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A common factor in the progression of metastasis, atherosclerosis and inflammation is excessive cell growth prompted by both endogenous or exogenous stimuli; e.g. ocogenes, cytokines and thrombin. Excessive cell growth in all of these pathologic responses requires multiple cell cell interactions. There is an abundance of literature suggesting that arachidonic acid metabolites derived from both the cyclooxygenase and lipoxygenase pathways, influence these processes, but it is only recently that our attention has included the importance of linoleic acid metabolism and the relative roles of linoleic and arachidonic acid metabolites in these disease processes.

Atopy is primarily a condition of hypersensitivity. Atopic disease include atopic eczema, allergic bronchial asthma or hay fever. Atopic dermatitis signs and symptoms are dry itching skin, and eczematous inflammation. Pathophysiology involve: genetics, trigger factors as aeroallergens, superantigens or stress, Th2 lymphocyte cytokine profile (Interleukin (IL)-4,-5,-10) dominance, hyper IgE, monocyte phosphodiesterase increased activity, impaired epidermal barrier function and abnormal linoleic acid metabolism.

Platelet/vessel wall interactions following injury play an important role not only in hemostasis, but also in acute thrombosis and subsequent atherogenesis1. In cardiac surgery, particularly coronary artery bypass grafting (CABG), these platelet/vessel wall interactions are thought to contribute to acute thrombus formation and chronic vessel wall hyperplasia and subsequent vessel wall restenosis. To date, the most common approach to attenuate these responses is the short-term administration of high dose heparin during cardiac surgery (to inhibit thrombin activity) and the long-term administration of low dose aspirin to inhibit platelet thromboxane A2 (TxA2) generation (which is thought to promote platelet aggregation and vasoconstriction 2 . Despite these approaches, acute thrombosis and chronic restenosis remain significant problems in 5 – 40% of these patients within 6–12 months post surgery.

In 1985, we demonstrated that 13-hydroxyoctadecadienoic acid (13-HODE) is synthesized from endogenous linoleic acid triglyceride stores by vascular wall cells via the lipoxygenase pathway1–2. Specifically, we demonstrated that endothelial cells synthesize more 13-HODE than smooth muscle cells, which in turn, synthesize more 13-HODE than fibroblasts. Since then, we and other investigators have demonstrated that both human and animal vascular wall cells, leukocytes and other white cells, tumour cells and epithelial cells all synthesize 13-HODE2–5. In addition, Lamie et al 6 reported that anucleated platelets contain acylated 13-HODE. The levels of endogenous 13-HODE in all of these cells are highest under basal (unstimulated) conditions, and decrease following cell cell interactions; i. e. at a time when the cells respond to injury, pertubation or stimulation. These observations led us to hypothesize that 13-HODE contributes significantly to blood cell vessel wall biocompatability; i. e. 13-HODE appears to downregulate vessel wall thromboresistance, thereby attenuating thrombogenesis and downregulates extravascular invasion during inflammation and metatasis7.

Tumor cells (TC)/vascular endothelial cell (EC) adhesion is important in metastasis. In vitro studies indicate that the EC linoleic acid (18:2) derived monohydroxide, 13-HODE 1/αwith TC/EC adhesion and with EC expression of the vitronectin receptor (VnR). In addition, the ability of tumor cells to adhere 1/α with its intracellular ratio of 13-HODE and the arachidonic acid derived monohydroxide, 15- hydroxyeicosatetraenoic acid (15-HETE). These data suggest that changing TC or EC 13-HODE synthesis will alter TC/EC interactions and subsequent metastasis in vivo Consistent with this possibility, we found that the abilities of TCs to arrest and metastasize in the rodent lung 1/αwith the ratio of TC 13- HODE: 15-HETE. We also found that when vascular wall (VW) 13-HODE synthesis is inhibited, acute TC/lung entrapment and chronic TC metastasis increase, p

