Anti-inflammatory Effects of Zileuton in a Subpopulation of Allergic Asthmatics

Abstract

The objective of this study was to determine the effects of allergen exposure on leukotriene generation and inflammation within the airways of allergic asthmatics and evaluate the effects of the 5-lipoxygenase inhibitor zileuton on these responses. We measured leukotriene-B(4) (LTB(4)) and LTC(4)/D(4)/E(4), inflammatory cytokine mediators, and cellular responses in bronchoalveolar lavage fluid (BALF) before and 24 h after segmental ragweed antigen challenge in 18 asthmatic subjects at baseline. Before initiating therapy with the 5-lipoxygenase inhibitor or placebo, only nine of 18 asthmatic subjects had a significant increase (234 +/- 102-fold, mean +/- SE) in BALF LTC(4)/D(4)/E(4) levels 24 h after segmental antigen challenge, whereas leukotriene levels were essentially unchanged (1.14 +/- 0.22-fold) in the other nine subjects. The high LT producers also had higher postantigen BALF levels of LTB(4), total protein, IL-5, IL-6, TNF-alpha, and recovery of more eosinophils than the low LT producers. Treatment with the 5-lipoxygenase inhibitor zileuton reduced postantigen BALF eosinophil count by 68% in the high LT producers, but had no detectable effect on BALF composition in the low LT producers. These data suggest that leukotriene inhibition may be more effective in a subset of asthmatics in whom leukotrienes are a major contributory factor in causing allergic inflammation.

Zileuton induces hemoglobin F synthesis in erythroid progenitors: role of the l-arginine–nitric oxide signaling pathway

“…[24][25][26][27][28][29] To date there are no published studies that address the potential significance of ZL as a therapeutic agent in the treatment of sickle hemoglobinopathies. HU is the only drug currently approved for the treatment of sickle cell disease (SCD) that is known to ameliorate its most common symptom, pain, 3 and Figure 3.…”

Variability and lack of predictive ability of asthma end-points in clinical trials

“…These responses are hypothesised to be due in part to distinct genotypes, like those reported for bronchial reactivity to inhaled methacholine in parents of asthmatic children [17]. Consequently, there is a growing interest in studying and relating distinct patient genotypes to certain therapies in asthmatics, as with b-agonist [18] and leucotriene modifier therapies [19,20].…”

Investigative Bronchoprovocation and Bronchoscopy in Airway Diseases

“…Bronchoprovocation with methacholine has been standardized and is considered to be acceptably safe when established procedures are followed. The most important (3,12,40,41) • Characterization of Th1 versus Th2 lymphocyte-directed inflammatory response in asthma (12,40,41) • Differential inflammatory features in different clinical phenotypes of asthma (3,12,37,38,48,73) • Insight into patterns of airway remodeling (73) • Characteristics of the cellular, cytokine, and chemokine responses to allergen challenge (50,51,53,54,58,59) • Effects of asthma therapy on features and characteristics of airway inflammation (32,66,69) • Characteristics of airway inflammation in childhood asthma (85,86,(90)(91)(92) • Evidence for parenchymal involvement of inflammation in asthma (62,69) • Description of inflammatory cellular and cytokine profiles in chronic obstructive pulmonary disease (44)(45)(46)(47) contraindication to performing this and other whole lung inhalational tests is a low baseline FEV 1 , usually considered to be below 70% predicted, as noted in the manufacturer's package insert for Provocholine. However, one study has reported that methacholine testing can be performed safely in subjects with FEV 1 values ranging between 22 and 59% of predicted (22), and several clinical networks and studies have used methacholine bronchoprovocation safely in subjects with severe asthma (22) and COPD (23).…”

“…BAL (30)(31)(32), endobronchial brush or forceps biopsy, and transbronchial biopsy (33) have emerged as the most widely used invasive research tools to assess inflammation and tissue remodeling in airway and interstitial lung diseases (Table 1) (34). Endo-* This program, sponsored by the Division of Lung Diseases, National Heart, Lung, Blood Institute, and initiated in September 2003, supports a collaborative multicenter study in humans to investigate the mechanistic basis for severe asthma and to identify novel targets for potential therapeutic intervention.…”

“…Moreover, the application of specialized techniques, such as bronchoscopic endobronchial ultrasonography, has been important for some of these findings (65). Finally, using appropriate clinical protocols designed to take into account intersubject variability and intrasubject reproducibility of airway sampling (54), bronchoscopic techniques have provided direct measurement of the effect of different drugs and therapy on airway inflammation and airway structural changes that occur in asthma and COPD (32,66,67). Recently, transbronchial lung biopsy has been performed in patients with asthma and demonstrated a significant inflammatory component in the lung periphery (42).…”