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Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Anti-Inflammatory and Anti-Allergy Agents) (v.9, #4)
Editorial [Hot topic: Alpha-1 Antitrypsin Deficiency: A Disease with Numerous Adverse Effects on Humans (Guest Editors: S. Ghavami, A.J. Halayko and F.J. de Serres)] by Saeid Ghavami, Andrew J. Halayko, Fredrick J. de Serres (pp. 276-278).
Alpha -1 antitrypsin (AAT) deficiency is a severe autosomal recessive hereditary disorder with an incidence second only to cystic fibrosis among inborn diseases of the lungs [1]. AAT deficiency was first described in 1963 [2, 3], but the earliest assumed case of reported AAT deficiency is in an Alaskan girl who was found frozen in the ice 800 years after her death [4]. Moreover, it is now believed that Frederic Chopin's premature death in 1849 was a AAT deficiency case [5]. In 1963 Laurell and Eriksson investigated 5 patients and#x201C;with a new type of dysproteinemia characterized by very pronounced alpha 1-antitrypsin deficiencyand#x201D; in their first description of AAT deficiency [2, 6]. Later, in 1965 it was concluded in a study of 33 severely affected patients that most PI*ZZ homozygous individuals are predisposed to early-onset emphysema [2, 6, 7]. In 1969, liver cirrhosis was first linked to AAT deficiency as the presence of periodic acid Schiff (PAS)- positive inclusions in the hepatocytes of AAT deficient individuals was described [8]. Liver involvement is now considered as a conformational feature caused by the accumulation of AAT within hepatocytes rather than the result of tissue breakdown from a protease-antiprotease imbalance [9]. In the four decades since the first description of ATT deficiency significant advances in the understanding its pathogenesis and in clinical management have been made, though important questions remain. Interest in the numbers of individuals affected by AAT deficiency began with a survey of the numbers in various European countries by Hutchinson [10]. This was followed by larger studies by de Serres and colleagues [11-13], revealing data on the frequency of each of the 5 phenotypic classes, PI*MS, PI*MZ, PI*SS, P{I*SZ and PI*ZZ, in 55 countries worldwide. Blanco and colleagues also surveyed for individuals at risk in different geographic regions in Spain (2001a) and others studies assessed the number of individuals at risk for AAT deficiency in countries inside and outside of Europe (2001b,c). de Serres published a paper in 2003 entitled and#x201C;Alpha-1 antitrypsin deficiency is not a rare disease but a disease that is rarely diagnosedand#x201D; in which he described environmental factors associated with different occupations that affect the health and well being of genetic carriers and homozygotes for ATT deficiency. Further work by a collaborative of investigators has surveyed the occurrence of AAT deficiency in all major geographic regions worldwide [12-15](de Serres et al. 2003 a,b, 2005, 2006). These data were summarized in two review papers, the first on 69 countries [16] and another on 98 countries worldwide [17]. The database in the latter paper provides the reader with the following numbers of those at risk in these 98 countries; PI*MS (144,814,982), PI*MZ (37,259,100), PI*SS (4,159,102), PI*SZ (1,467,429), and PI*ZZ (238,161). Collectively, these studies on the genetic epidemiology demonstrate that AAT deficiency is not a and#x201C;rareand#x201D; disease, rather with the exception of countries in the Far East, it affects many people worldwide. This special issue of Anti-Inflammatory and Anti-Allergy Agents in Medicinal Chemistry will address the latest progress in AAT biology, its deficiency, and emerging therapies. Besides lung disease, AAT deficiency has been associated with many different diseases like psoriasis [18-20], gasterointestinal disease [21, 22], and ocular inflammation [23, 24]. In their article, Hashemi et al. (pp. 279-288) address multiple aspects of AAT deficiency-induced diseases. They also address the latest detection method and nomenclature rules for AAT alleles. The liver is chiefly responsible for AAT synthesis (several grams per day), but AAT is also produced by leukocytes, enterocytes, and other tissues [25-27]. AAT deficiency can induce chronic liver disease [28-30], cirrhosis [31-34], and hepatocellular carcinoma [35, 36]. Over one-third of genetically susceptible adult patients with the most severe phenotype, PiZZ, exhibit severely depleted plasma levels of AAT [35, 37] because it is not effectively secreted from the hepatocytes. The clinical presentation of liver disease is variable, and the genetic and environmental factors that predispose some individuals to liver disease while sparing others are unknown. In his article, Teckman (pp. 289-298) reviews the latest understanding of mechanisms