Differential acceleration of healing of surgical incisions in the rabbit gastrointestinal tract by platelet-derived growth factor and transforming growth factor, type beta

Anastomotic dehiscence is a major cause of morbidity and mortality in gastrointestinal surgery. A unique model system of a gastric incision was developed to test the potential of polypeptide growth factors to enhance wound healing. Paired, deep partial-thickness incisions to but not including the gastric mucosa were made. A single topical application of transforming growth factor, type beta 1 (TGF-beta), platelet-derived growth factor, or control vehicle at the time of wounding was given. Wound breaking strength and detailed histologic analyses of wounds were evaluated as a function of time after wounding. TGF-beta (0.1 to 2.0 micrograms/wound) demonstrated a bimodal, dose-dependent acceleration of wound breaking strength 7 days after gastric wounding. An approximate 4-day acceleration of gastric wound breaking strength by TGF-beta (2 micrograms/wound) was seen at 7 and 11 days. Wounds treated with platelet-derived growth factor (10 micrograms/wound) displayed an increased cellular response but no enhancement of breaking strength at 7 and 11 days. These results demonstrate the ability of TGF-beta to accelerate gastrointestinal tissue repair by topical application and suggest significant potential for the use of growth factors in enhancing repair of surgical wounds of the gastrointestinal tract.     

Fascial incisions heal faster than skin: a new model of abdominal wall repair

BACKGROUND: Optimal healing of the fascial layer is a necessary component of complete abdominal wall repair. The majority of acute wound healing studies have focused on the dermis. We designed a model of abdominal wall repair that, to our knowledge, for the first time simultaneously characterizes differences in the wound healing trajectories of the fascia and skin. METHODS: Full-thickness dermal flaps were raised on the ventral abdominal walls of rats, and midline fascial celiotomies were completed. The dimensions of the flap were developed so as to have no detrimental effect on skin healing. The dermal flaps were replaced so that the fascial incisions would heal separately from the overlying skin incisions. Animals were killed 7, 14, and 21 days after operation and fascial and dermal wounds were harvested and tested for breaking strength. Fascial and dermal wounds were also compared histologically for inflammatory response, fibroplasia, and collagen staining. RESULTS: Fascial wound breaking strength exceeded dermal wound breaking strength at all time points (9.16 +/- 2.17 vs 3.51 +/- 0.49 N at 7 days, P <.05). Fascial wounds also developed greater fibroblast cellularity and greater collagen staining 7 days after the incision. There was no difference in wound inflammatory response. CONCLUSIONS: Fascial incisions regain breaking strength faster than simultaneous dermal incisions. The mechanism for this appears to involve increased fascial fibroplasia and collagen production after acute injury.     

Differential effect of tacrolimus on dermal and intestinal wound healing.

Tacrolimus, used in organ transplantation, inhibits cellular immune function. Little is known about the effect on dermal and colonic healing. Groups of 10 rats underwent dorsal skin incision, and polyvinyl alcohol sponges were implanted subcutaneously. Beginning at the day of wounding, rats were treated intraperitoneal with 1.0 or 2.0 mg tacrolimus/kg/day. Animals were sacrificed 10 d later to determine wound breaking strength and reparative collagen deposition. Expression of transforming growth factor (TGF)-beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma was studied in wounds. Groups of 8 rats underwent laparotomy and left colonic anastomosis. These rats were treated by subcutaneous injections with 2.0 or 5.0 mg tacrolimus/kg. Animals were sacrificed 5 d later to test colonic bursting pressure and reparative collagen deposition. Expression of TGF-beta, TNF-alpha, IFN-gamma, and CD4 and CD8 in the anastomosis was investigated. Tacrolimus impaired dermal healing (p < .05). This was paralleled by decreased expression of TGF-beta (stimulates healing) and increased expression of IFN-gamma and TNF-alpha (both inhibit healing) (p < .05). In contrast, tacrolimus did not inhibit healing of colonic anastomoses. No effect was seen on the expression of TGF-beta, TNF-alpha, IFN-gamma, and CD4 and CD8 in colonic anastomoses. We concluded that tacrolimus differentially effects tissue healing and expression of cellular mediators in dermal and intestinal wounds.     

