Inflammation & Allergy-Drug Targets (Discontinued) - Volume 13, Issue 4, 2014

Since the discovery and use of the microscope in the 17th century, we know that we host trillions of micro-organisms mostly in the form of bacteria indwelling the “barrier organs” skin, gut, and airways. They exert regulatory functions, are in a continuous dialogue with the intestinal epithelia, influence energy handling, produce nutrients, and may cause diabetes and obesity. The human microbiome has developed by modulating or avoiding inflammatory responses; the host senses bacterial presence through cell surface sensors (the Toll-like receptors) as well as by refining mucous barriers as passive defense mechanisms. The cell density and composition of the microbiome are variable and multifactored. The way of delivery establishes the type of initial flora; use of antibiotics is another factor; diet composition after weaning will shape the adult’s microbiome composition, depending on the subject’s life-style. Short-chain fatty acids participate in the favoring action exerted by microbiome in the pathogenesis of type-2 diabetes and obesity. Clinical observation has pinpointed a sharp rise of various dysimmune conditions in the last decades, including IBD and rheumatoid arthritis, changes that outweigh the input of simple heritability. It is nowadays proposed that the microbiome, incapable to keep up with the changes of our life-style and feeding sources in the past few decades might have contributed to these immune imbalances, finding itself inadequate to handle the changed gut environment. Another pathway to pathology is the rise of directly pathogenic phyla within a given microbiome: growth of adherent E. coli, of C. concisus, and of C. jejuni, might be examples of causes of local enteropathy, whereas the genus Prevotella copri is now suspected to be linked to rise of arthritic disorders. Inflammasomes are required to shape a non colitogenic flora. Treatment of IBD and infectious enteritides by the use of fecal transplant is warranted by this knowledge.

The renin-angiotensin system (RAS) conceived as a coordinated hormonal cascade plays an important role in controlling multiple functions in many organs and is much more complex than previously thought. The RAS has continued to expand, with the identification of new components, functions and subsystems. Angiotensin-converting enzyme (ACE) and its novel homolog angiotensin converting enzyme 2 (ACE2) are two key enzymes involved in the synthesis of bioactive components of the RAS. The main active peptides of the RAS include angiotensin II (Ang II), Ang III, Ang IV, and angiotensin-(1-7) [Ang-(1-7)] among which Ang II and Ang-(1-7) are much more important in health and disease. The axis formed by ACE2 represents an endogenous counter-regulatory pathway within the RAS, and its actions are opposite to those of the ACE axis. Conventionally the RAS has been considered to be important in the cardiovascular system, metabolism, cell growth and homeostasis. In recent years, a key role of ACE and ACE2 and their peptides has been recognized in the inflammatory process in conditions such as cardiac hypertrophy, pulmonary hypertension, glomerulonephritis, lung injury, sepsis, and acute pancreatitis. Investigations are ongoing to better understand the role of the RAS in inflammation. A comprehensive understanding of the RAS components in inflammation can provide new possibilities for therapeutic approaches against inflammatory diseases. In this review, we discuss our current understanding of the subject, based on recent findings, on the role of ACE and ACE2 in inflammation.

Heat shock proteins (HSP) are a shock induced family of proteins, whose most prominent members are a group of molecules dedicated to maintaining the function of other proteins. Interestingly, after being exposed to heat shock typical proinflammatory agonists modify the heat shock-induced transcriptional program and expression of HSP genes, suggesting a complex reciprocal regulation between the inflammatory pathway and that of the heat shock response. The specific task of Heat shock protein 70 (Hsp 70), the most widespread and highly conserved HSP, is to protect against inflammation through multiple mechanisms. So, the expression of immune reactivity to Hsp70 in the kidney could be a cause of hypertension. Hsp70 modulates inflammatory response, as well as down-regulates the nuclear factor kappa-lightchain- enhancer of activated B cells. Also, a decreased expression of renal Hsp70 may contribute to activate the toll-like receptor 4-initiating inflammatory signal pathway. In addition, several studies have revealed that Hsp70 is involved in the regulation of Angiotensin II, a peptide with proinflammatory activity. Increased inflammatory response is generated by nicotinamide adenine dinucleotide phosphate oxidase, following activation by Angiotensin II. Interestingly, Hsp70 protects the renal epithelium by modulation of nicotinamide adenine dinucleotide phosphate oxidase, a fundamental step in the pro-inflammatory mechanism. This article aims to summarize our understanding about possible mechanisms improving the renal inflammatory process linked to Hsp70 expression. Finally, from a therapeutic point of view, the notion of antiinflammatory tools regulating Hsp70 could directly affect the inflammatory renal disease.

