Current Pharmaceutical Design - Volume 16, Issue 38, 2010

Since its discovery, inflammation has been considered a byproduct of pathological situations and of immunological responses. However, mounting experimental evidences suggest that inflammation can be a cause of certain pathologies, and in this respect it should be regarded as a target of immunophysiological studies. Moreover, inflammation-like processes are common to all multicellular organisms investigated, thus dating back their origins at more than a billion of years ago, and could be driven by a pool of molecules sharing common evolutionary origin. Inflammatory activities may result in devastating pathologies and, consequently, studies on different aspects and on different animal models may increase the knowledge on common cellular and molecular activities. Accordingly, these common activies could be a target for pharmacological and immuno-pharmacological studies to be performed with updated experimental approaches. In this respect, this issue of Current Pharmaceutical Design has been focussed in collecting review papers describing current knowledge on inflammatory activities in key animal models and man. Where necessary, some of presented works are supported by original research result. The issue has been arranged in 8 contributions, for invertebrate model species Ottaviani et al. [1] describe the set of molecules and cell types involved in inflammatory activities in molluscs, whereas Jiravanichpaisal et al. [2] describe crustacean inflammatory activities, with emphasis on hematopoiesis for hemocyte recruitment to infection site and the gut as an important route of infection in arthropods. For vertebrate model species the fish play a pivotal role, being the oldest vertebrates having a physiological body plan for innate and acquired immune reponses conserved in all vertebrates. For fishes, Novoa et al. [3] review on gene expression studies describing the host innate immune response, concentrating upon the inflammatory response and its relationship toward anti-viral immunity in some fish species, whereas Zou et al. [4] summarizes recent progresses in pattern recognition receptors (PRRs), molecular triggers of inflammation involved in anti-viral responses. In the carp, Wiegertjes and Forlenza [5] review, for both host and parasite, the role of oxygen and nitrogen radicals in the induction of nitrosative stress as well as the importance of antioxidant compounds for protection against these radicals. More related to immuno-pharmacology studies, Costantini et al. [6] describe the structural analysis of three pro-inflammatory molecules conserved among Vertebrates, drawing the attention on invariant and variable molecular domains involved in the binding of respective cellular receptors. Regarding man, recent data suggest that inflammation plays a fundamental role in neurodegenerative processes and, in this respect, the review of Bossu et al. [7] describes the involvement of pro-inflammatory cytokines in Alzheimer disease pathology. Another important aspect related to inflammation in man is the gastric inflammation induced by the bacterium Helicobacter pilori, that may evolve toward chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue lymphoma, and gastric cancer, and the knowledge on this has been review by Ruggiero [8]. Concluding, the aim of this issue of Current Pharmaceutical Design has been to collect and present the current knowledge on comparative inflammatory activites.

Inflammation represents the rapid and efficient elimination of damaged tissue and microbes and eventually the restoration of tissue functionality. Inflammatory response is one of the vital reactions to body injury, acting alongside the restoration of homeostasis, wound repair and immune response. In mammals, wound healing is a process that seeks to restore tissue integrity and function, and is characterized by a series of biological processes including inflammatory response. Here, we review pioneering experiments and recent observations in invertebrate models suggesting that in highly divergent and evolutionary distant taxa, such as molluscs, insects and vertebrates, the inflammatory response could be driven by a pool of molecules sharing common evolutionary origin.

The inflammatory process in arthropods includes primarily the recruitment of circulating hemocytes to wounds or sites of microbial infections. Melanization, capsule formation and clotting reactions will finally result in the sealing of wounds. In this review we will focus on recent research about hemolymph clotting and melanization reactions, and the recruitment of hemocytes to wounds and infections. We further describe in more detail new knowledge about crustacean hematopoiesis that is crucial for hemocyte recruitment to the site of an infection and there develop an inflammatory response. Moreover, we pay special attention to the gut as an important route of infection in arthropods. Since the gastrointestinal tract provides a first line of defense and regulation of the indigenous bacteria and the intestine often harbors loads of potential pathogenic microorganisms, the integrity of intestinal epithelium and to maintain the correct flora is crucial to animal health.