Abdominal wall repair is delayed during hepatic regeneration

BACKGROUND: Abdominal wall wound failure remains a common surgical problem. The signals that activate normal fibroplastic repair versus regeneration pathways are unknown. Transforming growth factor beta levels rise during incisional healing but fall during hepatic regeneration. Changes in the injured host cytokine milieu may therefore differentially effect abdominal wall repair versus hepatic regeneration. MATERIALS AND METHODS: Forty-eight rats were divided into four groups (n = 12). Groups 1-3 underwent sham celiotomy, 70% hepatectomy, or 80% enterectomy with anastamosis. Incisions from Group 4 were treated with either 1 microg of transforming growth factor beta(2) (TGF-beta(2)) or vehicle following hepatectomy. Isolated fascial and dermal incisions were harvested and tested for breaking strength on POD 7. Serum (TGF-beta(2)) and hepatocyte growth factor (HGF) levels were measured by ELISA. RESULTS: Recovery of incisional wound breaking strength was delayed following hepatectomy but not enterectomy (P<0.002). The inhibitory effect was observed in both the fascia and the dermis of the abdominal wall. TGF-beta(2) levels were depressed in hepatectomy animals on POD 7, while at the same time HGF levels were elevated. Exogenous TGF-beta(2) shifted the healing trajectory of deficient wounds back toward a control pattern. CONCLUSION: Abdominal wall fascial and dermal healing is delayed during hepatic regeneration. Elevated HGF and depressed TGF-beta(2) suggest a host mechanism that prioritizes hepatic parenchymal regeneration over fibroplastic repair (scar). Observations such as these are needed as therapeutic wound healing enters the clinical realm.     

MHC-class-II-deficiency impairs wound healing

BACKGROUND: MHC-class-II-deficient mice lack T helper cell dependent immune reactions. T cell related immune functions are critical for normal wound healing. We hypothesized that MHC-II-deficiency compromises wound repair by affecting the normal wound immune response. MATERIAL AND METHODS: Groups of 10 male MHC-class II-knockout mice and wild-type controls underwent dorsal skin incision. Polyvinyl alcohol sponges were then inserted subcutaneously. The mice were sacrificed 10 days later to determine wound breaking strength and reparative collagen deposition. Activity of T cells and macrophages isolated from the spleens and from the healing wounds was investigated. Fibroblasts derived from the wounds were tested ex vivo for proliferative activity and collagen synthesis. RESULTS: Wound collagen deposition and wound breaking strength were impaired in MHC-class-II-knockout mice (P < 0.05). Impaired healing was reflected in diminished mitogen-reactivity of splenic T-cells (P < 0.01), and decreased CD4 expression in wounds. In addition, basal and LPS + IFN-gamma-induced synthesis of TNF-alpha and nitric oxide by wound-derived macrophages was impaired. Exvivo, fibroblast proliferation and fibroblast collagen production from MHC-II-deficient mice was decreased. CONCLUSION: MHC-II-deficiency compromises wound healing. This may be a reflection of impaired wound immune cell function and decreased activity of wound fibroblasts.     

Erythropoietin stimulates wound healing and angiogenesis in mice.