for AAT deficiency-induced-liver disease, with focus on the Z homo and heterozygote AAT phenotypes and their clinical and biochemical features. He also describes how the endoplasmic reticulum (ER) retention of unfolded Z AAT protein can trigger ER-stress induced liver pathogenesis in these patients. Neutrophil elastase (NE) plays a central role in tissue destruction in the lungs of patients with AAT deficiency, and is the major target proteinase of AAT [38]. AAT can also bind irreversibly to proteinase 3 and cathepsin G and inhibit their function [39]. Point mutations in the AAT mobile domain can prevent its effective secretion from the liver [39], leading to the low local levels of this protein within the lung and susceptibility to NE-induced damage [40]. Chronic obstructive pulmonary disease (COPD) is the most important lung disease that is induced by AAT deficiency [41, 42]. In his article Kalsheker (pp. 299-303) focuses on mechanisms of AAT deficiency in the pathogenesis of respiratory diseases. In particular the effect of cigarette smoking on AAT deficiency-induced lung disease states (COPD, emphysema and asthma). Enzymes play an essential role in the regulation of immunologic and inflammatory responses [23, 24, 43]. This often involves the regulation of cell function and the activation of inflammatory mediators such as the complement and kinin systems, as well as the coagulation and fibrinolytic pathways [43, 44]. Many of these mediators are themselves enzymes, and their activity is in most instances regulated by inhibitors [23, 24]. Some inhibitors are highly specific for one enzyme, but others, such as Pi and and#945;2 macroglobin have a broad range of activity.. In their article Leonardi et al. (pp. 304-313) consider the importance of AAT and its deficiency in ocular allergy and inflammation, emphasizing the role of AAT in uveitis and vernal keratoconjunctivitis (VKC). They describe their recent research focused on the role of metalloproteinase enzymes and immune response, and contrast their results with previous findings in this field [23, 24]. Local concentrations of AAT are reduced in many AAT deficiency-related diseases, and appears to be a key event in the development of emphysema. Thus a logical therapeutic strategy, as used for immunoglobulin deficiency, appeared to be to use replacement treatment (augmentation therapy) in AAT deficiency therapy, in particular for AAT deficiency related pulmonary diseases [45]. A guiding principal for such therapy, using research evidence-based clinical data, is that serum AAT concentration of and#x2265;11 and#956;mol are likely to be protective against AAT deficiency-induced pulmonary diseases. Several studies show it is possible to infuse AAT into the plasma, resulting in an increase in the concentration of AAT in the lung lining fluid [46]. On this basis, the United States Food and Drug Administration (FDA) approved the use of pooled human plasma on a weekly basis for patients with genetic deficiency associated with the PIZ or PI-null phenotypes [47, 48]. The therapy has also been licensed in Canada and some European countries. In their articles, Mahajan et al. and Reeves et al. (pp. 314-329) describe new improvements in AAT deficiency therapy, focusing on augmentation therapy. Moreover, Reeves et al. (pp. 330-335) describe the importance of strategies to rescue protease-antiprotease imbalance on AAT deficiency-dependent diseases, and describe alternate therapeutic approaches for AAT deficiency, such as naturally occurring antiproteases, synthetic and semi-synthetic engineered elastase inhibitors, and gene therapy. Accumulation of mutant AAT (Z) in the endoplasmic reticulum (ER) leads to liver injury by activating the ER-UPR pathway. It has been theorized that disease pathogenesis is linked with alteration in pathways responsible for removal of mutant AAT (Z) [49, 50]. Therefore genetic traits or environmental factors that can alter the function of a putative AAT disposal pathway may increase or decrease the risk of liver disease [9]. In their article, Carroll et al. (pp. 336-346) describe the mechanism for ER-stress induction and characterize UPR involvement in the ER-stress process. In this context they discuss recent research focusing on the role of the ER-UPR pathway in AAT Z phenotype-induced liver damage. Collectively, this volume provides fundamental information on the biological mechanisms associated with AAT-deficiency related diseases. Furthermore, an overview of translational research effort leading to new and improved treatment options, in relation to genotype-specific pathology, for this severe disease is provided. In total, this offers a comprehensive overview of the current state of knowledge that is opening windows and doors for development of new and better treatments for AAT deficiency.
