Biomedical subjects

G F Pierce

Publications and source records attributed to G F Pierce.

At least 55 records · Page 3Linked to original sources

PubMed1995

Keratinocyte growth factor causes proliferation of urothelium in vivo.

PURPOSE: To determine the effect of keratinocyte growth factor (KGF), a mesenchymally derived epithelial growth factor that can cause proliferation of pulmonary, gastrointestinal and mammary epithelia, on urothelium. MATERIALS AND METHODS: Recombinant human KGF was systemically administered to rats and Rhesus monkeys, and the proliferative effects on the bladder were evaluated. RESULTS: Keratinocyte growth factor causes proliferation of transitional epithelial cells. Proliferating cell nuclear antigen (PCNA) expression in rat bladder is dramatically increased along the basal layer of urothelium 1, 3, 7 and 14 days after daily injections of KGF. Incorporation of 5-bromodeoxyuridine (BrdU) at 7 and 14 days in the urothelium of KGF-treated rats parallels PCNA immunoreactivity and confirms that KGF increases DNA synthesis in urothelial cells. Urothelial cell proliferation is accompanied histologically by an increase in mitotic activity. Keratinocyte growth factor-induced PCNA expression is reversible upon cessation of KGF administration. Keratinocyte growth factor mRNA and receptor mRNA are detected by whole organ RNAase protection assays of the urinary bladder and the kidney of normal rats. Rhesus monkeys receiving KGF for 7 days demonstrate a dramatic incorporation of BrdU in the urothelium of the bladder and renal pelvis as well as in the collecting ducts of the kidney. CONCLUSION: Systemic administration of KGF causes rapid and striking proliferation of urothelium.

Animals↗

PubMed1994

Hemophilia A.

Explore the source record for details and available documents.

HIV Infections↗

PubMed1994

Stimulation of all epithelial elements during skin regeneration by keratinocyte growth factor.

Keratinocyte growth factor (KGF), a recently discovered 18.9 kD member of the fibroblast growth factor family has been shown to selectively induce keratinocyte proliferation and differentiation in tissue culture. To explore its potential stimulating keratinocyte growth and differentiation in vivo, we analyzed for the influence of KGF on epithelial derived elements within a wound created through the cartilage on the rabbit ear. KGF accelerated reepithelialization (p = 0.004) and increased the thickness of the epithelium (p = 0.0005) when 4-40 micrograms/cm2 recombinant KGF was added at the time of wounding. The regenerating epidermis showed normal differentiation as detected by cytokeratin immunostaining. Remarkably, however, KGF stimulated proliferation and differentiation of early progenitor cells within hair follicles and sebaceous glands in the wound bed and adjacent dermis. There was a transient but highly significant increase in specific labeling of cycling cells in both basal and suprabasal layers that extended into the spinous layer of the regenerating epidermis. As an indication of specificity, the inflammatory cells and fibroblasts within the wound were not influenced by KGF. The results indicate that KGF is unique in its ability to accelerate reepithelialization and dermal regeneration by targeting multiple epithelial elements within the skin. These results suggest that KGF may induce specific epithelial progenitor cell lineages within the skin to proliferate and differentiate, and thus may be a critical determinant of regeneration of skin. Furthermore, these findings illustrate the potential capacity of this system to analyze epithelial differentiation programs and disorders of epidermis, dermal glandular elements, and hair follicles.

Animals↗

PubMed1994

A phase II study to evaluate recombinant platelet-derived growth factor-BB in the treatment of stage 3 and 4 pressure ulcers.

OBJECTIVE: To determine the efficacy of the daily topical application of recombinant platelet-derived growth factor-BB (rPDGF-BB), a recognized vulnerary agent, in the treatment of deep pressure ulcers. DESIGN: Prospective, randomized, double-blind trial. SETTING: Patients were treated in a nursing home or a hospital setting before transfer to a nursing home. PATIENTS: Eligibility criteria included a clean pressure ulcer that had been adequately debrided and the absence of severe cardiac, pulmonary, or renal conditions. The causes of the ulcers were not related to a venous or arterial vascular disorder. The patients were elderly (mean age, 68 to 74 years). INTERVENTIONS: After randomization, patients were given daily topical aqueous rPDGF-BB (dosage, 100 or 300 micrograms/mL) or placebo and saline gauze dressings were applied daily in addition to frequent turning. MAIN OUTCOME MEASURE: Serial volume measurements of the healing wounds were taken using alginate molds. RESULTS: The ulcers of 41 patients were analyzed. At the end of 28 days, median ulcer volumes had decreased to 83%, 29%, and 40% of the initial size in the groups receiving placebo, rPDGF-BB, 100 micrograms/dL, and rPDGF-BB, 300 micrograms/mL, respectively. When adjusted for initial volume, ulcer volume after 28 days of treatment was smaller in the rPDGF-BB-treated groups compared with the placebo group (analysis of covariance, P = .056). Ulcers in the two rPDGF-BB-treated groups were significantly smaller in volume compared with those in the placebo group, using a linear contrast procedure. CONCLUSIONS: Data from this small trial suggest that local application of rPDGF-BB may be of therapeutic benefit in accelerating the healing of chronic pressure ulcers.