Erythropoietin exerts hematopoietic effects by stimulating proliferation of early erythroid precursors. Nonhematopoietic effects of erythropoietin have also been shown. It may act as a new angiogenic factor in wound healing. This study aimed to investigate the effect of systemic administration of recombinant human erythropoietin on wound healing in mice. Dorsal incisional wounds were performed in mice, which were then divided into two groups; a group treated for 7 days with recombinant human erythropoietin, and a control group. Sacrificing animals on day 7, the wound tissues were collected for analysis of wound breaking strength, malondialdehyde, a marker of lipid peroxidation, hydroxyproline, an index of reparative collagen deposition, reduced glutathione levels, and for histological evaluation. The immunohistochemical determination of vascular endothelial growth factor (VEGF) which is believed to be the most prevalent angiogenic factor throughout the skin repair process, was also studied. The treatment significantly increased wound breaking strength by decreasing malondialdehyde and increasing hydroxyproline levels on day 7 after wounding. No statistically meaningful change was observed in reduced glutathione content. VEGF was immunostained significantly more on wound tissue of treated animals compared to the control group. Recombinant human erythropoietin treatment may be effective in wound healing due to inhibition of lipid peroxidation, deposition of collagen, and VEGF expression in wound area.     

Effect of melatonin on wound healing in normal and pinealectomized rats

Melatonin usage is increasing gradually, but reports of its effects on wound healing are inconsistent. It has been shown that the hormone is synthesized in and secreted from the gastrointestinal system independently of the pineal gland. We have investigated, by means of a comparative study on the healing of incision and anastomotic wounds, whether melatonin has an effect on wound healing independent of the pineal gland. Rats were divided in five groups (n = 10), all of which were subjected to small intestine anastomosis. The first group (control) was otherwise untreated. Exogenous melatonin was given to the rats in second group. The calvaria was opened then closed in the third group (sham operated), whereas the fourth group was pinealectomized and the fifth group were pinealectomized and then treated with melatonin. After anastomosis bursting pressures and incision wound breaking strength were measured on the 7th postoperative day, tissue hydroxyproline levels were determined, and histopathological investigation was performed. It was found that while collagen deposition and epithelization increased concurrently in incision wounds after pinealectomy, only collagen deposition increased at the anastomosis line. Exogenous melatonin decreased collagen synthesis and epithelium proliferation and had negative effects on wound healing in both normal and pinealectomized rats.     

Fascial fibroblast kinetic activity is increased during abdominal wall repair compared to dermal fibroblasts

Abdominal wall fascial wound healing failure is a common clinical problem for general surgeons, manifesting in early postoperative fascial dehiscence as well as delayed development of incisional hernias. We previously reported that abdominal wall fascial incisions normally recover breaking strength faster than simultaneous dermal incisions in a rodent model. The accelerated fascial repair was associated with greater fibroblast cellularity within fascial wounds and increased wound collagen deposition. The current study was designed to determine whether accelerated fascial healing is the result of increased fascial fibroblast kinetic activity as measured by a more efficient fibroblast phenotype for binding to and remodeling a collagen matrix. Using a new model of abdominal wall repair, fibroblast cell cultures were developed from uninjured and wounded fascia and compared to dermal fibroblasts in order to define the fibroproliferative kinetic properties of abdominal wall fibroblasts. Fascial wound fibroblasts produced a more efficient and greater overall collagen lattice compaction compared to dermal fibroblasts. Acute fascial wound fibroblasts also showed enhanced cell proliferation compared to dermal fibroblasts but no significant differences in collagen production when normalized to cell number. These results suggest that fascial fibroblasts express distinct acute repair phenotypes and therefore a specific mechanism for fascial repair following injury.     

