Inflammation & Allergy-Drug Targets (v.13, #4)

The Gut Microbiome by Giovanni C. Actis (217-223).
Since the discovery and use of the microscope in the 17th century, we know that we host trillions of micro-organismsmostly in the form of bacteria indwelling the “barrier organs” skin, gut, and airways. They exert regulatory functions, are in acontinuous dialogue with the intestinal epithelia, influence energy handling, produce nutrients, and may cause diabetes andobesity. The human microbiome has developed by modulating or avoiding inflammatory responses; the host senses bacterialpresence through cell surface sensors (the Toll-like receptors) as well as by refining mucous barriers as passive defensemechanisms. The cell density and composition of the microbiome are variable and multifactored. The way of delivery establishesthe type of initial flora; use of antibiotics is another factor; diet composition after weaning will shape the adult's microbiomecomposition, depending on the subject's life-style. Short-chain fatty acids participate in the favoring action exerted bymicrobiome in the pathogenesis of type-2 diabetes and obesity. Clinical observation has pinpointed a sharp rise of variousdysimmune conditions in the last decades, including IBD and rheumatoid arthritis, changes that outweigh the input of simpleheritability. It is nowadays proposed that the microbiome, incapable to keep up with the changes of our life-style and feedingsources in the past few decades might have contributed to these immune imbalances, finding itself inadequate to handle thechanged 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 genusPrevotella copri is now suspected to be linked to rise of arthritic disorders. Inflammasomes are required to shape a noncolitogenic flora. Treatment of IBD and infectious enteritides by the use of fecal transplant is warranted by this knowledge.

ACE and ACE2 in Inflammation: A Tale of Two Enzymes by Ravinder Reddy Gaddam, Stephen Chambers, Madhav Bhatia (224-234).
The renin-angiotensin system (RAS) conceived as a coordinated hormonal cascade plays an important role incontrolling multiple functions in many organs and is much more complex than previously thought. The RAS hascontinued to expand, with the identification of new components, functions and subsystems. Angiotensin-convertingenzyme (ACE) and its novel homolog angiotensin converting enzyme 2 (ACE2) are two key enzymes involved in thesynthesis of bioactive components of the RAS. The main active peptides of the RAS include angiotensin II (Ang II), AngIII, Ang IV, and angiotensin-(1-7) [Ang-(1-7)] among which Ang II and Ang-(1-7) are much more important in health anddisease. The axis formed by ACE2 represents an endogenous counter-regulatory pathway within the RAS, and its actionsare opposite to those of the ACE axis. Conventionally the RAS has been considered to be important in the cardiovascularsystem, metabolism, cell growth and homeostasis. In recent years, a key role of ACE and ACE2 and their peptides hasbeen 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 ofthe RAS in inflammation. A comprehensive understanding of the RAS components in inflammation can provide newpossibilities 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 andACE2 in inflammation.

Heat shock proteins (HSP) are a shock induced family of proteins, whose most prominent members are a groupof molecules dedicated to maintaining the function of other proteins. Interestingly, after being exposed to heat shocktypical 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. Thespecific task of Heat shock protein 70 (Hsp 70), the most widespread and highly conserved HSP, is to protect againstinflammation through multiple mechanisms. So, the expression of immune reactivity to Hsp70 in the kidney could be acause 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-likereceptor 4-initiating inflammatory signal pathway.;In addition, several studies have revealed that Hsp70 is involved in the regulation of Angiotensin II, a peptide with proinflammatoryactivity. Increased inflammatory response is generated by nicotinamide adenine dinucleotide phosphateoxidase, following activation by Angiotensin II. Interestingly, Hsp70 protects the renal epithelium by modulation ofnicotinamide 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 processlinked to Hsp70 expression. Finally, from a therapeutic point of view, the notion of antiinflammatory tools regulatingHsp70 could directly affect the inflammatory renal disease.

Cutaneous Adverse Drug Reactions Caused by Antituberculosis Drugs by Saida Rezakovic, Zrinjka Pastar, Kresimir Kostovic (241-248).
Multidrug antituberculosis regimen is associated with diverse clinical patterns of cutaneous adverse drugreactions (CADR), ranging from mild and moderate such as pruritus, maculopapular exanthems, lichenoid eruptions, fixeddrug 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 toantituberculosis drugs are commonly observed adverse events. This is of particular importance for high HIV prevalencesettings and developing countries where tuberculosis is common infection resulting in higher occurrence rate of thesereactions. There is still significant heterogenity in definition and classification of CADR, as well as diversity in treatmentmodalities following adverse reactions and rechallenge management.;The aim of this review is to discuss clinical presentation, occurrence of CADR caused by antituberculosis drugs, toidentify risk factors for intolerance of the standard therapy as well as to draw attention to importance of multi-disciplinaryapproach, early detection, prompt diagnosis and in time management of antituberculosis drugs associated CADR. CADRcan 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 greatimportance to identify the best possible treatment and preventive regimens in order to enable continuity of theantituberculosis therapy to the full extent.

An Update on Disease Modifying Antirheumatic Drugs by Poorvashree Joshi, Suneela S. Dhaneshwar (249-261).
Disease modifying antirheumatic drugs (DMARDs) is a category of drugs which is used as medication invarious arthritic conditions to arrest the progression of disease along with relief from pain. About 83% of populationworldwide uses DMARDs. Withdrawal of COX-2 inhibitors because of cardiovascular side effects and short-term actionassociated with glucocorticoids provided a motivation for development of newer DMARDs. Currently non- biologicalDMARDs like methotrexate, sulfasalazine, hydroxychloroquine and azathioprine serve the purpose of relieving pain andinhibiting the progression of disease. Biological DMARDs like toclizumab, adalimumab, infliximab, golimumab andabatacept have shown more efficacy and lesser side effects as compared to non- biological DMARDs but their access topatient is less because of higher cost. DMARDs act by different mechanisms against inflammation like inhibition of tumornecrosis factor, suppression of IL-1 and TNF-α, induction of apoptosis of inflammatory cells, by increasing chemotacticfactors, inhibition of purine synthesis, pyrimidine metabolism or purine embolism. DMARDs have important applicationsin diseases like rheumatoid arthritis, Crohn's disease, juvenile idiopathic arthritis, psoriatic arthritis and myastheniagravis. Present review mainly focuses on DMARDs and their clinical applications giving an overview of their mechanismof 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 andsubtropical 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 representsa major public health concern. The co-existence of four different Dengue virus serotypes renders difficult the obtaining offull protective immunity against each one of them. On the contrary, these serotypes trigger significant cross-reactivities ofantibodies and T cells, both of which may lead to disease enhancement when reactivated in the context of reinfection witha heterologous serotype. Several immunological concepts have been developed to explain disease enhancement, and theuncertainty around the topic has consequently slowed down the development of Dengue vaccines. Recent advanceshowever have shed light on key aspects of both the immunoprotective and immunopathological mechanisms. In particularthe responses of specific antibodies and T cells have been a focus of many studies. These immunological players arethought to directly influence a cytokine dysbalance that eventually leads to severe disease and vascular leakage. In thisreview I outline current concepts and ongoing debates on the above topics. A better understanding of Dengue virusimmunopathogenesis is critically needed to optimize candidate vaccines including those currently under development. Inparticular, the results from large-scale human efficacy trials will offer outstanding opportunities to refine correlates ofprotection and design even more effective vaccines.

Biologics for ANCA-Associated Vasculitis by Giuseppe Murgia, Davide Firinu, Paolo E. Manconi, Stefano R. Del Giacco (275-287).
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.