Effects of Inflammatory Mediators on the Responsiveness of Isolated Human Airways to Methacholine

Abstract

Several studies have suggested that in asthmatics the quantities of inflammatory mediators such as histamine, thromboxane A2 (TxA2), prostaglandin D2 (PGD2), prostaglandin F2 alpha (PGF2 alpha), and leukotriene C4 (LTC4) that are present in the airway lumen are related to the degree of bronchial responsiveness to inhaled methacholine (MCh). Therefore, we studied the effect of these mediators on the cholinergic responsiveness of isolated human airway segments. Lung tissue collected at thoracotomy from 30 patients was studied. Dose-response curves to MCh were obtained from bronchial segments before, during, and after incubation with either a subthreshold or a threshold concentration of histamine (10(-10) or 10(-8) M), the stable TxA2 analogue U46619 (10(-11) or 10(-9) M), PGD2 (5 x 10(-9) or 5 x 10(-7) M), PGF2 alpha (10(-9) or 10(-7) M), or LTC4 (10(-11) or 10(-9) M). With the exception of LTC4, the presence of any of these mediators at either concentration increased the sensitivity to MCh by a factor of 1.1 to 2 (p less than 0.05, ANOVA). This increase did not depend on the dose of the mediator (p greater than 0.05, ANOVA). These data indicate that mediator-induced muscle hypersensitivity can explain a small part of the leftward shift of the dose-response curve to inhaled MCh as observed in asthma.

Residential exposure to plasticizers and its possible role in the pathogenesis of asthma.

“…The inflammatory mediators prostaglandin (PG) D2 and thromboxanes have a variety ofeffects on target cells in the airways, which may be relevant in the etiology of asthma. PGD2 induces a pronounced contraction of human airway smooth muscle and increases the bronchial sensitivity (43,45,46). This is supported by evidence that PGD2 is released in vivo in the human lower respiratory tract after acute allergic challenge (47).…”

“…Other TP receptor subtypes may exist, which could explain why the TP receptor is not very selective; however, strong evidence supports the existence of a single form of the TP receptor in both platelets and smooth muscle cells (5). Receptor binding is suggested as contributing actively to the pathogenesis of bronchial asthma (7,45,46).…”

The early allergic response in small airways of human precision-cut lung slices

“…For example, the EC50 of 3 mM for histamine-induced bronchoconstriction in human PCLS matches that in human tracheal preparations [28]. The EC50 value for methacholine-induced bronchoconstriction in human PCLS was 0.4 mM compared with 1 mM in isolated human bronchi [29]. This difference may be explained by the observation from rat PCLS that smaller airways are more sensitive to methacholine [14].…”

Methacholine-lnduced Histamine Liberation during Airway Challenge Tests in Ascaris Skin-Sensitive Sheep

“…Compared to MCH challenge, the ratio of AEdyn/AHiPl was in the same order as during histamine aerosol inhala tion [4], In allergic asthmatics an increased bronchial reponsiveness after allergen provocation tests was found, de pending on inflammatory reactions in the airway walls [6]. Several studies showed a correlation between concen trations of inflammatory mediators such as histamine, thromboxane A2, prostaglandin D2, prostaglandin F2a and leukotriene C4 in the tracheal lumen and the degree of bronchial responsiveness [2,26], Different mediators could be shown to interact and modify bronchial re sponses to single agonists [2,3,[27][28][29].…”