This Month in AJP| Volume 159, ISSUE 2, P385-386, August 2001

This Month in AJP

        Blockade of Receptor for Age (RAGE) Restores Effective Wound Healing in Diabetic Mice

        Wound healing is impaired in diabetic patients, often leading to the development of chronic, non-healing wounds. Diabetic wounds have an inadequate influx of inflammatory cells and decreased phagocytosis. However, it has also been proposed that effective healing is prevented by the production of proinflammatory cytokines and matrix metalloproteinases (MMPs). RAGE is a multiligand member of the immunoglobulin superfamily. Two RAGE ligands, advanced glycation endproducts (AGEs) and EN-RAGEs can initiate chemotaxis and increase the production of tumor necrosis factor, interleukin-6, and interleukin-1. Goova et al (Am J Pathol 2001, 159:513-525) tested the hypothesis that enhanced interaction between these ligands and RAGE would generate proinflammatory cytokines and MMPs diminishing collagen accumulation in diabetic wounds. Blockade of RAGE in genetically diabetic mice with poorly healing excisional wounds accelerated wound closure, suppressed TNF, IL-6, and MMP production and enhanced the development of PDGF-B and vascular endothelial growth factor producing vascularized granulation tissue. The work identifies RAGE activation as an important element in the pathogenesis of wound healing defects in diabetes.

        The Sonic Hedgehog Gene and Intestinal Tract Malformation

        Sonic hedgehog (Shh) is an endoderm-derived protein with a wide spectrum of activity in development. Shh induces mesodermal gene expression in chicken hindgut. Based on these observations, Mo et al (Am J Pathol 2001, 159:765-774) investigated whether Shh may be important in the development of distal hindgut in mammals. Mice with defects in the Shh signaling pathway had defects similar to human anorectal malformation. The abnormalities included imperforate anus, recto-urethral fistula, anal stenosis, and persistent cloaca. These defects were found in mice deficient for Gli 2 and Gli 3, which are transcription factors involved in Shh signaling. The pattern of abnormalities detected by crossing homozygous and heterozygous mutant mice suggests that the development of malformations depends on gene damage. Since anorectal malformations are relatively common defects in humans, these studies indicate that the role of Shh in human distal hindgut malformation should be investigated.

        Dissociation between Inflammation and Parasite Load in IL-4-Deficient Mice

        Chagas disease, caused by Trypanosoma cruzi infection can evolve into a cardiomyopathy characterized by an inflammatory reaction leading to heart enlargement and arrhythmias. It has been assumed that inflammation and parasitism are linked and work in parallel in the pathogenesis of the cardiomyopathy. Soares et al (Am J Pathol 2001, 159:703-709) show that IL-4-deficient mice had reduced parasitism by T. cruzi in their hearts and decreased mortality compared with wild-type control mice. Surprisingly, however, IL-4 knockout mice had an increased inflammatory response characterized by an enhancement of T helper (Th1) immune response. The modulation of the Th1 response may be critical in controlling the outcome of the infection by the parasite.

        VEGF May Be an Autocrine Mediator of Tumor Cell Motility

        Vascular endothelial growth factor (VEGF) is a well-known mediator of angiogenesis in tumors, acting by a paracrine mechanism. Soker et al (Am J Pathol 2001, 159:651-659) studied tumor production and cell motility in prostate cancer cells. They compared two prostate epithelial cell lines, NbE-1, which is non-tumorigenic, and FB2, a clonal derivative of NbE-1, which is highly motile and produces vascularized tumors in rat lung. FB2, the motile tumorigenic cells, expressed high levels of VEGF while VEGF production was negligible in NbE-1 cells. FB2 cells, but not NbE-1, expressed the Flt-1 VEGF receptor tyrosine kinase and had a chemotactic response to VEGF. The authors conclude that VEGF could have two roles in tumor progression: a paracrine role as angiogenesis factor and an autocrine mediator of cell motility.

        Detection of Neuroblastoma Cells in Bone Marrow

        Detection of solid tumor metastatic cells in bone marrow and circulating blood is an important element in assessing prognosis and treatment efficacy in cancer patients. Detection of these cells is particularly difficult because of their low numbers and a strict requirement for the specificity of the detection methods. Hoon et al (Am J Pathol 2001, 159:493-500) developed a sensitive method to detect neuroblastoma cells in bone marrow using GM2/GD2 synthetase (GalNAc-T) mRNA as a marker. The method involved reverse transcriptase-polymerase chain reaction and electrochemiluminescence assays and could detect one neuroblastoma cell among 107 normal blood or bone marrow cells. The technique detected GalNAc-T mRNA in the bone marrow of 15 neuroblastoma patients while tumor cells were detectable by immunocytochemistry in only eight of these patients. After ex vivo immunomagnetic bead purging of the bone marrow of these patients, GalNAc-T mRNA was detectable in five patients but immunocytochemical detection was negative in all patients. Although further comparisons between GalNAc-T mRNA and immunocytochemical analyses are required, the new technique may provide a specific and sensitive molecular marker to detect metastatic neuroblastoma cells in the bone marrow.

        Atherosclerosis as an Inflammatory Disease: IL-15 Expression in Mouse and Human Atherosclerotic Lesions

        In recent years, atherosclerosis has been increasingly considered as an inflammatory disease. Atherosclerotic lesions show macrophage as well as T cell infiltration. Interleukin-15 is a proinflammatory cytokine that promotes T cell recruitment to sites of inflammation. Wuttge et al (Am J Pathol 2001, 159:417-423) report that IL-15 is highly expressed in mouse and human atherosclerotic lesions. Immunostaining for IL-15 localized in both macrophages and smooth muscle cells in atherosclerotic lesions of ApoE-deficient mice. In atherosclerotic plaques of human carotid arteries, IL-15 was detected in macrophages. Upregulation of IL-15 in atherosclerotic lesions may contribute to T cell recruitment and activation during atherogenesis.