Administration, Topical↗

PubMed1994

Actions of platelet-derived growth factor isoforms in mesangial cells.

Platelet-derived growth factor (PDGF) occurs as homodimers or heterodimers of related polypeptide chains PDGF-BB, -AA, and -AB. There are two receptors that bind PDGF, termed alpha and beta. The beta receptor recognizes PDGF B chain and is dimerized in response to PDGF BB. The alpha receptor recognizes PDGF B as well as A chains and can be dimerized by the three dimeric forms of PDGF AA, AB, and BB. To characterize PDGF receptor signaling mechanisms and biologic activities in human mesangial cells (MC), we explored the effects of the three PDGF isoforms on DNA synthesis, phospholipase C activation, and PDGF protooncogene induction. PDGF-BB homodimer and AB heterodimer induced a marked increase in DNA synthesis, activation of phospholipase C, and autoinduction of PDGF A and B chain mRNAs, whereas PDGF-AA homodimer was without effect. The lack of response to PDGF AA could be accounted for by down-regulation of the PDGF-alpha receptor since preincubation of MC with suramin restored PDGF AA-induced DNA synthesis. Ligand binding studies demonstrate specific binding of labeled PDGF BB and AB and to a lower extent PDGF AA isoforms to mesangial cells. These results are consistent with predominant expression of PDGF beta receptor in MC, which is linked to phospholipase-C activation. The potent biologic effects of PDGF-AB heterodimer in cells that express very few alpha receptors and do not respond to PDGF AA are somewhat inconsistent with the currently accepted model of PDGF receptor interaction and suggest the presence of additional mechanisms for PDGF isoform binding and activation.

Biological Transport↗

PubMed1994

Role of hypoxia in growth factor responses: differential effects of basic fibroblast growth factor and platelet-derived growth factor in an ischemic wound model.

Both recombinant basic fibroblast growth factor and platelet-derived growth factor-BB homodimer are potent inducers of new tissue generation in models of normal dermal repair. However, their therapeutic targets include chronic wounds, which are frequently characterized by local tissue hypoxia. To explore the potential of recombinant basic fibroblast growth factor and platelet-derived growth factor-BB homodimer to stimulate more clinically relevant repair, we created an ischemic dermal wound on the rabbit ear by ligating two of the arteries which feed the ear. Both recombinant basic fibroblast growth factor and platelet-derived growth factor-BB homodimer stimulated marked neovascularization of the wound (p < 0.0001), but only recombinant platelet-derived growth factor-BB homodimer accelerated and augmented granulation tissue formation (p = 0.01) and reepithelialization. This study is the first demonstration of a direct angiogenic effect of recombinant platelet-derived growth factor-BB homodimer in vivo. India ink perfusion coupled with endothelial cell-specific histochemistry showed that nearly all the neovessels in all wounds were functional, indicating rapid capillary morphogenesis. In the nonischemic (normal) rabbit ear, recombinant basic fibroblast growth factor and platelet-derived growth factor-BB homodimer accelerated healing comparably, as expected. Higher doses of recombinant basic fibroblast growth factor also failed to elicit stimulatory effects in ischemic wounds. These results indicate that differential responsiveness to growth factors is related to local tissue hypoxia, angiogenesis alone is an insufficient stimulus for repair. These data also suggest new therapeutic approaches for the treatment of chronic wounds.

Journal Article↗

PubMed1994

Keratinocyte growth factor is a growth factor for type II pneumocytes in vivo.