Interleukin 2 enhances wound healing in rats

Antigen-stimulated lymphocytes secrete lymphokines which have been shown to enhance in vitro fibroblast migration, proliferation, and protein synthesis. In the present experiments, the effect of human recombinant interleukin 2 (RIL-2) on wound healing was assessed in vivo. Groups of male Lewis rats, 225-250 g, underwent intraperitoneal insertion of osmotic pumps and a 7-cm dorsal skin incision with subcutaneous placement of polyvinyl alcohol sponges under anesthesia. The dorsal wounds were closed with stainless-steel sutures. The dose of RIL-2 administered was 60,000 u/rat/day for 7 days in experiment I, and 140,000 u/rat/day for 7 days in experiment II. Controls received equal volumes of excipient. Animals were sacrificed 10 days post wounding and wound healing was assessed by fresh breaking strength, fixed breaking strength (following 72 hr of Formalin fixation which maximally crosslinks the collagen present), and sponge hydroxyproline content (an index of reparative collagen accumulation). In vivo RIL-2 administration significantly augmented wound fresh and fixed breaking strength and wound collagen synthesis. Higher doses of RIL-2 (experiment II) did not result in further increases in the parameters studied. The data suggest that lymphocytes participate directly in the process of wound healing.     

Exogenous transforming growth factor-beta 2 enhances connective tissue formation and wound strength in guinea pig dermal wounds healing by secondary intent.

The presence of transforming growth factor-beta (TGF-beta) at the site of acute injury, its ability to attract inflammatory and connective tissue cells, and its stimulatory effect on the deposition of connective tissue matrix combine to suggest that it may play a key role in the response to injury. The effect of exogenous TGF-beta form 2 on dermal wounds healing by secondary intent was investigated using a sponge composed of collagen and heparin as a delivery vehicle. Longitudinal lenticular-shaped wounds on the dorsum of adult guinea pigs were treated at the time of wounding with delivery vehicle containing 0.5, 1, or 5 micrograms of purified, bovine bone-derived TGF-beta 2, and were compared with wounds that received vehicle only or were untreated. At days 8 and 14 the amount of connective tissue in the wounds and the extent of epithelialization were determined by histomorphometric methods, and wound breaking strength was determined. At day 8, but not at day 14, wounds treated with 1 or 5 micrograms of TGF-beta 2 contained a significantly higher proportion of connective tissue than did wounds treated with vehicle only, and they also exhibited higher wound strength. No effect on wound size or re-epithelialization was detected. The observations provide evidence that a single treatment with exogenous TGF-beta 2 delivered in collagen/heparin sponge vehicle can accelerate repair in guinea pig dermal wounds allowed to heal by secondary intent.     

Treatment with bone marrow-derived stromal cells accelerates wound healing in diabetic rats

Bone marrow stem cells participate in tissue repair processes and may have a role in wound healing. Diabetes is characterised by delayed and poor wound healing. We investigated the potential of bone marrow-derived mesenchymal stromal cells (BMSCs) to promote healing of fascial wounds in diabetic rats. After manifestation of streptozotocin (STZ)-induced diabetic state for 5 weeks in male adult Sprague-Dawley rats, healing of fascial wounds was severely compromised. Compromised wound healing in diabetic rats was characterised by excessive polymorphonuclear cell infiltration, lack of granulation tissue formation, deficit of collagen and growth factor [transforming growth factor (TGF-beta), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor PDGF-BB and keratinocyte growth factor (KGF)] expression in the wound tissue and significant decrease in biomechanical strength of wounds. Treatment with BMSC systemically or locally at the wound site improved the wound-breaking strength (WBS) of fascial wounds. The improvement in WBS was associated with an immediate and significant increase in collagen levels (types I-V) in the wound bed. In addition, treatment with BMSCs increased the expression of growth factors critical to proper repair and regeneration of the damaged tissue moderately (TGF-beta, KGF) to markedly (EGF, VEGF, PDGF-BB). These data suggest that cell therapy with BMSCs has the potential to augment healing of the diabetic wounds.     

Biology of fetal wound healing: collagen biosynthesis during dermal repair.

