Current Drug Targets - Inflammation & Allergy - Volume 1, Issue 3, 2002

Allergic rhinitis is charterized as an inflammatory disease of the nasal mucosa. In clinical practice, H1-antihistamines and topical corticosteroids are most commonly used pharmacological agents for the treatment of allergic rhinitis. The beneficial effects of steroids depend upon their long-term anti-inflammatory effect rather than upon direct receptor antagonism. This is different to H1-antihistamines, which block both neural and vascular H1 receptors and have a clinical effect on symptoms such as nasal itching, sneezing, and rhinorrhea. H1-antihistamines are rapidly absorbed and most of them are metabolized by the hepatic cytochrome P system and begin to reduce nasal symptoms (itching and sneezing) within one hour. Understanding of both the efficacy and the pharmacological properties of these commonly used drugs in the treatment of nasal allergic inflammation and its related nasal symptoms is very important. From a clinical viewpoint, it will provide a useful guideline for an appropriate use of these drugs.

Numerous recent findings indicate the possible involvement of an immune mechanism in the pathogenesis of neurodegeneration. The immune reaction could either act as a primary event, generating changes leading to cell death, or could be a secondary response to neuronal injury. In various neurodegenerative disorders such as Alzheimer's, Huntington's or Pick's disease, Down's syndrome, multiple sclerosis and the AIDS-dementia complex, the inflammatory pathomechanism is strongly supported by experimental and clinical studies. Such inflammatory mechanisms have also been postulated in Parkinson's disease (PD). This review summarizes some generalities about inflammation and immune reactions in the context of the brain, and provides clinical, epidemiological and experimental data showing that inflammation and immunity, or even auto-immunity, could be implicated in PD, either in its initial step or in its progression. Different experimental models useful for studying the role(s) of inflammation and (auto)immunity in the neurodegenerative process of the dopaminergic neurons in PD are examined. The major similarities and differences between PD and other neurodegenerative disorders are discussed.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. This subfamily consists of three isotypes, α (NR1C1), γ (NR1C3), and β / δ (NRC1C2) with a differential tissue distribution. PPARα is expressed primarily in tissues with a high level of fatty acid catabolism such as liver, brown fat, kidney, heart and skeletal muscle. PPARβis ubiquitously expressed, and PPARγ has a restricted pattern of expression, mainly in white and brown adipose tissues, whereas other tissues such as skeletal muscle and heart contain limited amounts. Furthermore, PPARα and g isotypes are expressed in vascular cells including endothelial and smooth muscle cells and macrophages / foam cells. PPARs are activated by ligands, such as naturally occurring fatty acids, which are activators of all three PPAR isotypes. In addition to fatty acids, several synthetic compounds, such as fibrates and thiazolidinediones, bind and activate PPARαand PPARg, respectively. In order to be transcriptionally active, PPARs need to heterodimerize with the retinoid-X-receptor (RXR). Upon activation, PPAR-RXR heterodimers bind to DNA specific sequences called peroxisome proliferator-response elements (PPRE) and stimulate transcription of target genes. PPARs play a critical role in lipid and glucose homeostasis, but lately they have been implicated as regulators of inflammatory responses. The first evidence of the involvement of PPARs in the control of inflammation came from the PPARa null mice, which showed a prolonged inflammatory response. PPARa activation results in the repression of NF-κB signaling and inflammatory cytokine production in different cell-types. A role for PPARγin inflammation has also been reported in monocyte / macrophages, where ligands of this receptor inhibited the activation of macrophages and the production of inflammatory cytokines (TNFα, interleukin 6 and 1β), although part of the anti-inflammatory effects of these ligands seems to be mediated by a mechanism not involving PPARγ. All these findings suggest a role of PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases

Chlamydia pneumoniae infection is associated with atherosclerosis and may be an emerging risk factor in coronary artery disease. C. pneumoniae can infect, multiply within and modulate the function of all atheroma cell types. Specific chlamydial virulence determinants have been identified that permit interaction with host cells and dysregulate cell function. In particular, chlamydial heat shock protein 60 and lipopolysaccharide may modulate cell function to dysregulate lipid metabolism, induce inflammatory cytokine cascades and trigger production of cross-reactive antibodies that initiate and promote atherogenesis. This paper reviews chlamydial heat shock protein 60 and lipopolysaccharide as potential virulence determinants in atherogenesis.

