Wound healing involves a complex series of interactions between cells in the dermis and epidermis, and important relationships exist between keratinocytes and resident dermal cells. Monocytes and lymphocytes secrete cytokines that are capable of stimulating dermal repair and influencing keratinocyte and fibroblast migration and proliferation, although the mechanism by which mononuclear cells are recruited into the wound is unknown. We have tested the hypothesis that in wounded skin specialized endothelial cells are induced to mediate peripheral blood mononuclear cell (PBMC) emigration from the vasculature into the dermis. For this purpose, partial-thickness wounds made with a keratome on the backs of domestic pigs were excised 0 to 9, 12, 15, and 21 d after wounding. The biopsies were then tested for the capacity to adhere selectively to PBMC. The results indicated that PBMC overlaid onto sections of wounds from day 4 to 15 adhered selectively to dermal endothelium, with two distinct peaks of adherence observed on day 7 and day 12. In contrast, PBMC did not adhere to the tissue sections when overlaid onto frozen sections of normal skin or 0-, 1-, 2-, 3-, and 21-d-old wounded skin. Additional studies on the binding properties of PBMC subsets revealed that monocytes adhered maximally at day 7, whereas T cells adhered optimally at day 12 post-wounding. Furthermore, the adhesion process was energy and magnesium dependent but not calcium dependent and involved surface protein and carbohydrate moieties on PBMC surface. Pre-treatment of PBMC with monoclonal antibodies against the LFA-1 adhesive receptors inhibited the binding by greater than 80%, suggesting that LFA-1 adhesive receptors play an important role in the binding process. These studies provide evidence that the recruitment of monocytes and lymphocytes into wounds is an active, dynamic, and regulated process mediated at least in part by specific adhesive interactions between mononuclear leukocytes and dermal endothelial cells.
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[Show abstract][Hide abstract] ABSTRACT: Adhesion of leukocytes to the vascular endothelium is essential for the movements of cells from the bloodstream into inflammatory sites. In the present study, dermal microvascular endothelial cells (DMEC) isolated from normal porcine skin retained the capacity to adhere 51Cr-labeled porcine peripheral blood mononuclear cells (PBMC), nylon-wool-purified T cells, and isolated monocytes. Transforming growth factor-beta 1 (TGF-beta) decreased the capacities of DMEC to support the adhesion of these cells in a dose-dependent manner. Maximal inhibition was observed with a TGF-beta dose of 0.25 ng/ml and an incubation time of 6-12 h. TGF-beta did not affect the morphology of DMEC and had no adverse effect on the viability of the treated cells. The blocking effects of TGF-beta on PBMC adhesion to DMEC was neutralized by a polyclonal turkey anti-TGF-beta antiserum but not by control turkey serum. Although pretreatment of PBMC with TGF-beta decreased the capacity of these cells to adhere to normal DMEC monolayers, kinetic studies demonstrated that these effects required between 4 and 8 h incubation time. In addition, preincubation of DMEC with TGF-beta completely blocked their response to the stimulating effects of TNF-alpha, IL-1-beta, or both cytokines. Furthermore, TGF-beta also abrogated the enhanced adhesiveness of DMEC pretreated with TNF-alpha and IL-1-beta. These findings suggest that TGF-beta may play an important role in the down-regulation of inflammatory responses by decreasing vascular endothelial adhesiveness for mononuclear cells and monocytes.
[Show abstract][Hide abstract] ABSTRACT: Lymphocytes adhere to dermal microvascular endothelial cells (DMEC) as the first step in their migration from the bloodstream into diseased skin. Psoriasis is characterized by an intense T-lymphocytic infiltrate in the dermis, which may be a consequence of the abnormal regulation of endothelial adhesiveness by cytokines released locally. In the present study, we investigated the effects of tumor necrosis factor-alpha (TNF), interleukin-1 (IL-1), IL-4, and transforming growth factor-beta 1 (TGF-) on the adhesiveness of DMEC isolated from psoriatic plaques or normal skin for human peripheral blood mononuclear cells (PBMC). The results showed that DMEC from both normal and psoriatic skin retain the capacity to adhere to 51Cr-labeled PBMC. Pretreatment of DMEC from normal skin with human recombinant IL-1 or TNF alone or in combination for 8 h significantly (p < 0.01) enhanced their capacity to adhere to human PBMC. Similarly, treatment of normal DMEC with IL-4 also increased endothelial adhesiveness, although this cytokine required an incubation period of 24 h. In parallel studies, DMEC from psoriatic plaques were found to respond to the stimulatory effects of TNF, IL-1, and IL-4 in similar dose- and time-dependent manner. In contrast, although pretreatment of normal DMEC with TGF- (0.1 to 0.25 ng/ml) for 6 to 12 h significantly reduced (p < 0.01) both the unstimulated and IL-1 — and TNF-stimulated endothelial adhesiveness for normal PBMC, TGF- had no effect on the binding of unstimulated or cytokine-stimulated psoriatic DMEC to PBMC, even at concentrations as high as 2 ng/ml and incubation period of 36 h. These results suggest that cytokines stimulate the adhesiveness of DMEC through distinct pathways and provide evidence that TGF- may play an important regulatory role in the control of lymphocyte extravasation into normal skin. The altered responsiveness of psoriatic DMEC to TGF- may contribute to the intense dermal lymphocytic infiltrates in psoriasis.
[Show abstract][Hide abstract] ABSTRACT: Mononuclear cell infiltration is a characteristic feature of wounds and may play an important role in the healing process. We have previously shown that the recruitment of peripheral blood mononuclear cells into wounded skin is an active, dynamic, and regulated process mediated at least in part by specific interactions between mononuclear leukocytes and specialized dermal microvascular endothelial cells in the wounded skin. The purpose of this study was to investigate the capacity of dermal microvascular endothelial cells in wounds exposed to air or covered with occlusive dressings to promote the adhesion of monocytes and lymphocytes. The results showed that dermal microvascular endothelial cells in both air-exposed and occluded wounds were capable of supporting peripheral blood mononuclear cell and monocyte adherence. However, in comparison with air exposed wounds, the level of peripheral blood mononuclear cell binding was significantly higher in occluded biopsies obtained at 0 to 9, 12, 15, and 21 days after wounding. In addition, monocyte and peripheral blood mononuclear cells binding to occluded wounds peaked earlier than peripheral blood mononuclear cell binding to air exposed wounds. These studies provide evidence that differences in the kinetics and magnitude of mononuclear cell adherence may account at least in part for the beneficial effects of occlusive dressing on wound healing.
The Journal of dermatologic surgery and oncology 05/1992; 18(4):279-83. DOI:10.1111/j.1524-4725.1992.tb03672.x