Alpha-1 Antitrypsin: It's Role in Health and Disease by Mohammad Hashemi, Pawan Sharma, Mehdi Eshraghi, Mohammad Naderi, Abdolkarim Moazeni-Roodi, Hamid Mehrabifar, Mohsen Taheri (pp. 279-288).
Alpha-1 Antitrypsin (AAT) is a 52 kDa glycoprotein that is principally synthesized by the liver. It is the archetype of the serine protease inhibitor (Serpin) superfamily of proteins, which has a major role in inactivating neutrophil elastase and other proteases to retain protease - antiprotease equilibrium. AAT deficiency is a rare monogenic disorder characterized by low levels of AAT in serum and the lungs and it is well known to be associated with emphysema and liver disease. Inadequate knowledge of AAT deficiency might be due to under-recognition of this protein. To date, the exact role of AAT deficiency in various diseases has not been extensively elucidated. In this review, the current knowledge regarding the role AAT in various disorders will be discussed.
Alpha-1-Antitrypsin Deficiency and Mechanisms of Liver Disease by Jeffrey H. Teckman (pp. 289-298).
Alpha-1-antitrypsin (a1AT) Deficiency is a metabolic genetic disease in which individuals homozygous for the mutant Z a1AT gene are at risk for liver and lung disease. Homozygotes, called PIZZ in World Health Organization nomenclature, occur in approximately 1 in 2000 births in North American and European populations. A1AT is a protein synthesized in large quantities by the liver, leukocytes, and other tissues and then secreted into serum and extracellular fluid. Its physiologic function is to inhibit neutrophil proteases during periods of inflammation in order to protect host tissues from non-specific inflammatory injury. The mutant Z gene of a1AT directs the synthesis of a mutant protein which folds abnormally in the endoplasmic reticulum of hepatocytes during biogenesis and is retained intracellularly rather than being efficiently secreted. This intracellular accumulation of a1AT mutant Z protein within hepatocytes can cause liver injury, cirrhosis and hepatocellular carcinoma, and the lack of circulating anti-protease activity leaves the lung vulnerable to injury and the development of emphysema. There is a high degree of variability in the clinical manifestations among PIZZ patients, suggesting a strong influence of genetic and environmental disease modifiers. Cigarette smoking has been identified as an especially strong risk factor for the development of PIZZ associated emphysema. The accumulation of the a1AT mutant Z protein within hepatocytes triggers an injury cascade which includes aspects of ER stress, caspase activation, and apoptosis which appears to lead to liver injury, fibrosis and cirrhosis. There is no specific treatment for PIZZ associated liver disease, other than standard liver disease supportive care and liver transplantation. Studies of the processes of intracellular injury, and of new therapies for this disease, are areas of intense and ongoing investigation.
The Role of Alpha1-Antitrypsin Deficiency in Respiratory Disease by Noor Kalsheker (pp. 299-303).
