Pathogenesis Of Aspirin-induced Asthma Research Articles

Over-expression of the LTC4 synthase gene in mice reproduces human aspirin-induced asthma

The pathogenesis of aspirin-induced asthma (AIA) is presumed to involve the aspirin/non-steroidal anti-inflammatory drug (NSAID)-induced abnormal metabolism of arachidonic acid, resulting in an increase in 5-lipoxygenase (5-LO) metabolites, particularly leukotriene C(4) (LTC(4) ). However, the role of LTC(4) in the development of AIA has yet to be conclusively demonstrated. The aim of this study was to evaluate the contribution of the lipid product LTC(4) secreted by the 5-LO pathway to the pathogenesis of AIA. To evaluate antigen-induced airway inflammation, the concentrations of T-helper type 2 cytokine in bronchoalveolar lavage fluid (BALF) obtained from LTC(4) synthase-transgenic (Tg) and wild-type (WT) mice after challenge with ovalbumin were measured. Subsequently, the ex vivo and in vivo effects of the NSAID sulpyrine were investigated in these Tg and WT mice by measuring the secretion of LTC(4) from sulpyrine-treated BAL cells and the levels of LTC(4) in BALF following challenge with sulpyrine. Finally, the sulpyrine-induced airway response by the administration of pranlukast, an antagonist of the cysteinyl (cs)-LT1 receptor, was analysed. The concentrations of IL-4, -5, and -13 in BALF from Tg mice were significantly higher than those in WT mice. In addition, sulpyrine augmented the secretion of LTC(4) in BALF and by BAL cells in Tg mice, but not in WT mice. Additionally, the increased airway resistance induced by sulpyrine could be reduced by treatment with pranlukast. Furthermore, the secretion of LTC(4) from mast cells, eosinophils, and macrophages was increased in the allergen-stimulated LTC(4) synthase gene Tg mice, even in the absence of sulpyrine, as well as in BAL cells after sulpyrine. The over-expression of the LTC(4) synthase in a mouse asthma model also replicates the key features of AIA. And our study supports that cys-LTs play a major role in the pathogenesis of AIA in patients with chronic asthma.

Overexpression of the leukotriene C4 synthase gene in mice reproduces human aspirin-induced asthma

AbstractThe pathogenesis of aspirin-induced asthma (AIA) is presumed to involve the aspirin /non-steroidal anti-inflammatory drug (NSAID)-induced abnormal metabolism of arachidonic acid, resulting in an increase in 5-lopoxygenase (5-LO) metabolites, particularly leukotriene C4 (LTC4)&x3000;which is a highly potent bronchial constrictor. However, the role of LTC4 in the development of AIA has yet to be conclusively demonstrated. To elucidate the effect of LTC4 on the development of AIA, we generated LTC4 synthase (Ltc4s) gene transgenic (LTC4S-Tg) mice. In contrast to wild-type (WT) mice, LTC4S-Tg mice displayed NSAID-induced airway obstruction that was associated with increases of LTC4 and Th2 cytokines in lung tissue. This is the first study to demonstrate clearly that a balance shift towards the 5-LO pathway contributes to the pathogenesis of AIA in the presence of elevated levels of LTC4S.

Glutathione peroxidase activity in blood cells from aspirin-induced asthma patients.

Aspirin and other inhibitors of cyclo-oxygenase precipitate acute bronchospasm in about 10% of adult asthmatics. It has been assumed that cyclo-oxygenase is involved in the pathogenesis of bronchospasm, but the precise mechanism remains poorly understood. The oxygenation products of arachidonic acid include hydroperoxyeicosatetraenoic acid and cyclic endoperoxides. Glutathione peroxidase (GPX) reduces semi-stable hydroperoxides to less reactive alcohols and removes H(2)O(2) involved in inflammation. GPX could, therefore, modulate oxidation of arachidonic acid in the cyclo-oxygenase and lipoxygenase pathways, but the involvement of GPX in the pathogenesis of asthma has received little attention. We measured GPX activity in platelets, peripheral blood lymphocytes (PBL), red blood cells (RBC) and plasma from 13 patients with aspirin-induced asthma (AIA). Age- and sex-matched healthy individuals served as the comparison group. The patients had significantly higher GPX activity in platelets (P = 0.05) and tended to have high GPX activity (P = 0.08) in plasma but not in RBC or PBL. The results suggest that the increased GPX activity may be an adaptive advantage in AIA to protect against increased free radical production by inflammatory cells. That the higher GPX activity was not evident in all cell types studied may indicate a differential role played by them as effector cells in the pathogenesis of AIA.

