Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents - Volume 3, Issue 1, 2004

The natural polyamines, named 1,4-diaminobutane, N-aminopropyl-1,4-diaminobutane and N,N'-bisaminopropyl- 1,4-diaminobutane, are also designated respectively as putrescine, spermidine and spermine. They are polycationic compounds found in all eukaryotic cells. As they are deeply involved in cell functions, e.g. cellular growth, their concentration and their equilibrium in the intracellular pool are maintained in very narrow limits by regulatory mechanisms acting in a very fast, sensitive and precise way. These compounds are involved in gut inflammatory processes and in allergy. Indeed, they control the production of inflammatory mediators in several cell lines or tissues. Polyamine metabolism could be considered as a putative target for inflammation, allergy prevention or therapy.

Cysteinyl leukotrienes (LTC 4 , LTD4 and LTE4 ) and thromboxane A2 are important metabolites of arachidonic acid cascate involved in a variety of cellular functions and diseases. These eicosanoids have been implicated as key mediators in the development and progression of bronchial asthma. Therefore, several new therapeutic approaches are based on the design of drugs that can modulate their actions. These strategies can be represented by drugs that act as CysLT1 receptor antagonists (e.g., zafirlukast and montelukast), by inhibiting thromboxane synthase (e.g. ozagrel hydrochloride), or even as new symbiotic agents that can simultaneously modulate the actions of cysteinyl leukotrienes and thromboxane A2 (e.g. YM 158 and LASSBio 341).

Dietary antioxidants exhibit their antioxidant properties mainly through the inhibition of low density lipoprotein oxidation and cellular lipid peroxidation and / or preserving the cellular antioxidant pool and / or potentiation of each others' beneficial effects. Recent studies also demonstrated an association between increased intake of these dietary components and reduced risk for diseases in which inflammatory processes as well as oxidant stress are accused to have an aethiopathological role. Thus, besides their known antioxidant effects, new evidence attributes an antiinflammatory role for these agents. Alterations in the intake of antioxidant nutrients affect the progress of inflammation mainly by interacting with generation of ROS / RNS by activated phagocytes. Reducing structures found in dietary antioxidants depress activation of NF-kB, and upregulation of COX-2, iNOS and adhesion molecules involved in phagocyte recruitment. Thus nutritional modulation may indeed represent a safe and effective way for the prevention of pathologies in which both oxidation and inflammation play fundamental roles. Given the exciting evidence for a protective effect of dietary antioxidants in inflammatory processes, future research investigating the effects of these nutrients on multiple aspects of the inflammatory response deserves further attention. This review concentrates on the biochemical and metabolic aspects of 4 major groups of dietary antioxidants: vitamin C, vitamin E, carotenoids and plant phenols. Oxidant stress and inflammation mechanisms are reviewed before discussing some key points and unresolved issues related to the antiinflammatory effects of antioxidant nutrients. The last part of the review gives particular emphasis to atherosclerosis and Alzheimer's Disease. Finally, some future research and the development of new antiinflammatory agents is proposed based on the antiinflammatory effects of dietary antioxidants.

Leukocyte recruitment is a multistep process and a key feature of tissue injury at sites of inflammation. Tissue accumulation of leukocytes is orchestrated by specific adhesion molecules regulating leukocyte-endothelial cell interactions, including rolling, firm adhesion and transmigration. Since the discovery and cloning of the selectin family of adhesion molecules (i.e. P-, E- and L-selectin) extensive investigative effort has been devoted to define the role of the selectins in the extravasation process of leukocytes in the microcirculation. Indeed, convincing evidence has documented that the selectins play a critical role in mediating leukocyte rolling along the endothelial cell lining. This review focuses on the mechanisms of leukocyte recruitment, especially leukocyte rolling, and the function and expression of the selectin family of adhesion molecules. Moreover, the therapeutic potential in targeting the selectins in selected inflammatory diseases, such as ischemia / reperfusion injury, artherosclerosis and endotoxemic liver injury will be described.

Inflammation is a hallmark of several diseases of the lung including asthma and chronic obstructive pulmonary disease (COPD). There have been major advances in our understanding of the molecular processes underlying the development of inflammation in asthma and COPD. In this review we describe the development of novel anti-inflammatory strategies for the treatment of inflammatory lung disease such as chronic obstructive pulmonary disease, asthma, cystic fibrosis, acute respiratory distress syndrome, and pulmonary fibrosis. Basic concepts of inflammatory networks are described including overviews on involved cell types and mediators. The molecular mechanisms of current approaches of therapy for asthma and CODP such as corticosteroids, cromones, leukotriene inhibitors, antihistamines, and immunosuppressants are reviewed. The focus of the article is on novel approaches to treat inflammation in the airways. A general overview is given and includes new developments of steroids, receptor- and mediator-directed approaches, protease inhibitors, T cell modulators, inhibitors of cell signaling, and genetic therapy. Several examples of new therapies are outlined in more detail such as application of anti-IgE agents, CpG oligonucleotides, and therapies acting on transcription.

The increasing knowledge concerning pathomechanism of hypersensitivity reactions enabled development of new strategies of allergy treatment. Since the molecular background of allergy includes some, still poorly defined, abnormalities in immunoregulatory cytokines network, the successful treatment should restore proper cytokine balance. Therefore, numerous studies concerning administration of missing cytokines or inhibition of excessive one have been undertaken. The possibilities to use IgE- and cytokine-neutralizing antibodies as well as soluble cytokine receptors are discussed in this review. Moreover, attempts to create various mutant cytokines that competitively block cytokine-receptor binding have been detaily described. Although majority of clinical trials analyzing those novel treatment approaches are not finished yet, the evaluation of their preliminary results suggests potential clinical usefulness of such treatment. Obviously, these molecular methods still require further studies, nevertheless, they could be considered as novel standard in allergy treatment pretty soon.

The pathogenesis of allergy remains unclear. Therefore the standard treatment is mainly focused on reduction of clinical sympthoms of hypersensitivity reaction without eliminating the cause of that. Moreover, being multidirectional and unselective, such treatment affects quite frequently tissues not involved in allergic reactions and thus it could result in numerous adverse effects. The most popular hypothesis concerning pathogenesis of allergy assumes a pivotal role of some abnormalities in immunoregulatory cytokines network. Thus, it is obvious that major goal of causal allergy treatment should be restoration of cytokine balance. The recent advances in genetic engineering enabled creation of new treatment strategies also in allergy. Therefore, numerous studies concerning molecular therapy of allergic diseases have been undertaken. The most recent therapeutical approaches, including antisense oligonucleotides, RNA interference technology and gene therapy in allergy treatment have been detaily discussed in this review. Despite the fact that many of these topic methods are still in the trial phase, we suppose they will become a clinical reality in the near future.