The main aim of this review is to describe the role of alpha1-antitrypsin deficiency (AATD) in respiratory disease which accounts for over 50and#x25; of AATD associated deaths. Only about 10and#x25; of all patients with AATD are detected and the majority of cases go undetected or are asymptomatic. Cigarette smoking and other environmental exposures are important triggers for developing respiratory disease. This review examines the spectrum of respiratory manifestations of AATD, the epidemiology of AATD worldwide, the molecular pathophysiology underlying the respiratory component and the role of augmentation therapy in AATD related disease.
Role of Alpha-1 Antitrypsin (AAT) in Ocular Allergy and Uveitis by Andrea Leonardi, Francesca Urban, Massimo Bortolotti (pp. 304-313).
Ocular allergy and uveitis are varied groups of inflammatory eye disorders characterized by complex and as yet ill-defined pathogeneses. Alpha-1 antitrypsin (AAT) is the archetype of the serine protease inhibitor supergene family. AAT deficiency is one of many factors that may be involved in abnormalities such as liver and lung disease, inflammatory joint diseases, and inflammatory eye diseases. In the present review, the role played by AAT in ocular inflammation is analyzed, particularly in vernal keratoconjunctivitis (VKC) and uveitis. Tear trypsin inhibitory capacity was shown to be reduced in VKC patients. In uveitis patients, a significant difference in AAT phenotypes was found compared to normal subjects. We propose that a reduced inhibitory capacity of ATT and AAT might facilitate or prolong different types of ocular inflammation.
New Strategies in Drug Development Focusing on the Anti-Protease-Protease Balance in Alpha-1 Antitrypsin Deficiency by Emer P. Reeves, Sonya Cosgrove, David A. Bergin, Catherine M. Greene, Noel G. McElvaney (pp. 314-329).
Alpha-1 antitrypsin (AAT) is the most abundant proteinase inhibitor within the circulation and AAT deficiency is a genetic disorder characterised by serum levels of less than 11and#956;mol/L. The Z mutation is the most common AAT allele associated with the disease and causes the most severe plasma deficiency, as the mutant protein polymerizes and accumulates within the endoplasmic reticulum of hepatocytes. The retained polymers are associated with cirrhosis and reduced serum levels of AAT contribute to the development of chronic pulmonary disease in AAT deficient individuals. This article will review the importance of AAT as a serine anti-protease, the clinical manifestations of AAT deficiency and specific treatment of the disease. Current therapies including AAT replacement and treatment with synthetic or alternative protease inhibitors are reviewed, along with possible future therapies including those focusing on targeting AAT polymer formation or based on gene therapy.
Alpha-1 Antitrypsin Deficiency: Treatment Beyond Augmentation Therapy by Amit Mahajan, D. Kyle Hogarth (pp. 330-335).
Alpha-1-antitrypsin (AAT) deficiency is a debilitating disease characterized by progressive parenchymal lung destruction. Deficiency of AAT results in a protease-antiprotease imbalance with unregulated activity of neutrophil elastase (NE). This imbalance results in accelerated parenchymal lung damage and a subsequent decrease in pulmonary function. Repletion of AAT enzyme with augmentation therapy using human pooled AAT is the current focus of treatment for AAT deficiency. While augmentation is a cornerstone of therapy for individuals with AAT deficiency, practitioners must also maximize standard treatment for obstructive lung disease like chronic obstructive pulmonary disease (COPD) to provide improved quality of life in patients suffering from AAT deficiency. Interventions such as smoking cessation, inhaled medications, pulmonary rehabilitation, supplemental oxygen therapy, vaccinations, avoidance of environmental exposures, and prophylactic antibiotics are essential therapies for the management of AAT deficiency.
Gain of Function Effects of Z Alpha-1 Antitrypsin by Tomas P. Carroll, Noel G. McElvaney, Catherine M. Greene (pp. 336-346).
