Blocking the Leukotriene B4 Receptor 1 Inhibits Late-Phase Airway Responses in Established Disease

Abstract

Most of the studies investigating the effectiveness of blocking the leukotriene B4 (LTB4) receptor 1 (BLT1) have been performed in models of primary or acute allergen challenge. The role of the LTB4-BLT1 pathway in secondary challenge models, where airway hyperresponsiveness (AHR) and airway inflammation have been established, has not been defined. We investigated the effects of blocking BLT1 on early-and late-phase development of AHR and airway inflammation in previously sensitized and challenged mice. Female BALB/c mice were sensitized (Days 1 and 14) and challenged (primary, Days 28-30) with ovalbumin. On Day 72, mice were challenged (secondary) with a single OVA aerosol, and the early and late phases of AHR and inflammation were determined. Specific blockade of BLT1 was attained by oral administration of a BLT1 antagonist on Days 70 through 72. Administration of the antagonist inhibited the secondary ovalbumin challenge-induced alterations in airway responses during the late phase but not during the early phase, as demonstrated by decreases in AHR and in bronchoalveolar lavage neutrophilia and eosinophilia 6 and 48 hours after secondary challenge. The latter was associated with decreased levels of KC protein, macrophage inflammatory protein 2, and IL-17 in the airways. These data identify the importance of the LTB4-BLT1 pathway in the development of late-phase, allergen-induced airway responsiveness after secondary airway challenge in mice with established airway disease.

Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses

“…LTB4, a lipid mediator that is derived from membrane phospholipid, is thought to play an important role in the activation and recruitment of leukocytes, including neutrophils [44]. We have recently shown that chemoattraction and activation of neutrophils through LTB4-BLT1 may contribute, at least in part, to allergic airway inflammation in established asthma [45]. Further understanding of the relationship between neutrophils and eosinophils, and between LTB4-BLT1 and the PAR-2-neutrophil elastase pathway may help clarify the complicated mechanisms of asthma development.…”

IL-17A is essential to the development of elastase-induced pulmonary inflammation and emphysema in mice

“…KC, MIP-2 and IL-1β levels in the BAL fluid, and IL-17A levels in the supernatants of homogenized lungs were measured by ELISA as previously described [30]. For preparation of lung homogenates, lung tissue was frozen at −70°C immediately after euthanasia.…”

“…The specimens were homogenized and then centrifuged at 15,000 rpm for 15 min. The supernatants were frozen at −70°C until analysis [30]. All cytokine and chemokine ELISAs were performed according to the manufacturer’s directions (R&D Systems, Minneapolis, MN, USA).…”

“…Lung cells were isolated as previously described following collagenase digestion [30]. Intracytoplasmic cytokine staining was performed as previously described [31,32].…”

Effects of leukotriene D4 and histamine nasal challenge on airway responsiveness and inflammation in persistent allergic rhinitis patients

“…Demoly et al also reported that both the TSS and VAS correlated well with a quality-of-life questionnaire (RQLQ) and could be used to evaluate and manage AR. 26 Several explanations may account for the increase in neutrophils in sputum after nasal challenge. The mechanisms by which neutrophils were increased in the nasal lavage after histamine and LTD 4 nasal challenge might be summarized as follows.…”