Platelet interactions with the blood vessel wall following injury influence both the acute thrombotic event (platelet/vessel wall adhesion) and the chronic pathogenesis of arteriosclerosis (chronic vessel wall thickening and occlusion). Platelets are thought not to interact with the healthy intact endothelium, but only to adhere to vessel wall components exposed following endothelial cell damage and vessel wall injury (1–3). When platelets adhere to the injured vessel wall, they release a number of constituents which facilitate further platelet activation (3), activation of the coagulation cascade (1), and/or are mitogenic, facilitating smooth muscle cell proliferation and hyperplasia (4). Endothelial cells also synthesize and release a number of constituents which counterbalance the platelet responses, thereby enhancing fibrinolysis, inhibiting coagulation and preventing platelet aggregation and adhesion (5–7). Recently, with the development of endothelial cell culture techniques and a number of molecular biologic tools, we have learned that platelets and other blood cells actively interact not only with the injured vessel wall, but also with the intact endothelium itself. In this chapter, we will focus on the latter interaction and specifically on endothelial cell fatty acid metabolism and its possible consequence on the reactivity of adhesion molecule receptors on the surface of the intact endothelium which in turn may influence platelet/vessel wall interactions.

The intravascular transport of tumor cells and their attachment to the vessel wall are important steps in metastasis. However, little is known about the intracellular mechanisms which regulate tumor cell adhesion to the vessel wall, particularly, to intact endothelial cells. A number of studies have suggested that circulating tumor cells preferentially adhere to the exposed underlying extracellular matrix rather than to intact endothelial cells (1,2). However, other studies suggest that tumor cells can also adhere to endothelial cells, and that this adherence is dependant upon specific characteristics of the endothelium. It has also been suggested that the metabolic characteristics of tumor cells themselves influence their own adhesion to the vessel wall (3—4). Finally, a number of recent studies suggest that adhesion receptor molecules are expressed following cell stimulation, facilitating cell/cell adhesion (5—7). In this paper we will focus on the possible intracellular regulation of expression of these adhesion molecules by two lipoxygenase derived fatty acid metabolites synthesized from arachidonic and linoleic acids. In particular, we will review the relationship between 13-hydroxyoctadecadienoic acid (13-HODE) derived from linoleic acid and 15-hydroxyeicosatetraenoic acid (15-HETE) derived from arachidonic acid, and tumor cell endothelial cell adhesion.

Cancer cells frequently disseminate via the bloodstream where the endothelium acts as a barrier between the circulating tumor cells and the extravascular tissue. Free radicals generated by environmental factors or host cells can cause endothelial cell injury and we have postulated that such injury could promote the metastasis of intravascular tumor cells. In mice and rats endothelial damage was induced by intravenous cobra venom factor which activates circulating leukocytes. Endothelial cell damage was demonstrated by morphology and by altered vasopermeability. When 125IUdr-labelled cancer cells were injected intravenously, during periods of maximal endothelial cell injury there was a 3 fold increase in retention of these cells in the lung, 24 hours later. After 14 days there was a 3–20 fold increase in the number of metastatic tumors in CoF-treated animals. In both rats and mice, tumor cell localization was reduced 70–80% by pretreatment of the animals with catalase. In mice, endothelial injury induced by bleomycin (120 mg/kg) or by exposure to 90% oxygen for 2–4 days also significantly increased the metastasis of circulating cancer cells. Studies in vitro have demonstrated that rat Walker 256 cancer cells or host cells, when activated with the chemotactic peptide N-fMLP, generate oxygen-derived free radicals and can damage cultured endothelium. When fMLP-activated W256 cells were incubated with 3H-2-deoxyglucose-labelled endothelial cell monolayers, there was a 27% increase in the specific release of isotope within 90 minutes. Damage correlated with tumor cell-induced chemiluminescence and was inhibited by catalase. We conclude that free radical-mediated damage to the microvasculature facilitates the metastasis of circulating cancer cells.

The interaction of platelets with vascular wall structures, plasma proteins and other circulating cells is of fundamental importance in the regulation of hemostasis and in the pathogenesis of thrombosis. When platelets are stimulated, they release biologically active constituents which interact with vessel wall cells, plasma coagulation factors and circulating blood cells to modulate hemostasis. In this review we will discuss platelet adhesion, the platelet release reaction, platelet aggregation, the effects of these phenomena on the coagulation system and their importance in hemostasis and thrombosis.