Keratinocyte growth factor (KGF) administered as a single intratracheal injection causes a prominent dose-dependent proliferation of type II alveolar epithelial cells in the lungs of adult rats. The increase in mitotically active alveolar cells histologically appears as a micropapillary epithelial cell hyperplasia after 2 d and peaks after 3 d in the form of monolayers of cuboidal epithelial cells lining alveolar septae. Proliferating cell nuclear antigen immunohistochemistry confirmed the profound proliferative response induced by KGF. The hyperplastic alveolar lining cells contain immunoreactive surfactant protein B and are ultrastructurally noted to contain lamellar inclusions characteristic of surfactant-producing type II pneumocytes. Mild focal bronchiolar epithelial hyperplasia is noted but is much less striking than the proliferation of type II pneumocytes. Large airways are unaffected by KGF. Daily intravenous injection of KGF is also able to cause pneumocyte proliferation. The normal adult rat lung constitutively expresses both KGF and KGF receptor mRNA, suggesting that endogenous KGF may be implicated in the paracrine regulation of the growth of pneumocytes. In conclusion, KGF rapidly and specifically induces proliferation and differentiation of type II pneumocytes in the normal adult lung.

Animals↗

PubMed1994

De novo generation of permanent neovascularized soft tissue appendages by platelet-derived growth factor.

Treatment of wounds with pharmacologic doses of the BB homodimeric form of recombinant PDGF (rPDGF-BB) induces the recruitment, activation, and proliferation of mesenchymal cells, resulting in the deposition of provisional, and subsequently collagen-containing extracellular matrix. In preliminary experiments with an in vitro growth chamber model in the rat consisting of a silicone shell containing a dissected femoral vascular bundle, we found that rPDGF-BB incorporated into a rapidly dissolving collagen type I film induces the generation of a marked, but transient amount of de novo tissue around the femoral vascular bundle. In the present studies, the new tissue generated around the femoral vascular bundle was wrapped with a full thickness syngeneic skin graft to determine if functional support of the graft would lead to sustained maintenance of the underlying generated tissue and create an epithelialized soft tissue appendage. The tissue generated after a single application of rPDGF-BB was skin grafted on the 10th day, exteriorized 20 d later, and observed for an additional month. This led to the formation of soft tissue appendages which demonstrated marked neovascularization, fibroblast migration and proliferation, and increased glycosaminoglycan, fibronectin, and collagen fibril deposition, now leading to preservation of the newly generated tissue. In contrast, minimal new tissue was generated in control-treated vascular bundles or bundles treated with inactive PDGF-BB, and grafting with skin failed to sustain the underlying tissue. Thus, rPDGF-BB coupled with skin grafting induced the formation of functional large soft tissue appendages which are potentially useful clinically to fill tissue defects or to serve as a cell delivery system for transfected genes.

Animals↗

PubMed1994

Keratinocyte growth factor induces proliferation of hepatocytes and epithelial cells throughout the rat gastrointestinal tract.

Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, was identified as a specific keratinocyte mitogen after isolation from a lung fibroblast line. Recently, recombinant (r)KGF was found to influence proliferation and differentiation patterns of multiple epithelial cell lineages within skin, lung, and the reproductive tract. In the present study, we designed experiments to identify additional target tissues, and focused on the rat gastrointestinal (GI) system, since a putative receptor, K-sam, was originally identified in a gastric carcinoma. Expression of KGF receptor and KGF mRNA was detected within the entire GI tract, suggesting the gut both synthesized and responded to KGF. Therefore, rKGF was administered to adult rats and was found to induce markedly increased proliferation of epithelial cells from the foregut to the colon, and of hepatocytes, one day after systemic treatment. Daily treatment resulted in the marked selective induction of mucin-producing cell lineages throughout the GI tract in a dose-dependent fashion. Other cell lineages were either unaffected (e.g., Paneth cells), or relatively decreased (e.g., parietal cells, enterocytes) in rKGF-treated rats. The direct effect of rKGF was confirmed by demonstrating markedly increased carcinoembryonic antigen production in a human colon carcinoma cell line, LIM1899. Serum levels of albumin were specifically and significantly elevated after daily treatment. These results demonstrate rKGF can induce epithelial cell activation throughout the GI tract and liver. Further, endogenous KGF may be a normal paracrine mediator of growth within the gut.

Animals↗

PubMed1994

Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor: differential action on incisional wound healing.

