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Altered inflammation in the early stage has long been assumed to affect subsequent steps of the repair process that could influence proper wound healing and remodeling. However, the lack of explicit experimental data makes the connection between dysregulated wound inflammation and poor wound healing elusive. To bridge this gap, we used the established rabbit ear hypertrophic scar model for studying the causal effect of dysregulated inflammation. We induced an exacerbated and prolonged inflammatory state in these wounds with the combination of trauma-related stimulators of pathogen-associated molecular patterns from heat-killed Pseudomonas aeruginosa and damage-associated molecular patterns from a dermal homogenate. In stimulated wounds, a heightened and lengthened inflammation was observed based on quantitative measurements of IL-6 expression, tissue polymorphonuclear leukocytes infiltration, and tissue myeloperoxidase activity. Along with the high level of inflammation, wound healing parameters (epithelial gap and others) at postoperative day 7 and 16 were significantly altered in stimulated wounds compared to unstimulated controls. By postoperative day 35, scar elevation of stimulated wounds was higher than that of control wounds (scar elevation index: 1.90 vs.

Infection by Kaposi's sarcoma-associated herpesvirus (KSHV) is required for the development of Kaposi's sarcoma (KS), a highly inflammatory angiogenic tumor of endothelial cells commonly found in untreated AIDS patients. Angiopoietin 2 (Ang-2) modulates the vasculature during inflammation and angiogenesis, but the mechanism by which KSHV regulates Ang-2 expression has not been investigated. Here, we show that KSHV infection of primary human umbilical vein endothelial cells induced the expression and release of Ang-2, which in turn was required for KSHV-induced paracrine-dependent angiogenesis in vivo. Ang-2 was strongly expressed in small vessels and spindle tumor cells in KS tumors. Mechanistically, KSHV activated the Ang-2 promoter via AP-1 and Ets1 transcriptional factors, which were mediated by ERK, JNK, and p38 mitogenactivated protein kinase (MAPK) pathways. Our findings demonstrate the importance of Ang-2 in KS angiogenesis and define a novel role for AP-1 and MAPK pathways in regulating angiogenesis. This study also illustrates a distinct mechanism by which a tumor virus modulates vasculature to promote tumorigenesis and exemplifies the convergence of oncogenesis and angiogenesis pathways in tumor development.

Matrix metalloproteinases (MMPs) play important roles in cancer invasion, angiogenesis, and inflammatory infiltration. Kaposi's sarcoma is a highly disseminated angiogenic tumor of proliferative endothelial cells linked to infection by Kaposi's sarcoma-associated herpesvirus (KSHV). In this study, we showed that KSHV infection increased the invasiveness of primary human umbilical vein endothelial cells (HUVEC) in a Matrigelbased cell invasion assay. KSHV-induced cell invasion was abolished by an inhibitor of MMPs, BB-94, and occurred in both autocrine-and paracrine-dependent fashions. Analysis by zymography and Western blotting showed that KSHV-infected HUVEC cultures had increased secretion of MMP-1, -2, and -9. KSHV increased the secretion of MMP-2 within 1 h following infection without upregulating its mRNA expression level. In contrast, the secretion of MMP-1 and -9 was not increased until 6 h after KSHV infection and was correlated with the upregulation of their mRNA expression levels. Promoter analysis by reporter assays and electrophoretic mobility shift assays identified an AP-1 cis-element as the dominant KSHV-responsive site in the MMP-1 promoter. Together, these results suggest that KSHV infection modulates the production of multiple MMPs to increase cell invasiveness and thus contributes to the pathogenesis of KSHV-induced malignancies.

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