There is considerable evidence that the peripheral immune system can signal the brain to elicit a sickness response during infection and inflammation. The induction of the sickness response involves the expression of proinflammatory cytokines such as interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6, both in the periphery and in the brain. The mechanisms by which peripheral cytokines can affect brain function have been the subject of much debate. The precise mechanisms by which cytokines signal the central nervous system (CNS) are unknown, but possibilities include: 1) the direct entry of cytokine into the brain across the blood-brain barrier by a saturable transport mechanism: 2) the interaction of cytokine with circumventricular organs such as the orgnum vasculosum of the lamina terminalis [OVLT] and area postrema, which lack the blood-brain barrier, and 3) activation of afferent neurons of the vagus nerve. Increasing evidence has suggested that the afferent vagus nerve is an important pathway for immune-to-brain communication. However, there are inconsistent findings for the involvement of the afferent vagus nerve in the mediation of transmitting inflammatory signals to the brain. Thus, we describe here the functional relevance of the vagal afferent nerve in mediating these effects. An understanding of the mechanisms involved in immune-to-brain communication should permit us to create new drugs as therapeutic targets to decrease sickness or promote recovery. This review focuses on recent discoveries of the multipathway mechanisms for the induction of sickness behavior mediated through neuroimmune interactions in the CNS.

The incidence of allergic diseases has dramatically increased in recent decades, and it is socially and medically important to establish more useful strategies to overcome allergic disorders. Various kinds of drugs are utilized for allergic patients, however, some cases are unresponsive to these drugs and in others there are undesired adverse effects. On the other hand, a substantial body of evidence has accumulated pointing to the pivotal role of Th2-cytokines, interleukin (IL)-4, and IL-13, in the pathogenesis of bronchial asthma. The evidence is categorized as (1) expression of these cytokines in the bronchial lesions, (2) genetic association of the signaling molecules of these cytokines, (3) analyses of mouse models. In addition, the molecular mechanism of the signal transduction of these cytokines has also been well characterized. Based on such information, IL-4 and IL-13 have emerged as promising means of improving allergic states, and several IL-4 / IL-13 antagonists have been developed, among which soluble IL-4 receptor is now in human trials. Identifying the structure of the IL-13 variant and of the IL-4 / IL-13-inducing genes would be of great use. It is expected that in the near future, several drugs will emerge based on these strategies, which will give us wider choice in treating patients, depending on the pathogenesis of the diseases.

Only rarely in modern medicine is an entirely new class of drug developed. Recently, a number of drugs that act as leukotriene modifiers (LTM's) have been licensed for use in the treatment of asthma. Airway obstruction in asthma has two key components-bronchoconstriction of airway smooth muscle and airway inflammation. Although a number of mediators are involved in this process, it has been demonstrated that leukotrienes can precipitate both. Leukotrienes are formed in eosinophils, mast cells and neutrophils. LTM's have been shown to attenuate bronchial hyper-reactivity and reduce chemotaxis of inflammatory cells in the asthmatic airway. This article reviews the data from clinical trials of LTM's, discusses their role in asthma therapy and postulates on use in other common respiratory diseases.

Leptin was originally identified as an adipocyte-derived cytokine with a key role in the regulation of the energy balance. Subsequent research has, however, revealed that leptin's biological action is not restricted to its effects on appetite and food intake, but rather has a much more pleiotropic character. Evidence is now accumulating that it has important functions in reproduction, hematopoiesis, HPA-axis endocrinology and angiogenesis. In this review, we have focused on the effects of leptin in the immune system, which can be found in both the antigen-specific immunity and in the inflammatory effector system.

Inflammatory lung diseases such as asthma and Chronic Obstructive Pulmonary Disease (COPD) are characterised by systemic and local chronic inflammation and oxidative stress. The sources of the increased oxidative stress in patients with asthma and COPD derive from the increased burden of inhaled oxidants, and from the increased amounts of reactive oxygen species (ROS) generated by several inflammatory, immune and structural cells of the airways. Increased levels of ROS produced in the airways are reflected by increased markers of oxidative stress in the airspaces, sputum, breath, lungs and blood in patients with asthma and COPD. ROS, either directly or via the formation of lipid peroxidation products such as acrolein, 4-hydroxy-2-nonenal and F2-isoprostanes, may play a role in enhancing the inflammation through the activation of stress kinases (JNK, MAPK, p38, phosphoinositide 3 (PI-3)-kinase / PI-3K-activated serine-threonine kinase Akt) and redox sensitive transcription factors such as NF-κB and AP-1. Recent data have also indicated that oxidative stress and pro-inflammatory mediators can alter nuclear histone acetylation / deacetylation allowing access for transcription factor DNA binding leading to enhanced pro-inflammatory gene expression in various lung cells. Furthermore, oxidative stress may alter the balance between gene expression of pro-inflammatory mediators and antioxidant enzymes in favor of inflammatory mediators in the lung. Thus, the presence of oxidative stress may have important consequences for the pathogenesis of asthma and COPD. Identification of genes that predispose to the development of asthma and COPD may identify novel therapeutic targets. Future work is directed to understand the molecular mechanisms of antioxidants on ROS-mediated cell signaling pathways and inhibition of inflammatory response that would provide information for the development of novel antioxidant therapeutic targets in asthma and COPD. Effective wide spectrum antioxidant therapy that has good bioavailability and potency is urgently needed to control the localised oxidative and inflammatory processes that occur in the pathogenesis of asthma and COPD. In addition, development of such novel antioxidant compounds would be therapeutically useful in monitoring the oxidative and inflammatory biomarkers in the progression / severity of asthma and COPD.