The rapid restoration of tissue integrity and breaking strength in healing fetal wounds is mainly a function of fetal wound collagen. In this study, the fetal and adult tissue responses to injury were characterized in terms of changes in collagen biosynthesis. Linear wounds and unwounded skin were incubated with radioactive proline, and collagen synthesis was measured as isotope incorporation into collagenase-sensitive protein. Likewise, noncollagen protein synthesis was represented by isotope incorporation into collagenase-resistant protein. Adult wounds demonstrated a preferential stimulation of collagen as compared with noncollagen protein synthesis after wounding. In contrast, both collagen and noncollagen protein synthesis were significantly elevated in the fetus during the first 5 days postwounding. Despite marked increases in fetal wound collagen synthesis above both unwounded fetal skin and adult wound levels, fetal wounds exhibited no evidence of excessive collagen deposition or scar formation after wounding. These findings suggest that the fetal response to tissue injury is a function of the distinctive qualities of fetal fibroblasts associated with the extracellular wound matrix and may involve rapid collagen turnover and degradation.     

Initiating the inflammatory phase of incisional healing prior to tissue injury

BACKGROUND: The time required for incisional healing accounts for the majority of postoperative pain and convalescence. Impaired healing prolongs the process further. If a method for accelerating acute incisional wound healing could be developed, patients would benefit from decreased wound failure and an earlier return to their premorbid condition. MATERIALS AND METHODS: In a rat dermal model, cytokine or vehicle infiltration prior to incision was performed using a single dose or four daily doses preincision. Planned incision sites were primed with the proinflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) or platelet-derived growth factor BB (PDGF-BB) in an effort to activate the inflammatory phase of healing prior to wounding. At the time of incision closure, one half of the incisions were treated with transforming growth factor beta(2) (TGF-beta(2)). Incisional sites were biopsied and stained with hematoxylin and eosin and immunohistochemistry for inflammatory cells and fibroblast populations and breaking strength was measured. RESULTS: Priming skin with GM-CSF or PDGF-BB mimicked the early inflammatory phase of wound healing. Macrophage staining (EB1) and fibroblast staining (vimentin) were significantly increased prior to incision. Inflammatory priming as well as priming coupled with TGF-beta(2) at the time of the incision closure synergistically improved breaking strength. CONCLUSION: This study demonstrates that sequential therapy consisting of priming of tissue with an inflammatory cytokine followed by application of a proliferative cytokine at the time of incision closure nearly doubles the breaking strength of an acute wound. By manipulating the inflammatory and early proliferative phases of wound healing with tissue growth factors, it may be possible to accelerate acute wound repair and shift the wound healing trajectory to the left.     

Exogenous transforming growth factor-beta amplifies its own expression and induces scar formation in a model of human fetal skin repair.

OBJECTIVE: Fetal skin wounds heal without scarring. To determine the role of TGF-beta 1 in fetal wound healing, mRNA expression of TGF-beta 1 was analyzed in human fetal and adult skin wounds. METHODS: Human fetal skin transplanted to a subcutaneous location on an adult athymic mouse that was subsequently wounded heals without scar, whereas human adult skin heals with scar formation in that location. In situ hybridization for TGF-beta 1 mRNA expression and species-specific immunohistochemistry for fibroblasts, macrophages, and neutrophils were performed in human adult wounds, fetal wounds, and fetal wounds treated with a TGF-beta 1 slow release disk. RESULTS: Transforming growth factor-beta 1 mRNA expression was induced by wounding adult skin. No TGF-beta 1 mRNA upregulation was detected in human fetal skin after wounding. However, when exogenous TGF-beta 1 was added to human fetal skin, induction of TGF-beta 1 mRNA expression in human fetal fibroblasts occurred, an adult-like inflammatory response was detected, and the skin healed with scar formation. CONCLUSIONS: Transforming growth factor-beta 1 is an important modulator in scar formation. Anti-TGF-beta 1 strategies may promote scarless healing in adult wounds.     