Viral infections in fish are common in both natural and cultured fish populations and the spread of infectious disease is a serious threat to both natural ecosystems and commercial exploitations. A significant body of studies have addressed the host response to viral infection including the efficacy of DNA vaccines however we still have a fragmented vision of both pathologies associated with viral infection and the immune response to those across fish species. Many studies have concentrated upon freshwater fish including the zebrafish (Danio rerio) and the Rainbow trout (Oncorhynchus mykiss) whereas the majority of marine fish studies address the Atlantic salmon (Salmo salar). Here we provide a comprehensive review concentrating upon the salient pathological features of the most common viral infections including examples of the Betanodaviruses, Birnaviruses, Rhabdoviruses and the Isavirus in cultured fish with emphasis where possible upon non-salmonid cold water adapted marine species. In parallel we review the current state of the art mainly in reference to gene expression studies describing the host innate immune response concentrating upon the inflammatory response and its relationship toward anti-viral immunity in fish. Due to the complexity of the observed responses and the limitations of candidate gene expression studies to describe global biological processes, recent efforts in the use of microarray analysis for the study of the anti-viral response have been highlighted including members of the Pleuronectiform and the Perciform families. Finally we review the potential of the zebrafish to become a significant biological model in the elucidation of the molecular mechanisms underlying the piscine immune response to viral infection.

Vertebrates are armed with an array of pattern recognition receptors (PRRs) to sense viral pathogen associated molecular patterns (PAMPs). Upon activation, the PRRs trigger an interferon response which is central to host antiviral defence. Recent studies have demonstrated that the PRR surveillance system is well conserved in vertebrates during evolution. In fact, most classical PRRs characterised in mammals, such as Toll like receptors and the RIG-I-like receptors, have been identified in lower vertebrates. This review summarises recent progress in PRR recognition of viral PAMPs in teleost fish.

The inflammatory response should be considered a protective immune reaction of the host aimed at the removal of pathogens, sometimes irrespective of negative side-effects. In this review we discuss the differential contribution of macrophages and neutrophilic granulocytes to nitrosative stress in vivo and discuss how the timing and concentration of nitric oxide (NO.) are important factors determining the degree of nitrosative stress during parasite-induced inflammation. Infections of common carp (Cyprinus carpio) with the extracellular protozoan parasite Trypanoplasma borreli provide an excellent example of how adaptation and homeostasis are essential elements of the host-pathogen relationship. On the one hand, host-derived NO. interferes with clearance of IgM from the parasite surface and thus can be considered a protective immune reaction of the host. On the other hand, it is essential that the host limits the risks associated with the production of NO., preventing suppressive effects on lymphocyte proliferation. We review, for both host and parasite, the role of oxygen and nitrogen radicals in the induction of nitrosative stress and the importance of antioxidant compounds for protection against these radicals. Finally, mediators of inflammation such as cytokines, chemokines or alarmins that are involved in the inflammatory response will be discussed in the context of the carp-T. borreli infection model.

The inflammatory response is the reaction of all Metazoan organisms to pathogen invasion that initiates when pathogenderived molecules are recognized by specific pattern recognition receptors expressed mainly on cells of the innate immune system. The successive expression of pro-inflammatory cytokines and chemokines limits pathogen spread, and attracts and activates immune cells to help in the elimination of the invaders. In this paper we focused on the analyses of the 3D structures of three pro-inflammatory molecules (interleukin-1β, tumor necrosis factor-α, interleukin-8) from selected Teleost fish species (Oncorhynchus mykiss, Dicentrarchus labrax, Chionodraco hamatus) generated using as template models those of experimental homologous proteins. These structures were discussed with the aim to investigate the differences between them and mammalian counterparts and, moreover, to verify the presence of the structural requirements for their biological activities, known mainly in mammals.