The serine proteinase inhibitor alpha-1 antitrypsin (AAT) is produced principally by the liver from where it is secreted into the circulation and provides an antiprotease protective screen throughout the body. Mutations leading to deficiency in AAT are associated with liver and lung disease. The most notable is the Z mutation, which encodes a misfolded variant of the AAT protein in which the glutamic acid at position 342 is replaced by a lysine. ZAAT is not secreted effectively and accumulates intracellularly in the endoplasmic reticulum (ER) of hepatocytes and other AAT-producing cells. The ER has evolved a number of elegant mechanisms to manage the accumulation of incorrectly folded proteins; ZAAT interferes with this function and promotes ER stress responses and inflammation. Until recently it was thought that gain of function was the major cause of the liver disease whilst the lung disease was entirely due to loss of antiprotease protection in the lung. This belief is now being challenged with the discovery that ER stress is also activated in bronchial epithelial cells and inflammatory cells normally resident in the lung in ZAAT deficient individuals. Here we describe the gain of function effects of ZAAT. In particular we highlight the signalling pathways that are activated during ER stress in response to accumulation of ZAAT and how these events are linked to inflammation and may contribute to disease pathogenesis.
Mn-SOD and Chronic Inflammation of Gastric Mucosa by J. Dovhanj, D. Svagelj, M. Smolic, R. Smolic, I. Maric (pp. 347-354).
The involvement of reactive oxygen species in the inflammatory tissue destruction is well known. Significant changes in the activity and expression of several isoforms of superoxide dismutase were observed in the human gastric disease. Mn-SOD attracted the attention of researchers because of its inducibility by oxidative stress. There is increasing evidence that oxidative stress plays a role in the progression of mucosal damage leading to gastric cancer. The evaluation of possible modulation of Mn-SOD activity during chronic inflammation of gastric mucosa could reveal whether its assessment is important to prevent the accumulation of gastric epithelial cell damage and thereby reduce the risk of gastric carcinoma.
The Spectrum of Nimesulide-Induced-Hepatotoxicity. An Overview by Fernando Bessone, Luis Colombato, Eduardo Fassio, Maria Virginia Reggiardo, Julio Vorobioff, Hugo Tanno (pp. 355-365).
Nimesulide is the unique molecule of the sulphonanilides class of non-steroidal antiinflammatory drugs [NSAIDs]: Nimesulide has analgesic, anti-pyretic, potent anti-inflammatory activities and very good gastro-intestinal [GI] tolerability. Therapeutic action is multifactorial, including cyclooxigenase-2 (COX-2) inhibition, scavenging of free radicals and inhibition of various pathways of inflammation. Nimesulide is oxidatively metabolised via liver cytochromes P450. Several unproven hepatotoxicy-predisposing-factors thought to be present in rheumatologic patients have been linked to a higher incidence of hepatic reactions in this sub-population. However, the molecular mechanism underlying hepatotoxicy remains to be elucidated. Nimesulide has been associated over two decades with reports of severe liver damage. The clinical presentation of nimesulide-related-hepatoxicity includes, malaise, pruritus, a wide range of ALT/AST elevation, and an average 4 fold elevation of alkaline phosphatase and GGT. Liver biopsy shows a predominance of hepatocellular involvement, less frequently cholestatic and mixed patterns. Both, the hepatitis pattern and the mixed-type combining cholestatic jaundice, might evolve into fulminant hepatic failure. However, the incidence of nimesulide-inducedhepatotoxicity is not homogeneous across the medical literature. Indeed, most of the countries find it to be comparable to that of other NSAIDs, while a significant higher hepatotoxicity is suggested by reports from Finland, Ireland and Argentina. Our series in Argentina comprising 43 cases is worrisome particularly because it evidences a significant proportion of severe forms. In the present work we analyze the epidemilogical characteristics of nimesulide-induced-hepatotoxicity and we describe the clinical and histologic spectrum of nimesulide-associated-liver damage based on the comparison of our series of 43 cases and worldwide published observations in the pertinent medical literature.