Faculty Bibliography

Inhibitors of HMG-CoA reductase (statins) are cholesterol-lowering agents that dramatically reduce morbidity and mortality in patients with established cardiovascular disease. In addition, they exhibit pleiotropic effects that operate independently of lipid modification. Statin administration results in greater nitric oxide bioavailability, improved endothelial function, enhanced cerebral blood flow, immune modulation with anti-inflammatory action, decreased platelet aggregation and antioxidant activity. Some or all of these effects may improve outcome or ameliorate symptoms in neurological disorders. This article examines the potential role of statins in treating stroke, Alzheimer's disease, multiple sclerosis and Parkinson's disease. Studies are ongoing in this controversial area, but there are no firm conclusions. The appropriateness of initiating statin therapy for neurological disorders is not established at this time. The exception is stroke, in which recurrence is significantly reduced by statin therapy

Atherosclerosis is characterized by chronic inflammation and enrichment of inflammatory cells in the vessel wall. Acute inflammation can lead to damaged endothelium triggering the coagulation cascade and thrombus formation. Likewise, the clotting cascade may elicit an inflammatory response. The vascular endothelium regulates vascular tone, permeability, inflammation, thrombosis, and coagulation. Dysfunction of the vascular endothelium can promote atherosclerotic disease processes. Prostanoids (prostaglandins, thromboxane, and prostacyclin) have been established as inflammatory mediators in vascular endothelial function and there continues to be growing insights into their role in atherosclerotic disease. This review examines the role of prostanoids as paracrine inflammatory mediators of atherosclerotic vascular disease, highlighting the relevant physiology of eicosanoid production and endothelial dysfunction. We consider the role of prostanoids in systemic diseases associated with high cardiovascular morbidity and mortality, including diabetes mellitus, coronary artery disease, peripheral arterial disease, rheumatologic disorders, and dyslipidemia. We present emerging evidence that cardio-protective and lipid lowering medications, such as irbesartan and simvastatin may exert their effects via prostanoid mediated pathways. Both serum and urinary prostanoids may be utilized as diagnostic predictors of disease; for example 8-iso-PGF(2alpha) in the serum has recently been reported as an independent predictor of symptomatic peripheral arterial disease. In addition, we discuss current recommendations on established therapeutic uses of prostanoids for atherosclerotic diseases, such as the use of PGE(1) for the treatment of peripheral arterial disease. Finally, we investigate original therapeutic modalities of various prostanoids involved in the aforementioned diseases

Adenosine is a potent endogenous regulator of inflammation and tissue repair. Adenosine, which is released from injured and hypoxic tissue or in response to toxins and medications, may induce pulmonary fibrosis in mice, presumably via interaction with a specific adenosine receptor. We therefore determined whether adenosine and its receptors contribute to the pathogenesis of hepatic fibrosis.As in other tissues and cell types, adenosine is released in vitro in response to the fibrogenic stimuli ethanol (40 mg dl(-1)) and methotrexate (100 nM).Adenosine A(2A) receptors are expressed on rat and human hepatic stellate cell lines and adenosine A(2A) receptor occupancy promotes collagen production by these cells. Liver sections from mice treated with the hepatotoxins carbon tetrachloride (CCl(4)) (0.05 ml in oil, 50 : 50 v : v, subcutaneously) and thioacetamide (100 mg kg(-1) in PBS, intraperitoneally) released more adenosine than those from untreated mice when cultured ex vivo.Adenosine A(2A) receptor-deficient, but not wild-type or A(3) receptor-deficient, mice are protected from development of hepatic fibrosis following CCl(4) or thioacetamide exposure.Similarly, caffeine (50 mg kg(-1) day(-1), po), a nonselective adenosine receptor antagonist, and ZM241385 (25 mg kg(-1) bid), a more selective antagonist of the adenosine A(2A) receptor, diminished hepatic fibrosis in wild-type mice exposed to either CCl(4) or thioacetamide.These results demonstrate that hepatic adenosine A(2A) receptors play an active role in the pathogenesis of hepatic fibrosis, and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis.British Journal of Pharmacology advance online publication, 19 June 2006; doi:10.1038/sj.bjp.0706812

OBJECTIVE: Adenosine regulates inflammation and tissue repair, and adenosine A2A receptors promote wound healing by stimulating collagen matrix production. We therefore examined whether adenosine A2A receptors contribute to the pathogenesis of dermal fibrosis. METHODS: Collagen production by primary human dermal fibroblasts was analyzed by real-time polymerase chain reaction, 14C-proline incorporation, and Sircol assay. Intracellular signaling for dermal collagen production was investigated using inhibitors of MEK-1 and by demonstration of ERK phosphorylation. In vivo effects were studied in a bleomycin-induced dermal fibrosis model using adenosine A2A receptor-deficient wild-type littermate mice, C57BL/6 mice, and mice treated with adenosine A2A receptor antagonist. Morphometric features and levels of hydroxyproline were determined as measures of dermal fibrosis. RESULTS: Adenosine A2A receptor occupancy promoted collagen production by primary human dermal fibroblasts, which was blocked by adenosine A2A, but not A1 or A2B, receptor antagonism. Adenosine A2A receptor ligation stimulated ERK phosphorylation, and A2A receptor-mediated collagen production by dermal fibroblasts was blocked by MEK-1 inhibitors. Adenosine A2A receptor-deficient and A2A receptor antagonist-treated mice were protected from developing bleomycin-induced dermal fibrosis. CONCLUSION: These results demonstrate that adenosine A2A receptors play an active role in the pathogenesis of dermal fibrosis and suggest a novel therapeutic target in the treatment and prevention of dermal fibrosis in diseases such as scleroderma