A large body of evidence on brain development and ageing has revealed that inflammatory processes profoundly affect brain functions during life span of mammalians, including humans. Activation of innate immune mechanisms leading to pro-inflammatory cytokine up-regulation is involved in devastating and disabling human brain illnesses, as Alzheimer's disease (AD), a progressive neurodegenerative disease that causes dementia in the elderly. Emerging data indicate that the cytokine Interleukin (IL)-18, one of the key mediator of inflammation and immune response, has relevance in the physiopathological processes of the brain, by ultimately influencing the integrity of neurons and putatively contributing to AD. In this review, the relationship between specific IL-18-mediated processes and AD neurodegeneration is summarized and clinical studies pointing to a role of the cytokine in the pathology are discussed. Altogether, the presented data indicate that a more complete knowledge of the molecular mechanisms underlying IL-18 implication in neuroinflammatory and neurodegenerative pathways could contribute toward the development of new therapeutic strategies for AD.

Helicobacter pylori is a spiral-shaped, flagellated, microaerophilic Gram-negative bacillus which colonizes the gastric mucosa of more than 50% of human population. The chronic infection generates a state of inflammation, which however is asymptomatic in the majority of the subjects. Nevertheless, in a subset of the H. pylori-infected population, the gastric inflammation may evolve toward chronic gastritis, peptic ulcer, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer. In brief, the stages of the H. pylori colonization are the following: crossing of the gastric mucus layer, adhesion to the gastric epithelium, and then obtaining nutrients while avoiding to be defeated by the host immune response. For some H. pylori colonization/virulence factors a specific role has been suggested in the development of the inflammation and in the impact on the host immune system. On the other hand, some host's factors have been found relevant in originating chronic gastric inflammation and the subsequent pathological outcome in the presence of H. pylori infection. In other words, both bacterial action and host response contribute to the pathogenesis. The host-pathogen coadaptation resulted in a H. pylori colonization that in most of the cases might remain harmless; however, the concomitance of particular genotypes of both pathogen and host may concur to the development of severe pathology. Although a large body of clinical and experimental observations have been provided since the discovery of H. pylori, a further knowledge of the mechanisms of host-pathogen interaction and of those that lead to achieve protective immunity against this pathogen is still necessary to guide and make efficacious the fight against H. pylori.

The A1 adenosine receptors (A1AR), belonging to the rhodopsin-like superfamily of the G-protein-coupled receptors (GPCRs), may regulate many various cellular processes in cardiovascular, renal, and central nervous systems. In addition, since the A1AR possesses antilipolytic properties, numerous A1AR agonists and antagonists have been developed, but only some of them with the most promising selective properties in vitro have been advanced to animal studies and clinical trials. In this review, we have summarized the studies on the utility of A1AR selective agonists and antagonists in the regulation of lipid and carbohydrate metabolism and their potential therapeutic applications in diabetes.

Recent advances in research on depression have confirmed that it is common, recurrent and disabling mental disorder. Current medication for the treatment of depression have limited efficacy and delayed onset of therapeutic action. In view of the limitation of the current antidepressant pharmaceuticals, tremendous research efforts are ongoing to search for a pharmacological treatment which may improve antidepressive efficacy, onset of action or even both therapeutic parameters. To address these needs, numerous combination therapies that maintain the benefits associated with selective serotonin reuptake inhibitors (SSRIs) but attempts to improve efficacy or reduce side effects by additional mechanism (5-HT1A, 5-HT2C ) and newer approaches targeting excitatory (glutamate, NMDA,mGluR2, mGluR5) or inhibitory aminoacid system (GABA) or peptidergic system(neurokinin1, corticotrophin releasing factor1, melanin concentrating hormone1) have been identified. The goal of this review is to give a brief overview of the major advances in monoamine based treatment strategies and the new emerging approaches in the treatment of depression.