Endothelin in Bronchoalveolar Lavage Fluid and its Relation to Airflow Obstruction in Asthma

Endothelins (ETs) are 21 amino acid peptides which, in addition to their other properties, are potent bronchoconstrictors. Whilst there is evidence of the involvement of ET in the pathophysiology of chronic asthma, its contribution to the acute allergic response is undefined.To examine this, we have undertaken segmental bronchoprovocation with allergen and saline at separate sites in six atopic asthmatics receiving treatment with bronchodilators only and six atopic asthmatics additionally receiving treatment with inhaled corticosteroids. Each challenged segment was lavaged 10 min after bronchoprovocation and concentrations of immunoreactive ET were measured in bronchoalveolar lavage fluid.In the non-steroid-treated subjects, there were significantly lower ET levels at the allergen-challenged sites compared to the saline-challenged sites (p<0.05). In the steroid-treated subjects, on the other hand, there was no significant difference between the two sites. Levels of ET at the saline-challenged sites were significantly lower in the steroid-treated subjects compared to the non-steroid-treated subjects (p<0.04).These findings do not support the hypothesis that allergen exposure in asthma results in immediate release of endothelin. However, release at later time-points and a role for endothelin in late-phase bronchoconstriction are not excluded. Eur Respir J 1997; 10: 1026-1032 [8] in vitro, and to exert pulmonary proinflammatory effects in vivo in guinea-pigs [9]. Finally, ET-1 is mitogenic both for fibroblasts [10] and airway smooth muscle [11], suggesting a possible role in airway wall remodelling in asthma.Members of the ET family exert their effects via an interaction with specific membrane receptors. In a variety of systems, two receptors have been characterized, which are denoted ETA and ETB [12]. The ETA receptor has a higher affinity for ET-1 or ET-2 as compared with ET-3, whereas the ETB receptor has equal affinity for the three members. Contraction of human bronchi is believed to be principally ETB-mediated [13], whereas other properties of ETs relevant to asthma, such as secretion of mucus and mitogenic responses, are likely to involve ETA receptors.There are a number of potential sources of ET within the airway wall, including bronchial epithelial cells [14], vascular endothelial cells [2] and inflammatory cells, such as macrophages [15] and possibly also mast cells [16], although a mast cell origin has not yet been demonstrated in humans. In bronchial biopsies, a major site of immunoreactivity for ET is the airway epithelium [17,18]. Expression at this site is increased in asthma [19] and, consistent with this, ET levels in bronchoalveolar lavage (BAL) fluid from non-corticosteroid-treated asthmatics are increased in comparison with those in BAL fluid from healthy control subjects [20,21]. As these levels correlate with the degree of airflow obstruction in asthma [21], it has been proposed that ET contributes to the resting bronchomotor tone in this disease.We hypothesized that ET may be rele...

Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 65%

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

Airway endothelin levels in asthma: influence of endobronchial allergen challenge and maintenance corticosteroid therapy

Redington¹,

Springall²,

Ghatei³

et al. 1997

“…For example, both bronchoalveolar lavage fluid and circulating blood levels of endothelin are markedly elevated in this disease [14,15]. Furthermore, there is a significant increase in expression of endothelin-like immunoreactivity in airway epithelium and vascular endothelium of asthmatics compared with nonasthmatic individuals [16].…”

Section: Discussionmentioning

confidence: 99%

Bronchodilation by pituitary adenylate cyclase-activating peptide and related peptides

