Release of Endothelin-1 into Rat Airways following Sephadex-Induced Inflammation; Modulation by Enzyme Inhibitors and Budesonide

Abstract

The intratracheal (i.t.) instillation of Sephadex beads into the rat induced inflammation and a 30-fold increase in the endothelin-1-like immunoreactivity (ET-1-LI) of broncho-alveolar lavage fluid. The levels were highest 24 h after the instillation and had declined significantly after 48 h. At a dose of 1 mg kg^-1 i.t., the glucocorticosteroid budesonide almost abolished this response. Phosphoramidon, which inhibits neutral endopeptidase, an enzyme reported to degrade ET-1 and also to inhibit the endothelin-converting enzyme, potentiated the Sephadex-induced rise in ET-1-LI. Chymostatin and heparin, which are reported to reduce the formation of ET-1, did not affect the increase in ET-l-LI. The present model represents a very reactive system for analyzing the changes in ET-1 levels during inflammation.

The effect of endothelin receptor blockade on the development of the Sephadex‐induced inflammation in the rat lung

“…Instillation of Sephadex induced a great increase of ET-1-LI concentration in BALF, in agreement with previous results (Andersson et al 1996). In contrast, there was no detectable increase in ET-1-LI content in Table 1 Values for ET-1-LI (pmol L −" ), cell counts (10' mL −" ) and protein concentration ( µg mL −" ) in BALF in the rats pretreated with vehicle or bosentan (p.o.)…”

“…There is also a marked influx of inflammatory cells, mainly eosinophils, into the airways and lung parenchyma. In previous works we have found that there is a large but transient increase in ET-1-LI content in BALF ; this increase parallels the development of the inflammatory reaction (Andersson et al 1996). We have therefore hypothesized that ET-1 could be mediating part of the observed inflammatory response.…”

Association of Endothelin with Lung Hemorrhage Induced by Immune Complexes in Rats

“…This type of reaction, which is mediated by immune-complex deposition, could induce a particular type of lung inflammation with a marked neutrophil infiltration and activation leading to a neutrophil-dependent lung injury. A similar release of ET was observed in another model of lung inflammation where large amounts of ET were detected in rat BAL fluid following intratracheal instillation of Sephadex beads (28). Enhanced intrapulmonary ET-1 production and increased pulmonary pre-pro ET-1 mRNA expression were also observed in rats with idiopathic pulmonary hypertension (29).…”

Up‐Regulation of Endothelin Receptor Function and mRNA Expression in Airway Smooth Muscle Cells Following Sephadex‐Induced Airway Inflammation

“…A well‐known method to study early eosinophilic inflammation in airways is tracheal instillation of Sephadex (Andersson et al 1992). During this kind of inflammation the concentration of endothelin‐1 in broncho‐alveolar fluid has been shown to be increased 30 times with its peak at 24 hr (Andersson et al 1996). It has been suggested that endothelin‐1 is paracrine in the airways during inflammation and hence may contribute to airway hyperreactivity.…”

“…Accordingly, a number of studies have revealed that endothelin‐1 levels are significantly elevated in broncho‐alveolar lavage fluid and in plasma during asthmatic attacks (Vittori et al 1992; Michael & Markewitz 1996). Moreover, intratracheal instillation of Sephadex has been shown to create an eosinophilic airway inflammation with increased endothelin‐1 levels in broncho‐alveolar fluid (Andersson et al 1996) and that this elevation is preceded by a rapid entothelin‐1 mRNA synthesis (Finsnes et al 1998). These studies have suggested that this peptide plays an important role in the initial phase of an eosinophilic airway inflammation.…”