| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||
Metalloproteinase (MMP-9) Activity Is Required for Retinal Angiogenesis and Contributes to Choroidal Neovascularization: Cathepsin D Inactivation as an Animal Model for Macular Degeneration
We group together three papers dealing with the effect of proteases on eye structures. Two of these papers demonstrate an important role for MMP-9 in retinal angiogenesis and choroidal neovascularization (Hangai et al, Am J Pathol 2002, 161:1429–1437, Lambert et al, Am J Pathol 2002, 161:1247–1253). Another article (Rackoczy et al, Am J Pathol 2002, 161:1515–1524) describes an animal model for macular degeneration in transgenic mice expressing a mutant form of cathepsin D. Aberrant retinal neovascularization is associated with blindness in diabetic retinopathy and macular degeneration. Because the retinal changes caused by neovascularization are irreversible, early detection of vascular changes and knowledge of the mechanisms that regulate neovascularization are essential in preventing these diseases. Proteolytic remodeling may play a very important role in retinal angiogenesis, possibly by exposing cryptic sites in extra cellular matrix (ECM) molecules that may activate signaling pathways involved in neovascularization. Hangai et al show that exposure of a collagen type IV cryptic site is one of the earliest ECM remodeling events required for vessel outgrowth. MMP-9 but not MMP-2 is required for exposure of the cryptic site indicating that MMP-9 activity contributes to cell migration and neovascularization. The paper of Lambert et al demonstrates that MMP-9 expression is induced in choroidal neovascularization coinciding with the migration of inflammatory cells into the lesion. Thus, the papers by Hangai et al and Lambert et al are complementary. Rakoczy et al created a mouse model of age-related macular degeneration (AMD) based on the hypothesis that the pathogenesis of the disease involves the accumulation of photoreceptor outer segment breakdown products leading to damage of retinal pigment epithelial cells. They produced homozygous transgenic mice expressing a mutant form of cathepsin D that is inactive. The impaired processing of phagocytosed photoreceptors in retinal pigment epithelial cells produced to abnormalities similar to those present in AMD. This model is an important tool to study the pathogenesis of macular degeneration.
Error-Prone DNA Polymerase µ May Contribute to the Pathogenesis of B-Cell Non-Hodgkin’s Lymphomas
Maintenance of genetic integrity is highly dependent on the fidelity of DNA replication and the repair of DNA damage. Cells contain DNA polymerases that act on both of these processes. DNA polymerase ß (pol ß) is a well-characterized DNA repair enzyme. However, pol ß, as well as other repair DNA polymerases is error-prone and introduces mutations in DNA during the repair process. A new repair DNA polymerase, pol µ, has been recently described. It is an error-prone repair enzyme with significant homology with deoxynucleotidyltranferase (TdT). In contrast to other DNA polymerases, pol µ is preferentially located in germinal center B cells in lymph nodes and spleen. Chiu et al (Am J Pathol 2002, 161:1349–1355) hypothesized that pol µ may be involved in the development of B cell non-Hodgkin’s lymphomas (B-NHL) by causing mutations during DNA repair. Nineteen of 21 B-NHLs arising from post-germinal center B cells had high pol µ expression as determined by in situ hybridization. In contrast, only two of 16 B-NHLs originating from pre-germinal center B cells had high pol µ expression. Expression of the gene did not correlate with the proliferative index of the tumor and is thus unrelated to the aggressiveness of the tumors. The findings suggest that enhancement of pol µ activity may contribute to the pathogenesis of a subset of B-NHLs.
Molecular Mapping for Sentinel Lymph Nodes
Sentinel lymph node dissection (SLND) with intraoperative mapping has been used to assess the extent of cancer cell spread from a primary tumor. Randomized trials are in progress to determine potential clinical and cost benefit of the procedure. Blue dye and or radioisotopes are generally used as mapping agents. However, there are many limitations in the use of these markers to accurately and more permanently identify sentinel nodes. Taback et al (Am J Pathol 2002, 161:1153–1161) describe a procedure using a molecular probe that can be used to identify sentinel nods in frozen and paraffin sections and does not decay with time. The procedure was validated in experimental animals, but further studies need to be undertaken to determine the reliability and safety of the procedures in humans.
