The acute inflammatory response is the body's first system of alarm signals that are directed toward containment and elimination of microbial invaders. Uncontrolled inflammation has emerged as a pathophysiologic basis to many of the widely occurring diseases in the general population that were not initially known to be linked to events in the inflammatory response. These include cardiovascular diseases and neurodegenerative diseases (including Alzheimer's disease), and it has now become apparent that inflammation is an important component of cancer progression and the persistence of neuropathic pain. These are diseases that cross many disciplines. To better manage treatment, diagnosis, and prevention of diseases, multidisciplinary research efforts are under way in both academic and industry settings. Since knowledge of the acute inflammatory response in itself spans many disciplines, the editors' mission is to provide in this text an introduction to the cell types, chemical mediators, and general mechanisms that are involved in this primordial first response of the host to invasion. It is also now clear that the termination or the resolution of the acute inflammatory response is an active process, which is pivotal and is the outcome of the acute response. As an endogenous programmed response, the terrain of resolution holds many new possibilities for treatment and prevention of uncontrolled inflammation in a wide range of diseases.

INTRODUCTION

Autacoids are locally acting substances that are rapidly biosynthesized in response to specific stimuli, act quickly, and are usually deactivated by metabolism. Eicosanoids are a chemically diverse family of arachidonic acid–derived autacoids that have critical roles in cardiovascular, inflammatory, and reproductive physiology. Pharmacologic interventions in eicosanoid pathways – including the nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors, and leukotriene inhibitors – are useful in the clinical management of inflammation, pain, and fever. Given the many important bioactivities of lipid mediator eicosanoids, resolvins, and protectins, future research may lead to the development of new therapeutics for the treatment of inflammatory conditions, autoimmune diseases, asthma, glomerulonephritis, cancer, sleep disorders, and Alzheimer's disease.

BIOSYNTHESIS OF EICOSANOIDS

Eicosanoids are crucially involved in a number of metabolic pathways that have diverse roles in inflammation and cellular signaling. These pathways center on reactions involving the metabolism of arachidonic acid (Figure 12.1). The following considers the biochemical steps leading to arachidonic acid synthesis, then discusses the cyclooxygenase (COX), lipoxygenase (LOX), epoxygenase, and isoprostane pathways of arachidonic acid metabolism. Arachidonic acid (cis-, cis-, cis-, cis-5, 8, 11, 14-eicosatetraenoic acid), the common precursor to eicosanoids, must be synthesized from the essential fatty acid precursor linoleic acid (cis, cis-9, 12-octadecadienoic acid), which can be obtained only from dietary sources. In cells, arachidonic acid is esterified to the sn 2 position of the membrane phospholipids predominantly in phosphatidylcholine phosphatidylethanolamine, and phosphatidyl inositol.