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Tips from the American Journal of Pathology

Toxin Does Not Affect MRSA-Induced Pneumonia

A group led by Dr. James M. Musser at the Center for Molecular and Translational Human Infectious Diseases Research of The Methodist Hospital Research Institute in Houston, Texas has demonstrated that the cytotoxin Paton-Valentine leukocidin (PVL) does not affect methicillin-resistant Staphlococcus aureus (MRSA)-induced pneumonia. Their report can be found in the March 2010 issue of The American Journal of Pathology.

Community-associated-MRSA causes a wide spectrum of infections, ranging from mild skin problems to fatal invasive diseases. MRSA spreads rapidly from initial topical symptoms to affect vital organs, often resulting in widespread infection, toxic shock, and 'flesh eating' pneumonia. MRSA is resistant to traditional anti-staphylococcal beta-lactam antibiotics and is therefore much more difficult to treat.

The cytolytic toxin PVL is a CA-MRSA virulence factor that has been epidemiologically associated with the development of invasive, and sometimes fatal, pneumonia in affected patients and has therefore become a target for new therapeutics. To explore the role of PVL in invasive MRSA, Olsen et al examined both wild-type and PVL-deficient MRSA in a model of CA-MRSA pneumonia. They found no effect of PVL on virulence in MRSA-associated pneumonia, as a PVL-mutated strain caused similar lower respiratory tract pathology as a wild-type strain. These data highlight the importance of context in the pathogenesis of MRSA-associated pneumonia.

Addition studies are underway by Dr. Musser and colleagues "to test the hypothesis that PVL enhances pathogenesis during influenza virus co-infection. These studies are especially important in the context of the recent global spread of a H1N1 influenza strain and widespread concerns about a detrimental effect on human health."

Olsen RJ, Kobayashi SD, Ayeras AA, Ashraf M, Graves SF, Ragasa W, Humbird T, Greaver JL, Long D, Cantu C, Swain JL, Jenkins L, Blasdel T, Cagle P, Gardner DJ, DeLeo FR, Musser JM: Lack of a major role of Staphylococcus aureus Panton-Valentine leukocidin in lower respiratory tract infection in non-human primates. Am J Pathol 2010, 176: 1346-56

Novel Inhibitor of Tumor Angiogenenesis

Dr. Suneel S. Apte and colleagues at the Lerner Research Institute, Cleveland Clinic Foundation in Cleveland, OH have discovered that the metalloprotease ADAMTS9 inhibits tumor angiogenesis. They present these findings in the March 2010 issue of The American Journal of Pathology.

Angiogenesis, or the growth of new blood vessels, is a critical step in the transition of tumors from dormant to malignant. Therefore, angiogenesis inhibitors form a major therapeutic approach to cancer treatment.

The metalloprotease ADAMTS9 functions as a tumor suppressor in throat and nose cancer. Mice partially deficient for Adamts9 spontaneously form new blood vessels, suggesting that it may play an inhibitory role in tumor angiogenesis. Koo et al found that capillary cells in both healthy tissue and tumors expressed ADAMTS9. Moreover, mice that lack one copy of Adamts9 had a greater level of new vessel formation in tumors than wild-type mice, and blocking ADAMTS9 in vitro resulted in increased signs of vessel formation. Indeed, ADAMTS9 inhibits angiogenesis through a different mechanism than a similar molecule, ADAMTS1.

Dr. Apte and colleagues conclude that "ADAMTS9 may be of broad relevance to all angiogenesis-dependent cancers through its novel and constitutive expression in capillary [endothelial cells] and physiological anti-angiogenic role."

Koo B-H, Coe DM, Dixon LJ, Somerville RPT, Nelson CM, Wang LW, Young ME, Lindner DJ, Apte SS: ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells. Am J Pathol 2010 176, 1494-1504

New Pathway in the Development of Colon Cancer

Researchers led by Dr. Dalila Darmoul of the Institut National de la Sant et de la Recherche Mdicale (INSERM) in Paris, France have found that Kallikrein-related peptidase 4 (KLK4) may activated protease-activated receptors (PARs), promoting the development of colon cancer. They report their data in the March 2010 issue of The American Journal of Pathology.

Colon cancer causes 655,000 deaths worldwide per year and is the fifth most common form of cancer in the United States. Colon cancers arise from usually benign polyps in the colon, which may develop into cancer over time.

Proteases promote cancer progression both by degrading the extracellular matrix and by signaling through PARs, which can induce proliferation and motility in colon cancer cells. The physiological activators of PARs in colon cancer remain unknown. Gratio et al hypothesized that KLKs, which have been shown to function as PAR activators in vitro and in vivo, may activate PARs in colon cancer. They found that KLK-4 was expressed in colon adenocarcinomas, but absent from normal endothelium, and that KLK-4 expression resulted in loss of PAR1 and PAR2 in a colon cancer cell line. Taken together, these results suggest that KLK-4 may be an endogenous ligand for PAR activation in colon cancer and therefore may provide a novel therapeutic target.

Dr. Darmoul's group indicates that "concomitant upregulation of KLK4 and PAR1 in colonic tumors would suggest that KLK4-mediated PAR1 activation could play an important role in colon tumorigenesis."

Gratio V, Beaufort N, Seiz L, Maier J, Virca GD, Debela M, Grebenchtchikov N, Magdolen V, Darmoul D: Kallikrein-related peptidase 4 (KLK4): a new activator of the aberrantly expressed protease-activated receptor 1 in colon cancer cells. Am J Pathol 2010, 176 1452-1461.

Reversing Remodeling in Chronic Inflammation

Dr. Li-Chin Yao and colleagues of the University of California, San Francisco, CA have discovered that remodeling of lymphatic vessels may be more persistent than blood vessel remodeling as a result of inflammation. These results are presented in the March 2010 issue of The American Journal of Pathology.

Vessel remodeling plays a pathogenic role in a number of chronic inflammatory diseases, including asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, Crohn's disease, and skin lesions in psoriasis. Reversal of such remodeling could prevent long-term complications from these diseases.

Yao et al used mice infected with the bacteria Mycoplasma pulmonis to induce vessel remodeling as a result of inflammation; these mice were then treated with the anti-inflammatory corticosteroid dexamethasone to examine the reversibility of vessel remodeling. In the absence of dexamethasone, both blood and lymphatic vessel remodeling occurred, whereas concurrent dexamethasone treatment prevented this remodeling. In contrast, dexamethasone treatment after two weeks of remodeling reversed blood vessel changes but not lymphangiogenesis; it also decreased the number of lymphocytes but not neutrophils and macrophages. Thus, lymphatic remodeling may be more persistent than blood vessel remodeling and may play a larger role in future inflammatory episodes.

The study by Yao et al shows that "changes in blood vessels and lymphatics are easier to prevent than to reverse in chronic inflamed airways. A better understanding of the role of distinct growth and maintenance factors that first induce the growth of blood and lymphatic vessels and then protect them from regression in chronic inflammatory disease may provide insight to the vascular contribution to the course of inflammatory disease."

Yao L-C, Baluk P, Feng J, McDonald DM: Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. Am J Pathol 2010, 176: 1525-1541


Contact: Angela Colmone, Ph.D.
American Journal of Pathology

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