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Anti-Inflammatory
& Anti-Allergy Agents in Medicinal Chemistry
ISSN: 1871-5230
Anti-Inflammatory
& Anti-Allergy Agents in Medicinal Chemistry
Volume 9, Number 4, December 2010
Contents
Alpha-1 Antitrypsin Deficiency: A Disease with Numerous Adverse Effects on Humans
Guest Editors: S. Ghavami, A.J. Halayko and F.J. de Serres
Editorial: Pp. 276-278
Alpha-1 Antitrypsin: It’s Role in Health and Disease Pp. 279-288
M. Hashemi, P. Sharma, M. Eshraghi, M. Naderi, A. Moazeni-Roodi, H. Mehrabifar and M. Taheri
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Alpha-1-Antitrypsin Deficiency and Mechanisms of Liver Disease Pp. 289-298
J.H. Teckman
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The Role of Alpha1-Antitrypsin Deficiency in Respiratory Disease Pp. 299-303
N. Kalsheker
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Role of Alpha-1 Antitrypsin (AAT) in Ocular Allergy and Uveitis Pp. 304-313
A. Leonardi, F. Urban and M. Bortolotti
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New Strategies in Drug Development Focusing on the Anti Protease-Protease Balance in Alpha-1 Antitrypsin Deficiency Pp. 314-329
E.P. Reeves, S. Cosgrove, D.A. Bergin, C.M. Greene and N.G. McElvaney
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Alpha-1 Antitrypsin Deficiency: Treatment beyond Augmentation Therapy Pp. 330-335
A. Mahajan and D.K. Hogarth
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Gain of Function Effects of Z Alpha-1 Antitrypsin Pp. 336-346
T.P. Carroll, N.G. McElvaney and C.M. Greene
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General Articles
Mn-SOD and Chronic Inflammation of Gastric Mucosa Pp. 347-354
J. Dovhanj, D. Švagelj, M. Smolić, R. Smolić and I. Marić
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The Spectrum of Nimesulide-Induced-Hepatotoxicity. An Overview Pp. 355-365
F. Bessone, L. Colombato, E. Fassio, M.V. Reggiardo, J. Vorobioff and H. Tanno
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Abstracts
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Alpha-1 Antitrypsin: It’s Role in Health and Disease
M. Hashemi, P. Sharma, M. Eshraghi, M. Naderi, A. Moazeni-Roodi, H. Mehrabifar and M. Taheri
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.
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Alpha-1-Antitrypsin Deficiency and Mechanisms of Liver Disease
J.H. Teckman
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.
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The Role of Alpha1-Antitrypsin Deficiency in Respiratory Disease
N. Kalsheker
The main aim of this review is to describe the role of alpha1-antitrypsin deficiency (AATD) in respiratory disease which accounts for over 50% of AATD associated deaths. Only about 10% 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.
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Role of Alpha-1 Antitrypsin (AAT) in Ocular Allergy and Uveitis
A. Leonardi, F. Urban and M. Bortolotti
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.
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New Strategies in Drug Development Focusing on the Anti Protease-Protease Balance in Alpha-1 Antitrypsin Deficiency
E.P. Reeves, S. Cosgrove, D.A. Bergin, C.M. Greene and N.G. McElvaney
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 11µmol/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.
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Alpha-1 Antitrypsin Deficiency: Treatment beyond Augmentation Therapy
A. Mahajan and D.K. Hogarth
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.
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Gain of Function Effects of Z Alpha-1 Antitrypsin
T.P. Carroll, N.G. McElvaney and C.M. Greene
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 anti-protease 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.
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Mn-SOD and Chronic Inflammation of Gastric Mucosa
J. Dovhanj, D. Švagelj, M. Smolić, R. Smolić and I. Marić
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.
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The Spectrum of Nimesulide-Induced-Hepatotoxicity. An Overview
F. Bessone, L. Colombato, E. Fassio, M.V. Reggiardo, J. Vorobioff and H. Tanno
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-induced-hepatotoxicity 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.
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