Genetics of hypersensitivity to aspirin and nonsteroidal anti-inflammatory drugs.E-mail this Article Special Reviews. Instructions for Authors E-Submission. Korean J Med Search. The Korean Journal of Medicine ;87 6: Hypersensitivity to Aspirin and Anti-infllammatory Anti-inflammatory Drugs. Aspirin and nonsteroidal anti-inflammatory drugs NSAIDs are the most widely used medications, based on their antipyretic, analgesic, and anti-inflammatory effects. However, both aspirin and NSAIDs cause hypersensitivity reactions through immunologic as well as non-immunologic mechanisms.
Genetics of aspirin induced asthma | Thorax
Aspirin induced asthma AIA is more common in women than in men. The first symptoms of the disease are often a viral respiratory infection which is followed by a prolonged and perennial rhinitis. Within a few years bronchial asthma develops, characterised by aspirin intolerance.
Aspirin precipitates life threatening attacks of asthma accompanied by rhinorrhoea, conjunctive congestion, and facial and neck flushing.
The trait of aspirin sensitivity, despite avoidance of non-steroidal anti-inflammatory drugs to which patients usually have cross sensitivity, frequently remains for the patient's lifetime. Although asthma, nasal polyps, and aspirin intolerance are considered as an inherited disease in the catalogue of Mendelian Inheritance in Man , 2 reports on familial occurrence of AIA are rather scarce.
Miller described a pair of sisters with the trait. In the other family a late onset of AIA and discordance between identical twins raised the possibility of an interaction between environmental and genetic factors. Another multiple family with mild asthma sensitive aspirin and dominant inheritance of the trait was described by von Maur et al. In almost patients studied in the European Network on Aspirin Induced Asthma 6 familial occurrence of aspirin hypersensitivity was reported in 5.
In families with multiple cases of AIA, affected individuals were usually siblings. The course of their disease was characterised by an intense rhinitis and was more severe, as scored by the number of admissions to hospital, than in singleton families. We recently consulted two sisters aged 27 and 20 years with aspirin intolerance who had reported rhinitis since the age of 12 years.
In the older sister aspirin challenge precipitated an asthma attack. The younger sister was suffering from perennial rhinitis and had blood eosinophilia. Following aspirin challenge she developed marked nasal symptoms leading to a profound decrease in nasal airflow and ocular irritation, but without bronchial obstruction.
Although their parents and some other family members were atopic or had moderate eosinophilia, the aspirin challenge was negative in all. Signs of persistent inflammation of the bronchi in patients with AIA are characterised by eosinophilic infiltration, desquamation of epithelia, increased cytokine production, and expression of adhesion molecules.
Increased eosinophilia in the bronchi is accompanied by increased expression of interleukin IL -5, a cytokine directing maturation, activation, recruitment, and prevention of eosinophil apoptosis. Since the frequency of atopy is similar in patients with AIA and in aspirin tolerant asthmatics, 9 persistent eosinophilic inflammation has to result from another mechanism. Infiltrating eosinophils are a site of cysteinyl leukotriene cys-LT synthesis, as demonstrated by immunostaining of LTC 4 synthase.
The overexpression of LTC 4 synthase in bronchial biopsy specimens of patients with AIA correlates with aspirin sensitivity and is several times higher than in aspirin tolerant asthmatic subjects. Despite numerous attempts, no immune system mediated hypersensitivity to aspirin has been found in patients with AIA.
In addition, cross sensitivity to other non-steroidal anti-inflammatory drugs NSAIDs , represented by a variety of chemical compounds, would suggest that any immune response dependent mechanism is improbable. Administration of aspirin further suppresses PGE 2 production, but this is not reflected by inhibition of the synthesis of other prostanoids as can be seen on COX inhibition in aspirin tolerant asthmatics. This prostaglandin, in addition to its anti-inflammatory properties, can relax smooth muscles.
