Oliver S: Retinoids as regulators of macrophage function. Immunology 40:467-472, 1980. 9. Cohen BE, Cohen IK: Vitamin A: Adjuvant and steroid antagonist in the immune response. J Immunol 111:13761380, 1973. 10. Garber LE, Erdman JW Jr: Effect of dietary retiny] acetate, beta-carotene and retinoic acid on wound healing in rats. J Nutr 112:1555-1564, 1982. 12. Lee KH, Fu CC, Spencer MR, et al: Mechanism of action of retinyl compounds on wound healing 1II: Effect of retinoic acid homologs on granuloma formation. J Pharm Sci 62:895-899, 1973. 12. Lee KH, Tong TG: Mechanism of action of retinyl compounds on wound healing I: Structural relationship of retinyl compounds and wound healing. J Pharm Sci 59:851-854, 1970. 13. Prutkin L: Wound healing and vitamin A acid. Acta Derm Venereol (Stockh) 52:489-492, 1972. 14. Bark S, Rettura G, Goldman D, et al: Effect of supplemental vitamin A on the healing of colon anastomosis. J Surg Res 36:470-474, 1984. 15. Hatchell DL, Ubels JL, Stekiel T, et al: Corneal epithelial wound healing in normal and diabetic rabbits treated with tretinoin. Arch Ophthalrnol 103:98-100, 1985. 16. Smolin G, Okumoto M, Friedlaender M: Tretinoin and corneal epithelial wound healing. Arch Ophthalmol 97:545-546, 1979. 17. Smolin G, Okumoto M: Vitamin A acid and corneal epithelial wound healing. Ann Ophthalmol 13:563-566, 1981. 18. Ubels JL, Edelhauser HF, Austin KH: Healing of experimental corneal wounds treated with topically applied retinoids. Am J Ophthalrnol 95:353-358, 1983. 19. Ehrlich HP, Tarver H: Effects of beta-carotene, vitamin A, and glucocorticoids on collagen synthesis in wounds. Proc Soe Exp Biol Meal 137:936-938, 1971. 20. Ehrlich PIP, Tarver H, Hunt TK: Effects of vitamin A and glucocorticoids upon inflammation and collagen synthesis. Ann Surg 177:222-227, 1973.
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