Effects of plasma fibronectin on the healing of full-thickness skin wounds in streptozotocin-induced diabetic rats

BACKGROUND: Fibronectin has been shown to assist in wound healing. Impaired wound healing in diabetes mellitus is characterized by a reduction in plasma fibronectin (pFn) at the wound site. This study investigated whether topical application of pFn could improve the impaired wound healing in diabetic rats. MATERIALS AND METHODS: Full-thickness skin wounds were created on the backs of streptozotocin (STZ)-induced diabetic rats. Immediately, human pFn was introduced into the wound bed, while wounds receiving human serum albumin or normal saline were used as controls. Wound closure was monitored using well-recognized wound-healing parameters: epithelialization, vascularization, collagen deposition, and migration of fibroblasts were examined histologically. Transforming growth factor (TGF)-beta1 was measured by immunochemistry. Hydroxyproline levels also were assessed in the wound skin. RESULTS: Wound closure was significantly accelerated by local application of pFn. Furthermore, pFn-treated wounds showed increased fibroblast vascularization, collagen regeneration, and epithelialization. The numbers of infiltrating fibroblasts expressing TGF-beta1 and hydroxyproline levels in pFn-treated wounds were significantly higher than those in the controls. CONCLUSIONS: pFn can improve the impaired healing of diabetic wounds and this effect might involve an increase in the activity of fibroblasts and increased release of TGF-beta1.     

Gene expression in normal and doxorubicin-impaired wounds: importance of transforming growth factor-beta

The function of transforming growth factor-beta (TGF-beta) in vivo remains unknown despite the fact that it has been identified in numerous biologic processes involving the regulation of cell growth including tissue repair. Doxorubicin is a potent antitumor drug that has been shown to have detrimental effects on wound healing. With specific complementary DNA probes for TFG-beta and type 1 collagen, RNA from wounds of rats treated with saline solution and doxorubicin was analyzed for the expression of each gene at different times after wounding. In a second study, either 2 micrograms exogenous TGF-beta or vehicle was added to wounds of rats treated with doxorubicin, and wound RNA was analyzed in a similar manner. In wounds from rats treated with saline solution, messenger RNA (mRNA) for TGF-beta peaks on day 7 after wounding and is also elevated on days 3 and 10; mRNA for collagen is elevated on days 7 and 10. Doxorubicin decreases mRNA for TGF-beta and collagen on each day. Topical application of TGF-beta to wounds of rats treated with doxorubicin increases collagen mRNA levels to normal or supranormal levels. This study suggests that the impaired healing induced by doxorubicin may be a result of decreased gene expression for TGF-beta and that topical replacement of this growth factor may correct the defect.     

Effect of enhanced macrophage function on early wound healing

Although the macrophage is important to wound healing, research has focused on its relationship to fibroblast and collagen synthesis. This study was designed to assess effects of enhanced macrophage function on early wound healing, before established collagen synthesis. Sprague-Dawley rats had dorsal incisions after one of three treatment regimens: (1) saline solution, 0.5 ml administered intravenously, (2) intravenous glucan, a macrophage stimulant, 20 mg; (3) topical glucan, 20 mg. Intravenous therapy was administered 24 hours before and after incision. Breaking strength was significantly increased (p less than 0.01) by both intravenous glucan (49.8 +/- 5.5 gm) and topical glucan (59.7 +/- 5.6 gm) on the fourth day after incision, compared with controls (22.0 +/- 2.6 gm). Similar results occurred on the seventh day after incision. Although formalin fixation significantly enhanced breaking strength in fresh control wounds (22.0 +/- 2.6 vs 39.5 +/- 2.2 gm), no increase occurred in wounds treated with intravenous glucan (49.8 +/- 5.0 vs 55.3 +/- 6.4 gm), indicating maximal cross-linking of collagen. Collagen synthesis, reflected by tritiated proline uptake, was no different in control versus glucan groups. Supernatants from control or glucan-activated macrophages were injected intraperitoneally or applied topically in the rat model. Activated supernatant, both intraperitoneal and topical, resulted in increased breaking strength on the fourth day after incision. Formalin fixation did not increase breaking strength in the activated supernatant groups. We conclude that enhanced macrophage function increases early wound breaking strength. This effect appears unrelated to collagen synthesis but may be related to increased cross-linking of collagen. Similar effects are seen with activated macrophage secretory products administered intraperitoneally or topically.     