Increased exhaled cysteinyl-leukotrienes and 8-isoprostane in aspirin-induced asthma.

The pathogenesis of aspirin-induced asthma (AIA) has not yet been clearly elucidated, although eicosanoid metabolites appear to play an important role. We hypothesized that levels of eicosanoids in exhaled air condensate are abnormal in patients with AIA and that they change in patients receiving steroid therapy. We measured cysteinyl-leukotrienes (cys-LTs), prostaglandin E(2) (PGE(2)), and leukotriene B(4) (LTB(4)), and also 8-isoprostane as a marker of oxidative stress, by enzyme immunoassay in exhaled breath condensate from patients with AIA (17 steroid naive; mean age, 41 +/- 23 years; FEV(1), 63%pred), 26 patients with aspirin-tolerant asthma (ATA) (11 steroid naive; mean age, 47 +/- 18 years; FEV(1), 69%pred), and 16 healthy subjects (mean age, 45 +/- 17 years; FEV(1), 93%pred). Cys-LTs were significantly higher in steroid-naive patients with AIA compared with steroid-naive patients with ATA and healthy subjects (152.3 +/- 30.4 and 36.6 +/- 7.1 versus 19.4 +/- 2.8 pg/ml; p < 0.05 and p < 0.05, respectively). Steroid-naive patients with AIA also had higher levels of 8-isoprostane than normal subjects (131.8 +/- 31.0 versus 21.9 +/- 4.5 pg/ml; p < 0.05). There were significantly lower levels of both cys-LTs and 8-isoprostanes in steroid-treated patients with AIA. There was no difference in either the PGE(2) or LTB(4) level between the patient groups. This is the first study to show that cys-LTs and 8-isoprostanes are elevated in expired breath condensate of steroid-naive patients with AIA, and that cys-LTs are decreased in steroid-treated patients. Exhaled PGE(2) levels are not reduced, so that it is unlikely that a deficiency of PGE(2) is an important mechanism, whereas exhaled LTB(4) levels are unchanged, indicating an abnormality beyond 5-lipoxygenase.

Effect of acyclovir on bronchoconstriction and urinary leukotriene E 4 excretion in aspirin-induced asthma

Background: Acyclovir (9-[2-hydroxyethoxymethyl] guanine), an inhibitor of the DNA polymerase of the herpes virus, has been reported to exhibit pharmacologic activity other than antiviral activity, including antiasthmatic effects. Objective: This study was designed to investigate the protective effect of acyclovir on airway responsiveness to the sulpyrine provocation test and to investigate whether this protective activity is associated with a reduction in aspirin-induced excretion of urinary leukotriene E 4 (u-LTE 4 ), a marker of cysteinyl leukotriene (LT) overproduction that participates in the pathogenesis of aspirin-induced asthma. Methods: We assessed the effects of pretreatment with acyclovir on bronchoconstriction precipitated by inhalation of sulpyrine in 16 adult patients with mild or moderate aspirin-induced asthma; those who were in stable clinical condition and were hyperresponsive to the sulpyrine provocation test were allocated to this study. A double-blind, randomized, cross-over design was used. u-LTE 4 was measured by a combined reverse-phase HPLC enzyme immunoassay. Results: Acyclovir protects against aspirin-induced attacks of asthma through mechanisms unrelated to its bronchodilator property but related to the improvement of bronchial hypersensitivity to sulpyrine; protection was nearly complete in all patients ( P < .0001). By contrast, after acyclovir, the maximum level of u-LTE 4 in patients was significantly lower than that in control subjects ( P < .01). Conclusion: Our results suggest that acyclovir is not only an antiviral drug but also an inhibitor of analgesic-induced bronchoconstriction, probably acting by inhibiting the release of cysteinyl LTs. (J Allergy Clin Immunol 1998;102:909-14.)

