The resolution of inflammation: the devil in the flask and in the details

In looking at the past, present and then to the future of this field of inflammation research, as in many facets of history and human experience, is it possible to accurately project the future of a scientific area? This is a particular challenge since many of the new and exciting discoveries in the biomedical sciences are, for the most part, serendipitous (1–3). As a result, our knowledge of pathophysiologic processes is nonlinear with time, entering as rather sporadic leaps in our appreciation of the complexities of human health and a given disease process. Certainly, from the relatively recent change in the concept of resolution as a passive means to complete an acute inflammatory response to the discovery and role of novel autacoid biosynthetic pathways for potent active mediators and mechanisms of resolution that can be used to stimulate the return to homeostasis is a 180° change in concepts and potential for new treatments in the past 25 yr (4–6). The prevailing notion in treating inflammation likely began with Hippocrates and the use of salicylates present in willow bark to knowledge of the cellular events in the acute inflammatory response and the ability of aspirin to inhibit key mediators of inflammation (7). Aspirin (a derivative of salicylates) proved to be one of the more commercially successful drugs. The total organic synthesis of aspirin was accomplished in the 1850s, and the drug was introduced into the market in the early 1900s. Therefore, many therapeutic agents were introduced with the goal of mimicking aspirin's mechanism of action, namely, inhibiting cyclooxygenases and prostaglandin biosynthesis (8, 9). The notion of blocking proinflammatory mediators, enzymes, and pathways, whether by small-molecule inhibitors, receptor antagonists, or neutralizing antibodies, is a concept that prevailed in the past century and is still in wide use today. Nonetheless, new evidence has emerged that points to an unobvious and new direction, namely, stimulating resolution and the return of the tissue to homeostasis with endogenous chemical mediators of resolution. For this Silver Anniversary edition of The FASEB Journal, I shall take a brief tour of our understanding and the changes in concepts that have evolved around the process of resolution of acute inflammation and its implications for human disease as well as the opportunities that now open in terms of novel therapeutics and treatments. It is appropriate to start with two definitions from Taber's Cyclopedic Medical Dictionary (10): resolution 1. Decomposition; absorption or breaking down of the products of inflammation. 2. Cessation of inflammation without suppuration. The return to normal. resolvent 1. Promoting disappearance of inflammation. 2. That which causes dispersion of inflammation. These two definitions evolved since ancient times in our appreciation of disease and injury at the gross and tissue levels and, most important, the effect of phagocytic cells in inflamed tissues as viewed from tissue histology by pathologists (Table 1). As early as the ancient medical encyclopedias, as recorded in several chapters of the Canon of Medicine in the 11th century CE and translated to Europe around the 12th century (11), the notion of “resolvent mollificants” for the treatment of inflammation was clearly evident. However, what a resolvent constituted was not clear, nor was its molecular form known. As indicated by the definition in Taber's, a resolvent promotes or causes the dispersion of inflammation. In the present day, the first notions of an agonist stimulating processes that can return the inflamed tissues to homeostasis arise from the identification and structural elucidation of potent mediators termed resolvins, or resolution-phase interaction products (12–14). Table 1. Timeline for resolution of inflammation and regeneration link to ω-3 PUFAs In the timeline of literature that gives rise to our appreciation of resolution of self-limited acute inflammation as an active biochemical process (Table 1), by 1979, Robbins and Cotran (15), in the second edition of their famous textbook of pathology, provided a schematic illustration (redrawn in Fig. 1) that depicts inflammatory exudate resolved vs. exudate reorganization. They also introduced the notion of precise cellular events involved in resolution vs. the path to chronic inflammation. Yet, at the time, these events were considered to be passive, in that the initial leukocyte stimulus, the chemoattractant, was thought to dissipate, simply burn out, or simply dilute the signal that would then lead to decreased infiltration or stopping of the leukocyte recruitment to the infected or injured tissues (16). Professor Ramzi Cotran (17) was first to recognize that the cells of the vessel wall, the endothelium, were activated, a process, along with neutrophil [polymorphonuclear (PMN) cell] activation (18), critical to mounting a well-integrated acute inflammatory response. The cellular events in the resolution of inflammation were further advanced from the studies of Savill, Henson, and Haslett in 1989 (19, 20), with the recognition that macrophages (the big eaters), which were already known to clear up tissue and cellular debris (21), advanced to uptake dead apoptotic PMN cells and cellular debris as part of the resolution sequence of events. Complete resolution as an ideal outcome of acute inflammation and the notion that chronic inflammation can evolve as a failure to resolve recurring bouts of acute inflammation emerged in 1994 in the fifth edition of the Cotran et al. (22) textbook. This set the stage for these cellular pictures and events in the resolution of inflammation when considering the context of an acute inflammatory response. Figure 1. Inflammation, repair, and resolution in 1979. A little more than 25 yr ago, Sune Bergstrom, Bengt Samuelsson, and Sir John Vane each shook the hand of the Swedish king as they received their Nobel Prize medals in December 1982, for their work on the discovery and biosynthesis of the prostaglandins and on the action of aspirin. Prostaglandins play important roles in many physiological responses, e.g., renal function, hemodynamics, reproduction, and, notably, inflammation, which was already recognized at the time (9, 23). The notion of chemical mediators was also already brewing in the air from the studies of von Euler on histamine (24). Considering inflammation, it was clear at that time that many chemical signals are involved in the acute inflammatory response and the usual associated collateral tissue damage: for example, the leakage of reactive oxygen species from the primary phagocytic vacuole to cause tissue destruction, the release of lysosomal enzymes, etc. (18), and the potent actions of the lipid-derived platelet-activating factor (PAF), arachidonic acid and its conversion to prostaglandins and leukotrienes, as well as complement, and the cytokines (25). The structure-function and biosynthesis of the eicosanoids, as carried out by Professor Bengt Samuelsson and colleagues (23), in many respects led our current understanding and appreciation of structure-activity relationships and what we today call chemical biology, as well as metabolomics, much of which emerged from the study of these very potent short-lived arachidonate-derived local-acting autacoids like prostacyclin and thromboxane (23). Following the award ceremony during the week of the Nobel Fest in December, there is a splendid Nobel dinner at which special utensils and glassware are used, including special Nobel schnapps flasks by Orrefors. The design was beautifully sculpted by Gunnar Cyren and introduced by the official glass artisans of the King of Sweden. The base of these flasks, pictured in Fig. 2, portrays the devil; hence, at the end of this momentous celebration, there is a thoughtful reminder of the alcohol and its power of intoxication, and the devil at the bottom of the glass serves as a caution. This image also reminds us that the devil is in the details in studying inflammation and its complex resolution mechanisms. The key to controlling inflammation, as needed to treat inflammatory diseases, lies in appreciating the molecules and mechanisms in resolution toward the structure-function or the molecular details in resolution of acute inflammation–the termination of this protective response of the host. Figure 2. Devil in the flask: 3 devil flasks from Orrefors, designed and sculpted by Gunnar Cyren. These schnapps flasks are used at the Nobel dinner in Stockholm during the Nobel Festival each year.