Editorial [Hot Topic: Nitric Oxide and Lipoxins: Role in Inflammation and Defence (Guest Editor: Stefano Fiorucci)]

The focus of this special issue of Inflammation & Allergy - Drug Targets is on anti-inflammation. The inflammatory response protects the body against infection and injury, but can itself become deregulated with deleterious consequences to the host. Several endogenous biochemical pathways activated during defense reactions can counter-regulate inflammation. It is increasingly recognized that chronic inflammation develops as a consequence of the failure of these systems to attenuate generation of inflammatory mediators. Bioactive eicosanoids represent the main mediators of inflammation. Synthesis of the eicosanoids (Reviewed in this issue by Dr. Mario Romano) originates when arachidonic acid is converted to the prostaglandins through the prostaglandin synthase pathways. Arachidonic acid can also be oxygenated by lipoxygenases to form HPETEs. 5-lipoxygenase catalyzes the production of leukotriene (LT) A4, which is in turn hydrolyzed to produce LTB4; alternatively, the addition of a glutathione moiety in the presence of glutathione S-transferase produces LTC4 and LTD4. In contrast to the LTs and the prostaglandins, the lipoxins (LXs), an acronym for lipoxygenase interaction products, are endogenously produced eicosanoids with anti-inflammatory actions. LX synthesis begins with the oxygenation of arachidonic acid by 15-lipoxygenase to form 15-HETE. Within leukocytes, 15-HETE is converted to LXA4 by 5-lipoxygenase and epoxide hydrase. LXs were first identified by Charles Serhan and colleagues in 1984 from purified fractions of leukocyte suspensions that were coincubated with the ionophore A-23187 and 15-hydroperoxyeicosatetraenoic acid. During the last 20 years, significant efforts have been directed toward identifying the physiological actions of LXs in the inflammatory response and to design metabolically stable analogs that could have been used for therapeutic purposes (Reviewed in this issue by Dr. John Parkinson). In contrast to the proinflammatory eicosanoids, LXs are proposed to act as endogenous "braking signals" in inflammation. Aspirin not only inhibits eicosanoids generation but can also trigger the formation of the 15-epi-LXs that are usually referred to as the aspirin-triggered LXs (ATLs). Thus, cyclo-oxygenase-2 acetylation by aspirin modifies its activity to generate 15Rhydroxyeicosatetraenoic acid, which can be oxygenated to produce 15(R)-epi-LXA4. Similarly to LXA4, ATL exerts potent anti-inflammatory actions. Synthetic ligands of LXA4 and ATLs have facilitated the characterization of distinct receptors for LXA4 that mediate the anti-inflammatory signals. These studies provide evidence that ATLa can directly or indirectly modulate T cell effector function in the setting of Th1- and Th2-dependent inflammation and adaptive immunity. In addition, a surprising interaction of LXs and glucocorticoids has been demonstrated in the context of the broad anti-inflammatory activity of these agents that represent the most potent endogenous anti-inflammatory mediators in mammals (Reviewed by Dr. Mauro Perretti). Nitric oxide (NO) is also regarded as an anti-inflammatory mediator. NO, synthesized from L-arginine by a family of constitutive and inducible NO synthases, is a small, diffusible, highly reactive molecule that serves a variety of functions in the cardiovascular system and accounts for most of the endothelium-dependent vasodilation. NO is considered a double sword mediator, since its excessive generation in the context of inflammatory states leads to vasodilation a key hallmark of inflammation (Reviewed by Dr. Giuseppe Cirino). In addition to controlling vascular tone and vasodilation however, NO also regulates adhesive interactions at the endothelium surface. Thus, exposure of endothelial cells to NO inhibits E-selectin, intercellular adhesion molecule and vascular cell adhesion molecule-1 expression, limiting the release of secretable cytokines IL-6 and IL-8 and prevents nuclear translocation of nuclear factor (NF)- B, suggesting that similar to LXA4 and ATLs, NO might act as a braking signal in regulating vascular inflammation. Development of anti-inflammatory agents that limit eicosanoid production and release NO seems the logical exploitation of our increasing understanding of the cross-talk between pro- and anti-inflammatory mediators. In the recent years, several of these agents, called the COX-inhibitor NO-donating agents (CINODs) have been reported (Reviewed by Dr. Stefano Fiorucci). Interaction of NO-releasing aspirin with the LXs system, and the ability of ATLs to trigger NO formation (Reviewed by Dr. John Wallace), highlight the tight interaction between these two functionally distinct families of mediators. This issue is a journey through these mediators and describes how exploitation of anti-inflammation can be used to treat human diseases. A special thanks goes to all the authors who have accepted the invitation to spend some of their time in writing these reviews, and to Samina Khan, the Senior Manager Publications at Bentham Science Publishers Ltd.