Heterogeneity of Intrahepatic Ductular Cells with Potential Stem-Cell Capacity
Ductular epithelial cells proliferate in toxic liver injury and bile duct damage. This population of cells is heterogeneous and may contain stem-like cells capable of generating both hepatocytes and biliary cells. Because of the lack of well-defined markers to distinguish ductular cells with different functional and developmental capabilities, little is known about the existence of specific lineages among ductular cells. Bisgaard et.al. (Am J Pathol 2002, 161:1187–1198), through the use of subtractive cDNA hybridization, identified 48 genes associated with ductular (oval) cell proliferation in rat liver. Two genes, alphafetoprotein (AF) and gp-340/DMBT1 ("Deleted in Malignant Brain Tumor 1") were specifically associated with the emergence of transit-amplifying stem-like oval cells. In human diseases, gp-340/DMBT1 was expressed in ductular reaction caused by acetaminophen injury or hepatitis B infection but was not detected in biliary diseases. The work demonstrates the modulation of cell lineages among ductular cells and describes a novel marker for the detection of ductular (oval) cells with broad differentiation capacity.
Role of PDGF in Atherosclerosis
Platelet-derived growth factor (PDGF) is released from activated platelets and other cells after injury. It has multiple effects including the ability to stimulate the proliferation of smooth muscle cells. PDGF attracts smooth muscle cells in acute models of vascular injury such as restenosis and vascular grafting. Although smooth muscle cells also accumulate in atherosclerotic lesions, it is not known whether PDGF plays a role in this process. Analysis of this problem is difficult because of the long time needed for the development of atherosclerotic lesions and the lack of an appropriate animal model in which PDGF can be deleted without causing embryonic lethality. Kozaki et al (Am J Pathol 2002, 161:1395–1407) used ApoE-deficient mice that develop atherosclerosis and replenished their circulating cells by transplantation of fetal liver cells of PDGF-B-deficient embryos into irradiated ApoE-deficient animals. Thirty-five weeks after transplantation, vascular lesions in the mice transplanted with PDGF-B-deficient cells were smaller and contained mostly macrophages compared to lesions in ApoE- deficient mice transplanted with PDGF-B-positive cells. However, 45 weeks after transplantation, smooth muscle cell accumulation in fibrous caps of ApoE-deficient mice was the same in PDGF-B negative and positive mice. Similar results were obtained by prolonged administration of PDGF receptor antagonists into ApoE-deficient mice. The results demonstrate that smooth muscle cell accumulation in advanced lesions of atherosclerosis does not depend on PDGF activity.
Blockage of Lung Granuloma Formation
Schistosoma mansoni infection produces a granulomatous response in the lungs which is mediated by cellular events involving the cytokines IL-4 and IL-13. A great deal of work has been done in knockout mice deficient in these cytokines and the STAT3 transcription factor. Based on this knowledge, Jakubzick et al (Am J Pathol 2002, 161:1283–1297) explored therapeutic strategies for S. mansoni-induced lung granulomas that target both cytokines. They injected infected mice with a protein (IL13-PE) which is a chimeric molecule containing human IL-13 and a deriviative of Pseudomonas exotoxin. IL13-PE administration caused an inhibition of IL-4, IL-13, and a large increase in IL-13 decoy receptor expression that further inhibited IL-13 effects. Animals injected with IL13-PE had smaller granulomas and lower collagen levels compared to non-treated infected mice. The results demonstrate that lung granuloma formation induced by S. mansoni eggs can be arrested by the administration of agents that target specific cytokine which are essential for the development of these lesions.
Related articles in Am J Pathol:
| ||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
