Urinary Excretion of Leukotriene E₄and 11-dehydro-Thromboxane B₂in Response to Bronchial Provocations with Allergen, Aspirin, Leukotriene D₄, and Histamine in Asthmatics

Abstract

In vivo production of thromboxane (TX) A2 and the cysteinyl-containing leukotrienes (LT) C4, D4, and E4 in correlation to airway responses was studied. Bronchial provocation with specific allergen in atopic asthmatics was followed by a significant increase in urinary concentration of immunoreactive LTE4 (34 +/- 6 before versus 56 +/- 7 ng/mmol creatinine after allergen challenge; n = 5) and 11-dehydro-TXB2 (164 +/- 29 versus 238 +/- 25 ng/mmol creatinine). In the presence of the leukotriene-antagonist ICI-204,219, which significantly increased the PD20 for allergen, the increment in urinary excretion of LTE4 was even higher (60 +/- 8 versus 288 +/- 128 ng/mmol creatinine; n = 5). In contrast, provocation with histamine (n = 5) did not provoke release of leukotrienes or thromboxane, nor was inhalation of LTD4 (n = 7) associated with increased urinary concentration of 11-dehydro-TXB2. Furthermore, bronchoconstriction induced by inhalation of lysine-aspirin in aspirin-sensitive asthmatics (n = 4) was followed by increased levels of LTE4 in the urine, whereas the levels of 11-dehydro-TXB2 remained the same. Finally, the basal levels of LTE4 in the urine of nine aspirin-sensitive asthmatics were elevated as compared with 15 other asthmatics (112 +/- 54 versus 38 +/- 20 ng/mmol creatinine; p less than 0.001). The findings support that the cysteinyl-leukotrienes are potential mediators of allergen-induced asthma and that the release of LTE4 and 11-dehydro-TXB2 into the urine appeared to be a direct and dose-dependent effect of the antigen-antibody reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Asthma and leukotrienes: antileukotrienes as novel anti‐asthmatic drugs

“…In contrast, the urinary levels of LTE 4 remained unchanged during the course of bronchoprovocation in five asthmatics who did not develop an airway obstruction to inhaled lysineaspirin [192]. This observation was in line with concurrent reports that oral aspirin challenge increased urinary LTE 4 [214,215].…”

“…The findings that bronchoconstriction induced by histamine [192] or methacholine [193] had no influence on urinary LTE 4 supported the idea that the leukotrienes were released as a primary and early consequence of the allergen challenge. For the early reaction, it appears most likely that the leukotrienes originate from the pulmonary mast cells.…”

“…Before pharmacological interventions were possible, it was furthermore established that allergen-induced airway obstruction was associated with increased urinary excretion of LTE 4 , at least during the early phase [191,192]. The findings that bronchoconstriction induced by histamine [192] or methacholine [193] had no influence on urinary LTE 4 supported the idea that the leukotrienes were released as a primary and early consequence of the allergen challenge.…”

“…It has consistently been observed that the baseline urinary excretion of LTE 4 is significantly higher in aspirin-intolerant asthmatics than in aspirin-tolerant asthmatics [192,214,215]. In addition, it was recently observed that there was a marked overexpression of the LTC 4 synthase in bronchial biopsies of aspirin-intolerant asthmatics [50].…”

Leukotriene receptor antagonists pranlukast and montelukast for treating asthma

“…The production of PAGE 9 cysLTs is increased in asthmatics, particularly during the early phase of bronchoconstriction that follows allergen challenge [14]. Cysteinyl LTs have far more powerful bronchoconstrictive effects than either methacholine or histamine, they induce AHR, vascular permeability and mucous production and exert proinflammatory effects including chemotactic activity for eosinophils and cytokine production from lymphocytes [15,16].…”