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) specifically stimulates granulocyte, macrophage, and eosinophil colonies; granulocyte colony-stimulating factor (G-CSF) acts directly on neutrophil-restricted progenitor cells in their proliferation. Those cells have been implicated in the process of wound healing. METHODS: Paired 6 cm incisions were made on rats; GM-CSF or G-CSF was given systemically (100 micrograms/kg/dose) or locally (30 micrograms/wound). The controls received vehicle alone. Impaired healing was induced by injection of methylprednisolone (30 mg/kg). White blood cells (WBC) were counted at day 2 after treatment. Tissue strips were evaluated for tensiometry and histologic features at days 7 and 14 after wounding. RESULTS: For local GM-CSF treated incisions, the breaking strength was 25% stronger than controls at day 7 (p = 0.004), 36% at day 14 (p < 0.0001), and 42% at day 7 (p = 0.012) in impaired animals. Local G-CSF and systemic GM-CSF and G-CSF increased circulating WBC (p < 0.05), but they had no effects on healing. Histologic studies revealed an increase of wound cellulity at day 7 and day 14 in topical GM-CSF treated wounds. CONCLUSIONS: These results suggest GM-CSF is an activator of tissue macrophages and that increasing circulating WBC did not affect wound healing.

Animals↗

PubMed1994

Keratinocyte growth factor induces pancreatic ductal epithelial proliferation.

Keratinocyte growth factor (KGF) causes a proliferation of pancreatic ductal epithelial cells in adult rats after daily systemic administration for 1 to 2 weeks. Even before the proliferation of intralobular ducts is histologically evident, KGF also induces proliferating cell nuclear antigen expression within the ductal epithelium of intercalated, intralobular, and interlobular ducts. KGF also causes incorporation of 5-bromodeoxyuridine in ductal epithelial cells. Epithelial cell proliferation is histologically most prominent at the level of the intralobular ducts adjacent to and within the islets of Langerhans. Pancreatic ductal proliferation is not histologically apparent in rats sacrificed 7 to 10 days after the cessation of KGF administration. The pancreatic hormones insulin, glucagon, somatostatin, and pancreatic polypeptide are normally distributed within islets that demonstrate intrainsular ductal proliferation. The proliferating ductal epithelium does not show endocrine differentiation as evidenced by the lack of immunoreactivity for pancreatic hormones. KGF is a potent in vivo mitogen for pancreatic ductal epithelial cells.

Animals↗

PubMed1994

Keratinocyte growth factor causes cystic dilation of the mammary glands of mice. Interactions of keratinocyte growth factor, estrogen, and progesterone in vivo.

Keratinocyte growth factor (KGF) is a paracrine mediator of epithelial cell proliferation that has been reported to induce marked proliferation of mammary epithelium in rats. In this study, systemic administration of KGF into naive and oophorectomized mice causes mammary gland proliferation, as evidenced histologically by the appearance of cysts lined by a single layer of epithelium and by hyperplastic epithelium. Whole mount preparations of the mammary glands reveal that the histologically noted cysts are actually ducts that are dilated along much of their length. The histology of the mammary glands of KGF-treated mice is similar to the histology of fibrocystic disease in the human female breast. The response in mice differs significantly from the appearance of the mammary glands in KGF-treated rats in which ductal epithelial proliferation is most prominent. Estrogen and progesterone when administered in combination but not alone cause the development of numerous endbuds in the mouse mammary gland. KGF in estrogen- and progesterone-pretreated mice causes the growth of dilated ducts, hyperplastic epithelium within ducts and endbuds, and a fibrous metamorphosis of periductal adipose tissue. The mammary epithelial hyperplasia caused by KGF is rapidly reversible in both mice and rats after cessation of KGF treatment. The spectrum of KGF-, estrogen-, and progesterone-induced mammary histopathology in mice provides a model for the study of fibrocystic and hyperplastic breast disease.

Animals↗

PubMed1994

Tissue repair processes in healing chronic pressure ulcers treated with recombinant platelet-derived growth factor BB.