Lindén¹,

Cardell²,

Yoshihara³

et al. 1999

That endothelin-1(ET-1) plays a mediator role in asthma is consistent with reports of ET-1-induced potentiation of cholinergic nerve-mediated contraction in airways from various animal species. This study examined the effect of ET-1 on cholinergic contractions in human isolated bronchus.Macroscopically nondiseased human bronchial tissue was obtained from 23 patients with respiratory tumours. An electrical field stimulation (EFS) frequency that produced one third of the contraction at 30 Hz (EFS30) was estimated. The effect of ET-1 on these EFS-evoked contractions was assessed.EFS-evoked contractions were frequency-dependent and abolished by either atropine or tetrodotoxin. Thus, EFS-induced contractions were mediated by acetylcholine from cholinergic nerves. ET-1 (3 nM) potentiated EFS-evoked contractions by 102% EFS30 (p<0.05) without any significant effect on contractions induced by exogenous acetylcholine.Neither the ET A receptor-selective antagonist BQ-123 (3 mM) nor the ET B receptorselective antagonist BQ-788 (10 mM) alone significantly altered ET-1-induced potentiation of EFS-evoked contractions. However, in the combined presence of both BQ-123 and BQ-788, ET-1-induced potentiation of EFS-evoked contractions was abolished.Thus, prejunctional endothelin A and endothelin B receptors appear to mediate endothelin-1-induced potentiation of electrical field stimulation-evoked cholinergic contractions in human bronchus. This suggests another potentially important mechanism through which endothelin-1 could increase bronchial tone in asthma. Eur Respir J 1999; 14: 439±442. There is growing evidence to suggest that the endogenous airway smooth muscle spasmogen endothelin (ET)-1 plays an important mediator role in asthma [1]. In addition, it has been suggested that, in some cases, asthma may be accompanied by an increase in airway cholinergic tone [2,3]. A number of agents have been shown to modulate acetylcholine release from airway nerves and there is accumulating data to indicate that ET-1 modulates cholinergic neurotransmission in the airways [4]. For example, ET peptides have been shown to markedly potentiate electrical field stimulation (EFS)-induced cholinergic contractile responses in rabbit [5,6], mouse [7,8] and rat [9] airways. These potentiations of EFS-induced contractions were mediated via activation of prejunctional ET receptors. Furthermore, data obtained in 3 H-cholineloaded rat tracheal tissue indicates that the mechanism of ET-1-induced potentiation of these responses was enhanced acetylcholine release [9]. Evidence obtained in rabbit [6], mouse [8] and rat [9] airways showed that both ET A and ET B receptors were involved in this phenomenon.A preliminary report from the authors' laboratory showed that the ET B receptor-selective agonist sarafotoxin S6c potentiated EFS-induced cholinergic contractions in human bronchus [10]. The present study significantly extends this earlier work by focusing on the role of the endogenously released ligand ET-1 which can activate ET A and ET B receptor...

“…Even though ET-1 concentrations in BAL fluid are generally below the threshold level required for contraction of airway smooth muscles, ET-1 levels in local airways are possibly high enough to elicit bronchoconstriction [31]. However, it is also important to determine the physiological effects of a subthreshold concentration of ET-1 acting as a local hormone.…”

Section: Discussionmentioning

confidence: 99%

Subthreshold concentration of endothelin-1-enhanced, capsaicin-induced bronchoconstriction in anaesthetized guinea-pigs

Kanazawa

Fujiwara²,

Hirata³

et al. 1998

aaEndothelin-1 (ET-1) is a 21 amino acid peptide originally isolated from porcine endothelial cells [1], which has potent spasmogenic activity in both vascular and airway smooth muscle [1,2]. Bronchial asthma is an inflammatory airway disorder characterized by bronchoconstriction and bronchial hyperreactivity. Recent observations suggest that an increased intrapulmonary production of ET-1 may specifically occur in asthma. The bronchial epithelium of asthmatic patients has been found to express preproendothelin-1 messenger ribonucleic acid (mRNA) [3], to contain endothelin immunoreactivity [4] and to release large amounts of . The high potency of ET-1 in inducing contraction of airway smooth muscle both in vivo and in vitro [2,6] led to the assumption that it may play an important role in the pathogenesis of asthma. However, the precise mechanisms through which ET-1 causes bronchoconstriction are unclear. Moreover, it should be stressed that the amount of ET-1 recovered in the bronchoalveolar lavage (BAL) fluid of patients with asthma is quite low compared with the dose of ET-1 found to be effective in eliciting bronchial smooth muscle contraction [7]. It was previously found that a subthreshold concentration of ET-1 which was not able to elicit bronchial smooth muscle contraction markedly augmented the magnitude and duration of bronchoconstriction caused by other mediators, such as histamine [8].The pulmonary airways of rodents and humans are innervated with sensory C-fibres [9], which provide an afferent pathway for central neural reflex control of airway functions. These neurons also synthesize and store neuropeptides in granules found within their terminal varicosities. A variety of chemical, physical and electrical stimuli can cause sensory C-fibres to release their neuropeptides locally into innervated structures, where these substances often initiate important physiological effects. In the airways, C-fibre stimulation causes the release of two classes of neuropeptides, tachykinins including substance P (SP) and neurokinin A (NKA), and calcitonin-gene related peptide (CGRP) [10]. Capsaicin is thought to stimulate pulmonary and bronchial C-fibre endings directly [11] and has been used as a research tool to identify C-fibre endings. Furthermore, activation of capsaicin-sensitive C-fibres leads to the local release of sensory neuropeptides. It is well known that sensory neuropeptides mimic many of the pathological features of bronchial asthma, including bronchospasm [12] ABSTRACT: An increasing number of studies have been performed to address a possible role for endothelin-1 (ET-1) as a significant mediator in asthma. However, the effects of subthreshold concentrations of ET-1, which cannot elicit bronchial smooth muscle contraction itself, in asthma has yet to be determined. This study determined these effects of ET-1 on capsaicin-induced bronchoconstriction in anaesthetized guinea-pigs.Aerosolized ET-1 administered at doses of 10 -9 M and higher induced a dosedependent increase in pulmonary resistance, but E...