Genetic screening of COX genes has not revealed any alterations to explain this phenomenon. PGE 2 synthase, which is an inducible and glutathione dependent enzyme, has been newly cloned 13 but no studies in patients with AIA are yet available. LTC 4 seems to be the most important bronchoconstrictor mediator of asthma in aspirin sensitive disease. During inhalatory aspirin challenge, a further transient increase in LTE 4 excretion in the urine is observed in patients with AIA.
Expression of 5-LO is modulated by a genetic variation in the SP1 transcription factor binding motif of the 5-LO gene, although no association between allelic variants of 5-LO gene promoter and AIA have been found. Overexpression of LTC 4 synthase could result from an intense enzyme induction in cells infiltrating bronchi of patients with AIA, but the possibility of a genetic mechanism facilitating the LTC 4 synthase gene transcription has been tested.
LTC 4 synthase is expressed in eosinophils, basophils, and macrophages. In some other cells such as the epithelia, endothelia, and platelets the enzyme is an orphan because of lack of 5-LO expression. The LTC 4 synthase gene has been cloned and its sequence, molecular organisation, and functional analysis have been described.
This increase correlated with the presence of the allelic C variant of LTC 4 synthase. Patients grouped according to their LTC 4 S genotypes. Incubations of double strand oligonucleotides encompassing the transversion with nuclear extracts had a three times higher affinity of transcription factor AP2 for allele C.
The nature of the interaction which orchestrates LTC 4 synthase expression in inflammatory cells of patients with AIA has not been fully elucidated.
A transient increase in urinary LTE 4 after aspirin challenge in sensitive patients fig 3 is significant only in carriers of the C allele. Allele — A has an AP2 transcription factor core sequence — to — Urine samples collected in two hour intervals.
Patients were grouped according to their LTC 4 synthase genotypes: Aspirin sensitive asthmatic subjects have overexpression of LTC 4 synthase in their airways. Increased production of cys-LTs at baseline and in response to aspirin provocation suggests that these mediators are the main cause of the disease.
Genetic polymorphism of the promoter region of the LTC 4 synthase gene effects its expression in cells by an increase in the transcription rate in eosinophils and a change in its inducibility in response to pro-inflammatory mediators. The association of allelic variant C of LTC 4 synthase with AIA is moderate and similar to other genetic polymorphisms contributing to common diseases.
Aspirin induced asthma is a disease manifested by dysregulation of eicosanoid synthesis after exposure to NSAIDs which is enhanced by the genetically determined overexpression of LTC 4 synthase. You will be able to get a quick price and instant permission to reuse the content in many different ways. Skip to main content.
Latest content Current issue Archive Authors About. Log in via Institution. Genetics of aspirin induced asthma. Familial history of aspirin intolerance Although asthma, nasal polyps, and aspirin intolerance are considered as an inherited disease in the catalogue of Mendelian Inheritance in Man , 2 reports on familial occurrence of AIA are rather scarce. Eosinophilic inflammation of airways in AIA Signs of persistent inflammation of the bronchi in patients with AIA are characterised by eosinophilic infiltration, desquamation of epithelia, increased cytokine production, and expression of adhesion molecules.
Lipid mediators of asthma and aspirin sensitivity Despite numerous attempts, no immune system mediated hypersensitivity to aspirin has been found in patients with AIA. Genetic polymorphism of LTC 4 synthase controls biosynthesis of leukotrienes LTC 4 synthase is expressed in eosinophils, basophils, and macrophages.
Conclusions Aspirin sensitive asthmatic subjects have overexpression of LTC 4 synthase in their airways. Miller FF Aspirin-induced bronchial asthma in sisters. Ann Intern Med J Allergy Clin Immunol J Clin Invest Bochenek G , Nizankowska E , Szczeklik A Atopy trait in hypersensitivity to nonsteroidal anti-inflammatory drugs. Szczeklik A Aspirin-induced asthma as a viral disease.
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