The epidermal growth factor receptor is a regulator of epidermal complement component expression and complement activation.

The complement system is activated in response to tissue injury. During wound healing, complement activation seems beneficial in acute wounds but may be detrimental in chronic wounds. We found that the epidermal expression of many complement components was only increased to a minor extent in skin wounds in vivo and in cultured keratinocytes after exposure to supernatant from stimulated mononuclear cells. In contrast, the epidermal expression of complement components was downregulated in ex vivo injured skin lacking the stimulation from infiltrating inflammatory cells but with intact injury-induced epidermal growth factor receptor (EGFR)-mediated growth factor response. In cultured primary keratinocytes, stimulation with the potent EGFR ligand, TGF-α, yielded a significant downregulation of complement component expression. Indeed, EGFR inhibition significantly enhanced the induction of complement components in keratinocytes and epidermis following stimulation with proinflammatory cytokines. Importantly, EGFR inhibition of cultured keratinocytes either alone or in combination with proinflammatory stimulus promoted activation of the complement system after incubation with serum. In keratinocytes treated solely with the EGFR inhibitor, complement activation was dependent on serum-derived C1q, whereas in keratinocytes stimulated with a combination of proinflammatory cytokines and EGFR inhibition, complement activation was found even with C1q-depleted serum. In contrast to human keratinocytes, EGFR inhibition did not enhance complement component expression or cause complement activation in murine keratinocytes. These data demonstrate an important role for EGFR in regulating the expression of complement components and complement activation in human epidermis and keratinocytes and, to our knowledge, identify for the first time a pathway important for the epidermal regulation of complement activation.

Gene expression demonstrates increased resilience toward harmful inflammatory stimuli in the proliferating epidermis of human skin wounds.

We examined the epidermal gene expression during the proliferative phase of wound healing. Matrix metalloproteases were the group of proteases most prominently up-regulated in skin wounds, whereas serine protease inhibitors were the most strongly up-regulated protease inhibitors. Furthermore, we found down-regulation of genes involved in the extrinsic pathway of apoptosis. This together with the up-regulation of inhibitors of leukocyte serine proteases likely represents a protective step to ensure survival of keratinocytes in the inflammatory wound environment. The down-regulation of proapoptotic genes in the extrinsic pathway of apoptosis was not accompanied by a down-regulation of receptors indicating that the keratinocytes in skin wounds did not become less responsive to external stimuli. Examining the transcription factor binding sites in the promoters of the most differentially expressed genes between normal skin and skin wounds a significant overrepresentation of binding sites were found for STAT-5, SRY and members of the FOXO-family of transcription factors.

Pelvic exenteration for advanced and recurrent malignancy.

BACKGROUND: Improved surgical techniques and oncological treatment render many advanced pelvic tumors amenable to curative resection. We evaluated morbidity, survival, and quality of life (QoL) after extended pelvic procedures. METHODS: From January 2003 to November 2008, 85 patients underwent multivisceral pelvic resection; 87% had colorectal or anal malignancies. Preoperatively, endoscopy and imaging procedures were performed, followed by multidisciplinary assessment. Fifty-eight percent received preoperative chemotherapy and pelvic irradiation. Exenteration was total in 32 patients and posterior in 48. Five posterior resections included partial cystectomy and 21 encompassed resection of the bony pelvis. Myocutaneous flaps were used for reconstruction in 33 cases. Urinary diversion was achieved by ileal conduit in 24 and by continent pouch in 8. QoL was evaluated prospectively in 22 late cases. RESULTS: All patients were evaluated. Clear margins were obtained in 66%. Median duration of surgery was 680 (310-1,320) min, and blood loss was 1,800 (350-19,000) ml. Morbidity was 68%, whereof major complications constituted 13%. Median hospital stay was 18 (5-70) days. There was no 90-day mortality. Median follow-up was 24 (3-71) months. Local control was obtained in 77 patients. Twenty-seven manifested disseminated disease without local recurrence, two developed isolated local recurrence, and six had local and systemic recurrences. Twenty-one died after a median of 11 (4-55) months follow-up. Survival was correlated with clear margins and time to relapse. QoL was improved at 16 months after surgery. CONCLUSIONS: Multivisceral pelvic surgery is possible with acceptable morbidity and QoL. Thorough patient selection and multimodal therapy are necessary to attain maximum benefit.

Injury is a major inducer of epidermal innate immune responses during wound healing.

We examined the importance of injury for the epidermal innate immune response in human skin wounds. We found that injury, independent of infiltrating inflammatory cells, generated prominent chemotactic activity toward neutrophils in injured skin because of IL-8 production. Furthermore, injury was a major inducer of the expression of antimicrobial (poly)peptides (AMPs) in skin wounds. In human skin, these injury-induced innate immune responses were mediated by activation of the epidermal growth factor receptor (EGFR). Consequently, inhibition of the EGFR blocked both the chemotactic activity generated in injured skin and the expression of the majority of the AMPs. The importance of injury was confirmed in mouse experiments in vivo, in which injury independent of infection was a potent inducer of AMPs in skin wounds. To our knowledge, these data thereby provide a previously unreported molecular link between injury and neutrophil accumulation and identify the molecular background for the vast expression of IL-8 and AMPs in wounded epidermis. Conceptually, these data show that the growth factor response elicited by injury is important for the recruitment of neutrophils in skin wounds.

Osteopromotion: A Soft-Tissue Exclusion Principle Using a Membrane for Bone Healing and Bone Neogenesis.

The research reviewed in this paper constitutes a series of investigations intended to develop and evaluate a new membrane technique, which provides improved conditions for osteogenesis during healing of bone defects and restitution of earlier existing bone. The technique has also been shown to aid in bone grafting as well as having the capacity to create new bone for reconstructive purposes. According to this methodology, membranes are utilized to create a space in the tissue in which osteogenesis can occur relatively unimpeded. The paper provides a review of our initial animal experimental work as well as some clinical studies with special emphasis on membrane use in conjunction with dental implants. Possible mechanisms behind the efficacy of the membrane technique are reviewed, and future perspectives of development are also discussed. The osteopromotive membrane technique represents a principally new and major advance in bone biology and reconstructive skeletal surgery. Based on the results obtained by us and by others, the technique is presently utilized clinically in some routine applications. J Periodontol 1993; 64:1116-1128.