Cellular and molecular mechanisms responsible for the observed vulnerary effects of recombinant human platelet-derived growth factor BB (rP-DGF-BB) in man have not been elucidated. In a double-blinded trial, patients having chronic pressure ulcers were treated topically with either rPDGF-BB or placebo for 28 days. To explore how rPDGF-BB may induce chronic wounds to heal, biopsies were taken from the ulcers of a cohort of 20 patients from the trial and evaluated in a blinded fashion by light microscopy for 1), fibroblast content, 2) neovessel formation, and 3), collagen deposition. Electron microscopy also was used to assess fibroblast activation and collagen deposition. Before initiation of therapy most wounds had few fibroblasts and most of those present were not activated. When mean scores for the total active treatment phase (days 8, 15, and 29) for rPDGF-BB-treated ulcers were compared with the scores for placebo-treated ulcers, fibroblast content was significantly higher for the rPDGF-BB-treated ulcers (P = 0.03, Kruskal-Wallis test). More significant differences in fibroblast and neovessel content were observed when six nonhealing wounds were eliminated from the analysis (three placebo, three treatment). Thus, in all healing wounds, rPDGF-BB therapy significantly increased fibroblast (P = 0.0007) and neovessel (P = 0.02) content. These results were correlated with increased collagen fibrillogenesis by fibroblasts from healing rPDGF-BB-treated wounds, as assessed by intracellular procollagen type I immunostaining, and by electron microscopy, and were concordant with clinical measurements (eg, area of ulcer opening and ulcer volume) which showed greater healing in rPDGF-BB-treated wounds. These results suggest induction of fibroblast proliferation and differentiation is one mechanism by which rPDGF-BB can accelerate wound healing and that rPDGF-BB can augment healing responses within a majority of, but not all, nonhealing chronic pressure ulcers in man.

Antibodies↗

PubMed1994

Keratinocyte growth factor is a growth factor for mammary epithelium in vivo. The mammary epithelium of lactating rats is resistant to the proliferative action of keratinocyte growth factor.

Keratinocyte growth factor (KGF) is a member of the fibroblast growth factor (FGF) family. KGF is secreted by stromal cells and affects epithelial but not mesenchymal cell proliferation. KGF injected intravenously was found to cause dramatic proliferation of mammary epithelium in the mammary glands of rats. KGF causes ductal neogenesis and intraductal epithelial hyperplasia but not lobular differentiation in nulliparous female rats. KGF causes ductal and lobular epithelial hyperplasia in male rats. KGF causes proliferation of ductal and acinar cells in the mammary glands of pregnant rats. On the other hand, the ductal epithelium of lactating postpartum rats is resistant to the proliferative action of KGF. The mammary glands of lactating rats did not express less KGF receptor mRNA than the glands of pregnant rats, suggesting that the resistance of the ductal epithelium to KGF during lactation is not related to KGF receptor mRNA down-regulation. The mammary glands of both pregnant and postpartum lactating rats express KGF mRNA with more KGF present in the glands of lactating rats. In conclusion, the KGF and KGF receptor genes are expressed in rat mammary glands and recombinant KGF is a potent growth factor for mammary epithelium.

Animals↗

PubMed1993

Role of platelet-derived growth factor in osteoblast function and bone synthesis.

In vitro studies have shown that platelet-derived growth factor binds to specific receptors on osteoblasts and induces proliferation. Some reports also indicate that platelet-derived growth factor may inhibit differentiation of bone cells. Such findings are difficult to interpret, however, because many of these studies used impure platelet-derived growth factor extracted from platelets (rather than pure, recombinant platelet-derived growth factor), used mixed cell populations, and added serum to the culture media (likely introducing additional growth factors). In vivo studies also have yielded conflicting results regarding the effects of platelet-derived growth factor on bone formation. Platelet-derived growth factor may act in concert with insulin-like growth factor I to induce bone formation in a canine periodontal system. Other investigators, however, have shown that platelet-derived growth factor inhibits the effects of osteoinductive proteins such as osteogenin. No evidence of bone formation has been detected in patients receiving platelet-derived growth factor treatment of soft tissue wounds overlying bony prominences in clinical trials. Thus, despite the observations that osteoblasts can specifically bind and proliferate in response to platelet-derived growth factor in tissue culture, platelet-derived growth factor alone has not yet been proved to be osteoinductive in vivo. These observations suggest that in the presence of the many cytokines and multiple cell types found in wounds and fractures, the direct effects of platelet-derived growth factor on osteoblasts are eclipsed.

Journal Article↗

PubMed1993

Platelet-derived growth factor inhibits bone regeneration induced by osteogenin, a bone morphogenetic protein, in rat craniotomy defects.

