Editorial [Hot Topic: New Approaches to the Treatment of Inflammatory Disorders (Guest Editor: Mark L. Richards)]

Inflammation is an exceedingly complex physiological response involving mixed cellular infiltration into blood vessel walls and surrounding tissues of the affected organ. Neutrophils, macrophages, lymphocytes, and mast cells release cytokines and chemokines that can directly cause tissue damage, enhance local cellular proliferation, provide a chemotactic signal for recruitment of other cells, and upregulate adhesion proteins for promoting the interaction of circulating immune cells with vascular endothelium. Self-limited inflammatory reactions are vital to our resistance to foreign antigens. However, inappropriate inflammatory responses can cause disease, which may take the form of an over-zealous response to foreign antigens, such as allergic reactions, or a response to self-proteins, such as in systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases. The inflammatory process may begin with an identifiable insult but in the case of chronic inflammatory diseases such as Crohn's the initiating event is usually unknown. The difficulty in treating inflammatory diseases arises from the fact that we are attempting to exert control over a "normal" physiological response. Inherent in this process is that inhibition of the normal albeit over-zealous response implies a similar inhibition of desirable responses mounted by the immune system. Thus, drug development efforts have had to balance the positive effect on the diseased tissue with a negative effect on the rest of the body. Recently however, the pharmaceutical industry has produced enormously successful drugs for treating chronic inflammatory diseases, particularly the therapeutic antibodies such as anti-TNFα, anti-CD20, and other proteins that mimic or inhibit natural intermediates. Despite these successes, however, there is considerable room for improvement in this area, particularly in the development of small molecules. Contained in this issue of CTMC are several papers that highlight recent contributions to the field of anti-inflammatory drug development, including inhibitors of nitric oxide synthase (NOS) and p38 MAP kinase, inhibitors of inflammation associated with coronary artery disease (CAD), and lesser known targets of anti-inflammation such as estrogen receptors, neuropeptide receptors, and the secretory pathway. These contributions should provide invaluable assistance to ongoing NOS and MAPK inhibitor programs, as well as perhaps stimulate the establishment of new approaches to anti-inflammatory drug development. Alan Tinker and Alan Wallace begin by providing a lucid description of the biology and chemistry of NOS, and dissect our current knowledge of the complicated role of the NOS isoforms in inflammation. They then provide a critical and thorough examination of the anti-NOS agents currently under development, providing some recent encouraging results in a field that has had its share of frustration. Charlie Meng makes a convincing argument for atherosclerosis and the attendant CAD as an inflammatory disorder. He provides epidemiological and biochemical evidence to support his assertion that much of the action of statin drugs in CAD is through a reduction of inflammation, which is independent of cholesterol lowering. He concludes by describing a group of principally antioxidant drugs and a more recent generation of multifunctional agents that have shown benefit in treating CAD. Robert Steffan and his group at Wyeth present a novel approach to the treatment of inflammatory disease through an estrogen receptor-mediated inhibition of NF-kB, describing their screening approach and providing in vivo confirmation of the activity of their selective inhibitors. Stefan Laufer and his colleagues Christian Peifer and Gerd Wagner provide an extensive and coherent examination of the recent progress in the development of p38 MAP kinase inhibitors. Their dissection of the SAR of the important structural features of p38 MAPK inhibitors serves as a valuable roadmap for the future development of these important agents. James Waschek together with Catalina Abad and Rosa Gomariz share their invaluable insight into the potential of neuropeptides in the treatment of inflammatory diseases. In outlining the receptors and ligands that comprise the VIP and PACAP systems, they reveal a fertile but largely unexplored system that has the potential to alter the Th1/Th2 cell balance, which has enormous ramifications for the treatment of inflammatory disease. Finally, Jeff Ludwig and I review the functions and potential intervention points within the secretory pathway. This area is vital to normal cellular processes, and harbors thousands of potential targets that can mitigate cellular activation. We provide examples of agents that act on targets within this system, and conclude by summarizing our work with a group of agents that are effective in inflammatory diseases through their action on a target within the Golgi apparatus.