Thromboxane A₂Biosynthesis in Acute Asthma and after Antigen Challenge

Abstract

Thromboxane A2 is a potent bronchial smooth muscle spasmogen in vitro, and it has been implicated in airway inflammation and in the genesis of bronchial hyperresponsiveness in asthma. We have examined the urinary excretion of a variety of products derived from thromboxane A2 (thromboxane B2, 2,3-dinor, and 11-dehydro-thromboxane B2) and prostacyclin (6-oxo-PGF1 alpha and 2,3-dinor-6-oxo-PGF1 alpha) using gas chromatography-mass spectrometry in patients admitted acutely to hospital with severe asthma and in atopic volunteers after bronchial antigen challenge. Urinary excretion of all thromboxane-derived products was markedly increased in a number of patients with severe acute asthma compared with that in a nonsmoking control population, in some cases approaching those previously described in myocardial infarction: TXB2, 31.6 +/- 12.0 versus 6.5 +/- 0.9; 2,3-dinor-TXB2, 79.0 +/- 19.2 versus 29.5 +/- 2.7; and 11-dehydro-TXB2, 234.3 +/- 65.3 versus 25.0 +/- 2.1 ng/mmol creatinine (p less than 0.001). Urinary prostacyclin-derived products were also significantly raised in acute asthma. In contrast, after inhaled allergen challenge in atopic volunteers, which caused significant bronchoconstriction, urinary excretion of thromboxane-derived products was not significantly elevated: TXB2, 5.6 +/- 1.1 versus 5.7 +/- 1.0; 2,3-dinor-TXB2, 41.2 +/- 12.5 versus 28.5 +/- 6.9; and 11-dehydro-TXB2, 69.8 +/- 17.6 versus 39.7 +/- 11.2 ng/mmol creatinine. In a separate experiment, less than 2% of exogenously administered TXB2 to the airway appeared as urinary thromboxane-derived products, suggesting that production of greater than or equal to 1 microgram of TXA2 in vivo would be required to increase urinary thromboxane excretion twofold.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamics and pharmacokinetics of BAY x 7195 aerosol, a new and selective receptor antagonist of cysteinyl‐leukotrienes, in normal volunteers

“…allergen induced increase in bronchial hyperresponsiveness [ 28,29]. To date, only little data on long term The present results argue in favour of this explanation.…”

Excretion of metabolites of prostacyclin and thromboxane by rats with nephrotoxic nephritis: effects of interleukin‐1

“…(Fitzgerald et al, 1981; reviewed in Fitzgerald et al, 1987). In man, we gave TXB2 both by inhalation and by mouth (Taylor et al, 1991) and demonstrated an increase in excretion of both TXB2 (3-4 fold) and 2,3-dinor-TXB2 (5-7 fold) suggesting that TXB2 is not exclusively renally derived. Consistent with this evidence of extra-renal cyclo-oxygenase activation is histological evidence of damage in organs other than the kidney, notably the lung.…”

Thromboxane A2 receptor +795T>C and chemoattractant receptor-homologous molecule expressed on Th2 cells -466T>C gene polymorphisms in patients with aspirin-exacerbated respiratory disease

“…In the present study, we extended our investigations to explore the genetic determinations of AERD. The role of TBXA2, one of the prostanoids induced by COX, in asthma has been reported to be evident through its induction of bronchoconstriction and airway hyperreactivity (10,11). PGD 2 , a major prostanoid of activated mast cells, has also been shown to play an important role in allergic asthma (12) by acting as a chemoattractant for Th2 lymphocytes, eosinophils and basophils (25).…”

“…TBXA 2 exerts its action, such as bronchoconstriction and bronchial hyper responsiveness (10,11), by interacting with the G protein- (13) showed a positive association between the TBXA2R polymorphism and the development of atopy and asthma. On the other hand, Kim et al (14) showed that the TBXA2R polymorphism was not associated with asthma susceptibility and the clinical parameters of asthma.…”