Multidrug antituberculosis regimen is associated with diverse clinical patterns of cutaneous adverse drug reactions (CADR), ranging from mild and moderate such as pruritus, maculopapular exanthems, lichenoid eruptions, fixed drug eruptions and urticaria to severe and even life threatening ones like acute generalized exanthematous pustulosis (AGEP), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). These adverse reactions to antituberculosis drugs are commonly observed adverse events. This is of particular importance for high HIV prevalence settings and developing countries where tuberculosis is common infection resulting in higher occurrence rate of these reactions. There is still significant heterogenity in definition and classification of CADR, as well as diversity in treatment modalities following adverse reactions and rechallenge management. The aim of this review is to discuss clinical presentation, occurrence of CADR caused by antituberculosis drugs, to identify risk factors for intolerance of the standard therapy as well as to draw attention to importance of multi-disciplinary approach, early detection, prompt diagnosis and in time management of antituberculosis drugs associated CADR. CADR can cause significant treatment interruption and alteration, resulting in increased risk of treatment failure, drug resistance, relapses and increased risk of complications including even lethal outcome. Finally, it can be concluded that it is of great importance to identify the best possible treatment and preventive regimens in order to enable continuity of the antituberculosis therapy to the full extent.

Disease modifying antirheumatic drugs (DMARDs) is a category of drugs which is used as medication in various arthritic conditions to arrest the progression of disease along with relief from pain. About 83% of population worldwide uses DMARDs. Withdrawal of COX-2 inhibitors because of cardiovascular side effects and short-term action associated with glucocorticoids provided a motivation for development of newer DMARDs. Currently non- biological DMARDs like methotrexate, sulfasalazine, hydroxychloroquine and azathioprine serve the purpose of relieving pain and inhibiting the progression of disease. Biological DMARDs like toclizumab, adalimumab, infliximab, golimumab and abatacept have shown more efficacy and lesser side effects as compared to non- biological DMARDs but their access to patient is less because of higher cost. DMARDs act by different mechanisms against inflammation like inhibition of tumor necrosis factor, suppression of IL-1 and TNF-α, induction of apoptosis of inflammatory cells, by increasing chemotactic factors, inhibition of purine synthesis, pyrimidine metabolism or purine embolism. DMARDs have important applications in diseases like rheumatoid arthritis, Crohn’s disease, juvenile idiopathic arthritis, psoriatic arthritis and myasthenia gravis. Present review mainly focuses on DMARDs and their clinical applications giving an overview of their mechanism of action, pharmacokinetic properties, advantages over conventional therapies, shortcomings and recent trends.

Dengue fever is a mosquito-borne viral disease infecting several hundred million people in tropical and subtropical areas every year. Its clinical manifestations range from mild fever to severe life-threatening shock syndrom. No therapeutics or licensed vaccines are available yet and with half of the world’s population already at risk, it represents a major public health concern. The co-existence of four different Dengue virus serotypes renders difficult the obtaining of full protective immunity against each one of them. On the contrary, these serotypes trigger significant cross-reactivities of antibodies and T cells, both of which may lead to disease enhancement when reactivated in the context of reinfection with a heterologous serotype. Several immunological concepts have been developed to explain disease enhancement, and the uncertainty around the topic has consequently slowed down the development of Dengue vaccines. Recent advances however have shed light on key aspects of both the immunoprotective and immunopathological mechanisms. In particular the responses of specific antibodies and T cells have been a focus of many studies. These immunological players are thought to directly influence a cytokine dysbalance that eventually leads to severe disease and vascular leakage. In this review I outline current concepts and ongoing debates on the above topics. A better understanding of Dengue virus immunopathogenesis is critically needed to optimize candidate vaccines including those currently under development. In particular, the results from large-scale human efficacy trials will offer outstanding opportunities to refine correlates of protection and design even more effective vaccines.

The antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of necrotizing vasculitides with a potential fatal outcome. Conventional therapy is based on the use of glucocorticoids (GCs) and cyclophosphamide (CYC), which is associated with severe toxic effects and is unable to control the disease activity in some refractory and relapsing cases. Several authors focused their efforts on the identification of safe and more efficient drugs, primarily investigating biological agents. Rituximab (RTX) demonstrated to be an alternative to CYC as remission-induction therapy for microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) in two clinical controlled randomized trials. Contrasting data emerged regarding anti-TNF-α agents, and their use should be limited to some selected refractory or relapsing cases. Mepolizumab (MPZ) and Omalizumab (OMZ) are potentially beneficial treatments for patients with eosinophilic granulomatosis with polyangiitis (EGPA). Hereby, we perform a review focused on the use of biological drugs for AAV treatment.