Tips from the American Journal of Pathology

The following highlights summarize research articles that are published in the July 2010 issue of The American Journal of Pathology.

Dr. Einar Eriksson and colleagues at the Karolinska Hosptial, Stockholm, Sweden demonstrate that neutrophils may contribute to atherosclerosis. Their report can be found in the July 2010 issue of The American Journal of Pathology.

Atherosclerosis is a hardening of the arteries due to the build-up of plaques made up of fatty materials such as cholesterol. These plaques may eventually rupture, leading to clots and subsequent arterial narrowing or blockage, which results in insufficient blood supply to tissues and organs.

Although immune cells have been shown to play important roles in the genesis of artherosclerotic plaques, the contribution of neutrophils, the most abundant white blood cell in circulation, remains unclear. Therefore, Rotzius et al examined the role of neutrophils in a mouse model of atherosclerosis. They found that neutrophils accumulate in atherosclerotic lesions, although at lower levels than other white blood cells. Moreover, neutrophils are the predominant immune cells in the high inflammatory shoulder regions of plaques, suggesting that these cells may play a hitherto unappreciated role in the immunological processes of atherogenesis.

Dr. Eriksson's group concludes that "[their] data provide strong evidence for the presence and invasion of significant numbers of neutrophils in atherosclerotic lesions. These findings call for further investigation of the functional importance of neutrophils and their interplay with complex immunological processes in atherogenesis."

Rotzius P, Thams S, Soehnlein O, Kenne E, Tseng C-N, Björkström NK, Malmberg K-J, Lindbom L, Eriksson EE: Distinct infiltration of neutrophils in lesion shoulders in ApoE-/- mice. Am J Pathol 2010, 177: 493-500

A group led by Dr. Andreas Lösche of the University of Leipzip, Germany has discovered that hyperploid neurons, which have greater than the normal number of chromosomes, are more prone to cell death in Alzheimer's disease. They present these findings in the July 2010 issue of The American Journal of Pathology.

Alzheimer's disease, the most common form of dementia, affects nearly 19% of people 75-84 years of age. Alzheimer's disease in incurable and degenerative, and results in death for the patient and considerable burden on the caregiver. Disease progression is associated with neuronal cell death.

Although a low-level of aneuploidy, an abnormal number of chromosomes, may contribute to neuronal diversity, high levels of aneuploidy may result in developmental abnormalities and disease. Ardendt et al explored the effects of hyperploidy, having greater than the normal number of chromosomes, in Alzheimer's disease pathogenesis. They identified increased numbers of hyperploid cells in preclinical stages of Alzheimer's disease and showed that hyperploid neuronal cells in Alzheimer's disease have selectively higher levels of cell death than normal neuronal cells. These results highlight hyperploidy, perhaps as a result of a failure of neuronal differentiation, as critical pathogenic event in neurodegeneration.

Dr. Lösche's group suggests that "hyperploidy … [is one] critical molecular event … shared between neurodegeneration and malignant cell transformation … [and that these data] direct our attention to a failure of neuronal differentiation as the critical pathogenetic event and potential therapeutic target in neurodegeneration."

Arendt T, Brückner M, Mosch B, Lösche A: Selective cell death of hyperploid neurons in Alzheimer´s disease. Am J Pathol 2010 177: 15-20

Researchers led by Dr. Claudine S. Bonder of the University of Adelaide, Adelaide, South Australia, Australia implicate sphingosine kinase-1 in neutrophil recruitment to sites of inflammation. They report their data in the July 2010 issue of The American Journal of Pathology.

Neutrophils, which make up nearly 70% of white blood cell in the blood stream, are first-responder immune cells that migrate to sites of infection and inflammation, where they secrete inflammatory molecules and fight pathogens. These and other white blood cells are targeted to sites of inflammation and infection via adhesive molecules, such as integrins, that are upregulated on the surface of blood vessels.

To determine if sphingosine kinase-1, an enzyme that both cleaves and generates important signaling molecules within cells, contributes to integrin-mediated neutrophil recruitment, Sun et al examined inflammatory responses in a model of human blood vessels. Sphingosine kinase-1 was required for integrin activation and subsequent neutrophin adhesion in this system. Taken together, these data support sphingosine kinase-1 as a broad-spectrum target for inhibiting neutrophil recruitment and subsequent inflammatory and immune disorders.

Dr. Bonder and colleagues "suggest that [sphingosine kinase-1 may be the single target required for an effective broad spectrum therapeutic target to combat inflammatory and immune disorders."

Sun WY, Pitson SM, Bonder CS: Tumor necrosis factor-induced neutorphil adhesion occurs via sphingosine kinase-1-dependent actuaion of endothelial 51 integrin. Am J Pathol 2010, 177: 436-446

Dr. Ali Hafezi-Moghadam and colleagues at the Harvard Medical School, Boston, MA have developed a noninvasive imaging technique to detect early stages of eye disease. These results are presented in the July 2010 issue of The American Journal of Pathology.

Uveitis, inflammation of the middle layer of the eye, is the most common form of eye disease, causing up to 10% of visual loss in the United States. Early detection of uveitis could lead to earlier treatment and prevent irreversible tissue damage and loss of sight.

In uveitis, white blood cells accumulate in affected regions of the eye. Therefore, Xie et al used fluorescently-labeled molecules (microspheres) that bind to P-selectin, an adhesion molecule that binds to white blood cells, to identify areas of the eye with uveitis. These microspheres mimicked white blood cell accumulation in an animal model of uveitis, and binding was decreased when these animals were treated with topical anti-inflammatory drugs, allowing for quantification of the immune response. As microvessel accumulation precedes clinical signs of disease, this noninvasive imaging technique may provide a model system for studying the early stages of anterior uveitis.

Dr. Hafezi-Moghadam's group concludes that "our imaging approach detects the earliest signs of disease, even prior to the occurrence of clinical symptoms, such as leakage, pain, or vision deterioration. Upon subclinical detection of molecular changes, effective treatments could be instituted to halt inflammation, before irreversible structural damage occurs. Besides being a powerful research tool, this versatile imaging approach has a high chance of being translated to the clinical realm and impacting the way medicine is practiced."

Xie F, Sun D, Schering A, Nakao S, Zandi S, Liu P, Hafezi-Moghadam A: Novel Molecular Imaging Approach for Subclinical Detection of Iritis and Evaluation of Therapeutic Success. Am J Pathol 2010, 177: 39-48

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.