Platelet-derived growth factor (PDGF) is a potent moderator of soft tissue repair through induction of the inflammatory phase of repair and subsequent enhanced collagen deposition. We examined the effect of recombinant BB homodimer PDGF (rPDGF-BB) applied to rat craniotomy defects, treated with and without bovine osteogenin (OG), to see if bone regeneration would be stimulated. Implants containing 0, 20, 60, or 200 micrograms rPDGF-BB, reconstituted with insoluble rat collagenous bone matrix containing 0, 30, or 150 micrograms OG, were placed into 8-mm craniotomies. After 11 d, 21 of the 144 rats presented subcutaneous masses superior to the defect sites. The masses, comprised of serosanguinous fluid encapsulated by fibrous connective tissue, were larger and occurred more frequently in rats treated with 200 micrograms rPDGF-BB, and were absent in rats not treated with rPDGF-BB. The masses underwent resorption within 28 d after surgery. OG (2-256 micrograms) caused a dose-dependent increase in radiopacity and a marked regeneration of calcified tissue in a dose-dependent fashion within defect sites. However, OG-induced bone regeneration was inhibited 17-53% in the presence of rPDGF-BB. These results suggest that rPDGF-BB inhibited OG-induced bone regeneration and stimulated a soft tissue repair wound phenotype and response.

Animals↗

PubMed1993

Tissue generation with growth factors.

BACKGROUND: An in vivo experimental model was introduced to determine whether the mitogenic effect of recombinant platelet-derived growth factor (rPDGF) could be used to generate potentially useful tissue. METHODS: In Lewis rats, the extended femoral arteriovenous bundle was placed within silicone chambers containing collagen disks. The disks could deliver their content of rPDGF-BB (125 to 131 micrograms/disk) either as a rapid pulse or as a slow release. The time course of tissue generation was determined by harvesting the specimens at various postoperative days. The effect of continuous versus pulsed delivery was determined at 30 days. Analysis of the generated tissue was performed by use of histomorphometry. RESULTS: Pulsed delivery of rPDGF-BB induced the formation of a substantial amount of tissue that peaked at 10 to 15 days (145.9 +/- 13.8 vs 35.0 +/- 6.8 mm3, p < 0.0001); however, the generated tissue completely subsided by day 30. Sustained delivery of rPDGF-BB caused continuous growth of the tissue and was more effective than pulsed delivery. CONCLUSIONS: In an experimental model that approximates an in vivo tissue culture system, rPDGF-BB can induce a tenfold increase in tissue within the chamber. However, that tissue is labile and its survival necessitates continuous rPDGF-BB delivery. To become useful for reconstructive purposes, means to stabilize this new tissue growth are needed.

Animals↗

PubMed1993

Acceleration of tissue repair by transforming growth factor beta 1: identification of in vivo mechanism of action with radiotherapy-induced specific healing deficits.

BACKGROUND: Transforming growth factor beta 1 (TGF-beta 1) is an effective accelerator of soft tissue repair in both normal and impaired healing models; however, its in vivo mechanism of action remains unclear. Modern radiation techniques can create unique healing deficits, allowing for a more specific definition of tissue response to growth factor therapy. In the rat linear skin incision model, cobalt 60 photon beam total body irradiation (TBI), 800 rads, causes a marked depression of circulating monocytes and largely spares the skin tissue. Megavoltage electron beam surface irradiation (SI), 2500 rads, markedly impairs surface healing while sparing the bone marrow. With these models of selective healing deficits, the ability of TGF-beta 1 to accelerate tissue repair directly in the absence of circulating macrophage precursors (TBI) or in the presence of damaged dermal fibroblasts (SI) was evaluated. METHODS: Adult male Sprague-Dawley rats were randomly assigned to groups of TBI, SI, or nonirradiated sham controls and received radiation 2 days before wounding. Paired linear full-thickness skin incisions were created and a single dose of TGF-beta 1 (2 micrograms/wound) or vehicle control was applied to each wound. RESULTS: Both radiation techniques produced a marked healing deficit when assessed on postwounding days 7 and 12. TBI treatment was characterized by severe monocytopenia, confirmed by a tissue macrophage-specific immunohistochemical technique. On days 7 and 12 after wounding, TGF-beta 1 significantly accelerated soft tissue repair and wound-breaking strength in the TBI-treated rats, demonstrating an ability to directly promote the induction of collagen synthesis in the absence of monocytes/macrophages. In contrast, TGF-beta 1 was unable to reverse the SI-induced healing deficit characterized by impaired function of dermal fibroblasts. CONCLUSIONS: These in vivo observations provide further evidence for a direct mechanism of action by TGF-beta 1 on collagen synthesis by wound fibroblasts during soft tissue repair.

Animals↗