Significance of T-lymphocytes in wound healing

To determine the importance of T-lymphocytes in wound healing, we examined the effect of T-lymphocyte depletion on the healing of surgical wounds. Thirty Balb/c mice were injected intraperitoneally with 1 mg of rat anti-mouse (IgG2b) cytotoxic monoclonal antibody (30H12) against the Thy1.2 (all T) determinant. Twenty-four hours later animals showed a greater than 95% depletion of Thy1.2 cells in peripheral blood and spleen. Thirty control mice received nonspecific rat immunoglobulin (1 mg). Twenty-four hours after treatment mice underwent a 2.5 cm dorsal skin incision with subcutaneous placement of polyvinyl alcohol sponges. Injections were repeated at weekly intervals. Wound healing was assessed at 2, 3, and 4 weeks by the breaking strength of wound strips and by the hydroxyproline content of sponge granulomas (an index of wound reparative collagen deposition). Thy1.2 depletion at death was 95% to 57% in peripheral blood and 86% to 68% in the spleen. Both groups gained weight equally. We found that T cell depletion significantly impairs wound breaking strength and wound collagen deposition at all times studied. The data strongly suggest that T-lymphocytes modulate fibroblast activity during normal wound healing.     

Organ preservation I. kidney and pancreas

The present study was performed to determine the effect of cortisosteroid hormones on the mechanical properties and collagen content of healing wounds in rat stomach and duodenum. Long-term cortisol (hydrocortisone) treatment was started 4 weeks before wounding and continued until sacrifice. Wounds were made in the nonglandular part (rumen) and in the glandular oxyntic part (corpus) of the stomach and in duodenum. The wounds were tested 7 and 20 days after operation. Cortisol treatment decreased the mechanical strength of healing wounds in stomach and duodenum. A reduction was found for breaking strength as well as breaking energy. The inhibition was most pronounced early after (7 days) operation, while an apparently normal increase of wound strength was found between 7 and 20 days of healing. A relation between mechanical strength and total collagen content was shown. These findings indicate that the increase of mechanical strength and collagen content in wounds from stomach and duodenum is impaired by systemic long-term corticosteroid treatment. The effect is a delay of the healing process rather than a real inhibition.     

Sirolimus impairs wound healing

Background and aims Clinically, the immunosuppressive drug sirolimus, used in organ transplantation, appears to impair wound healing. Little is known about the mechanisms of action. We investigated the effect of sirolimus on wound healing, and we analyzed the expression of stimulating mediators of angiogenesis (VEGF, vascular endothelial growth factor) and collagen synthesis (nitric oxide) in wounds. Materials and methods Groups of ten rats underwent dorsal skin incision, and polyvinyl alcohol sponges were implanted subcutaneously. Beginning at the day of wounding, rats were treated with 0.5, 2.0, or 5.0 mg sirolimus/kg/day. Animals were killed 10 days later to determine wound breaking strength and reparative collagen deposition. Expression of VEGF and nitric oxide was studied in wounds. Results Splenic lymphocyte proliferative activity was significantly decreased by sirolimus (p < 0.05). Sirolimus levels in wound fluid were found to be approximately two- to fivefold higher than blood levels (p < 0.01). Sirolimus (2.0 and 5.0 mg kg⁻¹ day⁻¹) reduced wound breaking strength (p < 0.01) and wound collagen deposition (p < 0.05). This was paralleled by decreased expression of VEGF and nitric oxide in wounds. Conclusion Experimentally, our data show that sirolimus impairs wound healing, and this is reflected by diminished expression of VEGF and nitric oxide in the wound. Best abstracts — Surgical Forum 2007.