アスピリン喘息とその鼻茸

Asthma, aspirin intolerance and nasal polyps form the triad of aspirin-induced asthma (AIA). The prevalence of AIA is thought to be approximately 10% in asthmatic pati ents in general. This side effect is known also to be caused by non-steroidal anti-inflammatory drugs (NSAID) and dyes such as tartrazine, parabens, etc. The diagnosis usually can be established easily on the basis of the history. AIA is not a rare disease in Japan. Fourtyfour cases of AIA,14 male and 30 female, were seen at our clinic as of 1990. Asthma was found in 41 of 44 cases (93.2%) and sinusitis in 28 of 43 (65.1%). The incidence of nasal polyps, so-called aspirin-induced polyps (AIP), was very high, ranging from 60% to 95%. In our clinic, AIP were found in 29 of 43 cases (67.4%). AIP are characteristically bilateral and recur easily. Histological findings show significant infiltration of eosinophils with marked eosinophilia in the blood and nasal secretions. Nasal polypectomy is useful for AIA, because asthma is aggravated by mouth breathing caused by severe nasal obstruction. The pathogenesis of AIA and AIP is obscure but is probably related to inhibition of prostaglandin biosynthesis, though other factors may also be related, including viral infection.

In vitro tests for the diagnosis of aspirin-sensitive asthma

In patients with aspirin-sensitive asthma, no significant changes in plasma beta-thromboglobulin or bicyclic prostaglandin (PG) E2 were observed during aspirin challenge. The addition of aspirin to platelet suspensions from patients with aspirin-sensitive asthma produced no detectable chemiluminescence. Small concentrations of aspirin generated PGF2 alpha but not PGE2 or PGD2 from plasma in vitro. PGF2 alpha levels were significantly higher in plasma from aspirin-sensitive patients and distinguished aspirin-sensitive from aspirin-tolerant patients with asthma. The results of this study suggest that the displacement of protein-bound PGF2 alpha may be of importance in the pathogenesis of aspirin-induced asthma.

Experimental Investigation on the Pathogenesis of Aspirin-Induced Asthma

Experimental Investigation on the Pathogenesis of Aspirin-Induced Asthma

Thromboangiitis of pulmonary vessels associated with aneurysm of pulmonary artery: Report of a case: Thompson, L. E., and Gerstl, B.: Arch. Int. Med. 77: 614 (June), 1946

Aspirin is not only one of the best-documented medicines in theworld, but also one of the most frequently used drugs of all times. Inaddition to its role as an analgesic, aspirin is being increasinglyused in the prophylaxis of ischemic heart disease and strokes. Theprevalence of aspirin intolerance is around 5 to 6%. Up to 20% of theasthmatic population is sensitive to aspirin and other nonsteroidalanti-inflammatory drugs (NSAIDs) and present with a triad of rhinitis,sinusitis, and asthma when exposed to the offending drugs. Thissyndrome is referred to as aspirin-induced asthma (AIA).The pathogenesis of AIA has implicated both the lipoxygenase (LO) andthe cyclooxygenase (COX) pathways. By inhibiting the COX pathway,aspirin diverts arachidonic acid metabolites to the LO pathway. Thisalso leads to a decrease in the levels of prostaglandin (PG)E2, the anti-inflammatory PG, along with an increase in thesynthesis of cysteinyl leukotrienes (LTs). Evidence suggeststhat patients with AIA have increased activity of LTC4synthase, the rate-limiting enzyme in the cysteinyl LT synthesis, intheir bronchial biopsy specimens, thereby tilting the balance in favorof inflammation. LT-modifying drugs are effective in blocking thebronchoconstriction provoked by aspirin and are used in the treatmentof this condition. Aspirin desensitization has a role in the managementof AIA, especially in patients who need prophylaxis from thromboembolicdiseases, myocardial infarction, and stroke. This review covers thelatest understanding of pathogenesis, clinical features, and managementof AIA.