Inflammation and Arachidonic Acid Metabolism in Chronic Disease
Michael F. McEntee
D.V.M., Cornell University
Section Chief Anatomic Pathology, Professor
Faculty Web Page
Dr. McEntee has maintained an active interest in the mechanisms of diverse chronic diseases ranging from mucopolysaccharidosis, an inherited storage disease, to prostatic cancer. The goal in all instances has been to better understand the pathology associated with these diseases through the use of dietary, pharmacologic, and genetic manipulations targeting biochemical and/or signaling pathways related to inflammation, tissue repair and cell proliferation. The arachidonic acid pathway has been of particular interest in this regard, studied primarily in the context of intestinal neoplasia.
Metabolism of arachidonic acid through several enzymatic pathways generates bioactive lipids that have a strong impact on tissue homeostasis, damage, and repair. The over-arching theme of these metabolic pathways is inflammation - the balance between tissue damage and repair associated with inflammatory responses defines whether arachidonic acid metabolism will have a net beneficial or detrimental affect in animals and humans. One arachidonate metabolic pathway involves the induced and constitutive expression of cyclooxygenase, which is the primary target of aspirin, ibuprofen and similar types of commonly used anti-inflammatory pain killers. Collaborative studies conducted with Dr. McEntee’s laboratory have helped characterize cyclooxygenase-dependent and -independent affects of this class of drugs on intestinal carcinogenesis. These studies have also defined how arachidonic acid metabolism through cyclooxygenase promotes intestinal cancer.
In addition to drugs, dietary components can also have a significant impact on the arachidonic acid pathway. Arachidonic acid is a form of polyunsaturated fat commonly found in animal meat. Consumption of animal fats directly enhances accumulation of arachidonic acid in tissues and therefore the production of downstream metabolites, such as those produced by cyclooxygenase. Conversely, diets containing higher levels of fish or fish oil tend to reduce tissue levels of arachidonic acid and therefore the production of associated bioactive lipids. Work in Dr. McEntee’s group has helped characterize the affects of these dietary fats on arachidonic acid metabolism and intestinal neoplasia. More recently, similar studies have suggested that dietary manipulation of tissue arachidonic acid levels may also significantly enhance the response of prostatic cancer to treatment.
Ongoing work in the laboratory is directed at understanding how signaling pathways related to inflammation promote the pathology of diverse diseases and whether these signaling pathways represent downstream manifestations of arachidonic acid metabolism. As such, the ultimate goal is a greater understanding of mechanisms of chronic disease and the identification of targets for pharmacologic and nutritional intervention.