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PUBLIC RELEASE DATE:
7-May-2010

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Contact: Angela Colmone, Ph.D.
acolmone@asips.org
301-634-7953
American Journal of Pathology

Tips from the American Journal of Pathology

May 2010

Intestinal Damage After Surgery

Dr. Joep Grootjans and colleagues at the Maastricht University Medical Center, Maastricht, the Netherlands demonstrate that intestinal ischemia/reperfusion (I/R) induces inflammation in humans. Their report can be found in the May 2010 issue of The American Journal of Pathology.

Intestinal I/R, the restriction and return of the blood supply to the intestine, is a common pathological side effect of surgery that leads to bacteria in the blood stream, systemic inflammation, and subsequent morbidity and mortality. Although intestinal I/R has been frequently studied in animal models, little is known about the inflammatory results of intestinal I/R in humans.

Using a human intestinal I/R model, Grootjans et al demonstrated that intestinal blood restriction in humans results in leakiness of the intestinal lining, which may allow bacteria to enter the blood stream. In addition, I/R-damaged intestinal tissue induced an inflammatory response. These data provide the basis for the development of future preventative and therapeutic strategies to treat I/R.

Dr. Gootjans and colleagues conclude that "[the] previously observed ability of the human small intestine to prevent intestinal I/R-induced inflammation is abolished by exposure to prolonged ischemia."

Grootjans J, Lenaerts K, Derikx JPM, Matthijsen RA, de Bruïne AP, van Bijnen AA, van Dam RM, Dejong CHC, Buurman WA: Human intestinal ischemia-reperfusion induced inflammation characterized: experiences from a new translational model. Am J Pathol 2010, 176: 2283-2291


Caveolin-1 is Critical Regulator of Innate Immunity

A group led by Dr. You-Yang Zhou at the University of Illinois College of Medicine, Chicago, IL have discovered that caveolin-1 modulation of endothelial nitric oxide synthase (eNOS) activity regulates innate immunity and inflammation-induced lung injury. They present these findings in the May 2010 issue of The American Journal of Pathology.

The innate immune system defends the body against infection in a non-specific manner. Nitric oxide, an antimicrobial agent, and eNOS, an enzyme that produces nitric oxide, play a key role in innate immunity and inflammation, as does caveolin-1, a protein involved in cell signaling. An interaction between caveolin-1 and eNOS is thought to be involved in this process.

To determine the respective roles of caveolin-1 and eNOS in innate immunity and inflammation, Mirza et al generated mice that lacked expression of both caveolin-1 and eNOS. They show that eNOS activation inhibited the immune system in caveolin-1-deficient mice, resulting in a decrease in the levels of proinflammatory molecules and improved survival when compared with mice deficient in both caveolin-1 and eNOS. In addition, eNOS activation in caveolin-1-deficient mice protected against inflammation-induced lung injury. The interaction between caveolin-1 and eNOS may therefore represent a new therapeutic target for inflammation and lung injury.

Dr. Zhou's group "present the first genetic evidence of the physiological significance of [caveolin-1] modulation of eNOS activity in regulating [innate immune] signaling. ...[They] show that [caveolin-1] modulation of eNOS activity is a key regulator of innate immunity and inflammatory lung injury."

Mirza MK, Yuan J, Gao X-P, Garrean S, Brovkovych V, Malik AB, Tiruppathi C, Zhao Y-Y: Caveolin-1 Deficiency Dampens Toll-Like Receptor 4 Signaling through eNOS Activation. Am J Pathol 2010 176, 2344-2351


Intestinal Immune Response

Researchers led by Dr. Rodney D. Newberry at the University of Washington, St. Louis, MO have found that development of intestinal lymphoid follicles (ILFs) is dependent on dendritic cell recruitment. They report their data in the May 2010 issue of The American Journal of Pathology.

Lymphoid tissues such as lymph nodes both host immune cells and serve as filters or traps for foreign and infectious antigens. These tissues are fully formed at birth. One type of lymphoid tissue, ILFs, is instrumental in the immune response against intestinal pathogens. However, in contrast to other lymphoid tissues, ILFs are induced by environmental stimuli from microorganisms in the intestinal lumen. Indeed, the formation of these tissues is fully reversible.

In an effort to further understand the development of ILFs, McDonald et al discovered that intestinal microbes recruited clusters of dendritic cells, immune cells that present antigen to other cells, to ILFs. Moreover, depletion of these immune cells resulted in regression of ILFs. Indeed, ILF differentiation was dependent on the cell-migration molecule CXCL13, which is expressed by ILF dendritic cells. Taken together, these data indicate that dendritic cell recruitment plays a key role in ILF development and function, perhaps through the secretion of CXCL13.

Dr. Newberry's group "suggest[s] that like other cellular components of [solitary intestinal lymphoid tissues], [dendritic cells] perform dual functions by shaping their microenvironment and generating immune responses."

McDonald KG, McDonough JS, Dieckgraefe BK, Newberry RD: Dendritic cells produce CXCL13 and participate in the development of murine small intestine lymphoid tissues. Am J Pathol 2010, 176 2367-2377.


microRNA (miRNA) Dysregulation May Contribute to Melanoma Development

Dr. Victor Tron and colleagues of Queen's University, Kingston, Ontario, Canada have identified differential expression of miRNAs as a contributing factor in melanoma development. These results are presented in the May 2010 issue of The American Journal of Pathology.

Melanoma, a malignant tumor of melanin-producing cells in the skin, is one of the least common forms of skin cancer, but causes most (75%) of skin cancer-related deaths. miRNAs are a class of small genetic molecules that, instead of coding for genes, regulate gene expression and thus may play a role in cancer development.

To examine the hypothesis that differential expression of miRNAs may contribute to melanoma development, Chen et al compared levels of miRNA expression between benign lesions and metastatic melanoma. Of the miRNAs examined, 31 were expressed differently between benign and cancerous lesions, with one, miR-193b, significantly decreased in all melanoma tissues examined. High levels of miR-193b expression in tumor cells inhibited proliferation as well as downregulated numerous genes, including a gene that regulates cell division. These results suggest that miR-193b dysregulation may contribute to melanoma development by altering cell proliferation.

Dr. Tron's group suggests that "further study of miR-193b in primary melanomas is necessary to understand whether downregulation of miR-193b is an early event in melanoma progression. Because miR-193b appears to have anti-proliferative effects in melanoma cells, it may have potential as a novel therapeutic agent for melanoma treatment. "

Chen J, Feilotter HE, Paré GC, Zhang X, Pemberton JGW, Garady C, Lai D, Yang X, Tron VA: MicroRNA-193b Represses Cell Proliferation and Regulates Cyclin D1 in Melanoma . Am J Pathol 2010, 176: 2520-2529

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For press copies of these articles, please contact Dr. Angela Colmone at 301-634-7953 or acolmone@asip.org.

The American Journal of Pathology, official journal of the American Society for Investigative Pathology, seeks to publish high-quality, original papers on the cellular and molecular biology of disease. The editors accept manuscripts that advance basic and translational knowledge of the pathogenesis, classification, diagnosis, and mechanisms of disease, without preference for a specific analytic method. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, animal, biological, chemical, and immunological approaches in conjunction with morphology.



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