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

Abstract

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...

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

“…Notably, cardiotrophin-1, a member of the gp130/IL-6 cytokine family that is synthesised by ASM cells, inhibits, via p42/ p44 mitogen-activated protein kinase (MAPK), human ASM cell apoptosis induced by serum deprivation or FasL/TNF-a exposure [96]. A subsequent study revealed that endothelin-1, which is elevated in asthmatic airways [97], may also promote increased ASM mass via its effects on cell growth and apoptosis [98]. Indeed, endothelin-1 markedly reduced the apoptosis of human ASM cells induced by serum withdrawal, and, in combination with cardiotrophin-1, further promoted ASM hypertrophy and accumulation of contractile apparatusassociated proteins [96,98].…”

Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells

“…ET-1 is released early in eosinophilic inflammatory cascades and causes an increase in airway microvascular leakage (11, 16) and extravascular sequestration of granulocytes (17). Asthma is associated with elevated expression and release of ET-1, which is thought to be primarily released from the bronchial epithelium (22,23,28). On the surface of human bronchial smooth muscle cells, the ET B receptor predominates, representing ϳ82-88% of the total ET receptor population (14).…”

Increased expression of inducible nitric oxide synthase and cyclo-oxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment

“…20 Briefly, subjects received premedication with nebulised salbutamol (2.5 mg) and ipratropium bromide (0.5 mg), intravenous atropine (0.6 mg), and intravenous midazolam. Topical lidocaine solution (10%, 4% and 1%) was used to anaesthetise the upper and lower airways.…”

“…Airway responsiveness to inhaled histamine was then measured as previously described. 20 Atopic status was determined by skin prick testing using the following allergen extracts: Dermatophagoides pteronyssinus, cat allergen, dog allergen, mixed grass pollens, and mixed feathers (Hollister-Steir, Elkhart, IN, USA). In addition, 10 ml peripheral blood was obtained at the time of bronchoscopy for estimation of total serum IgE (normal range <81 IU/ml).…”