endothelin-1 and Eosinophilia

Severe asthma is a highly incapacitating disease with no effective preventive or curative treatment. The 10% of patients with "refractory" or "difficult" asthma have chronic symptoms, episodic exacerbations and persistent airway obstruction, despite chronic? 2-agonist and steroid therapy. A major objective of current asthma research is to identify the underlying cellular and molecular mechanisms and thus to develop new treatments. Persistent airway eosinophilia is a hallmark of severe asthma. IL-5 is essential for terminal differentiation of committed eosinophil precursors and is also involved in eosinophily degranulation and priming. By releasing cytokines and cationic proteins, eosinophils contribute to airway inflammation and damage the bronchial mucosa. A monoclonal antibody against IL-5 has been shown to reduce exacerbations of refractory asthma. Interventions targeting eosinophil cationic proteins might have therapeutic potential. Structural changes in the bronchial wall, collectively known as airway remodeling, are believed to play a prominent role in the persistent airflow obstruction associated with severe asthma. In this setting the airway epithelium shows major abnormalities, including loss of barrier function, phenotypic changes, and functional disorders. The abnormal respiratory epithelium is believed to orchestrate airway remodeling through aberrant production of extracellular matrix components, fibrogenic cytokines and chemokines, and growth factors responsible for the proliferation, migration and activation of smooth muscle cells and fibroblasts. Recently, increased ET-1 synthesis by the bronchial epithelium was observed in severe refractory asthma, and was found to correlate with airway remodeling and airway obstruction. ET-1 might represent a novel therapeutic target in severe steroid-refractory asthma.

Topics: Anti-Asthmatic Agents; Antibodies, Monoclonal; Asthma; Endothelin-1; Eosinophilia; Humans; Receptors, Tumor Necrosis Factor; Respiratory Mucosa; Severity of Illness Index

Endothelin-1 (ET-1) is a strong bronchoconstrictor which possesses pro-inflammatory properties and is claimed to be an important mediator in bronchial asthma. The present study was undertaken to investigate whether ET-1 synthesis, in an inflammation dominated by neutrophilic granulocytes, is as pronounced as previously demonstrated in an airway inflammation dominated by eosinophils. Moreover, the authors compared the production of ET-1 and tumour necrosis factor (TNF)-alpha in rat lungs following intratracheal instillation of either lipopolysaccharide (LPS) (neutrophilic inflammation) or Sephadex (SDX) (eosinophilic). The lung tissue ET-1 messenger ribonucleic acid (mRNA) expression was not increased in LPS treated animals whereas a six-fold increase was measured after 30 min in the SDX group (p<0.05). TNF-alpha mRNA signals increased early following LPS instillation, peaking at 2 h, whereas elevated TNF-alpha mRNA in the SDX model was observed at 24 h. The ET-1 concentrations in bronchoalveolar lavage fluid (BALF) rose slightly, but significantly, 3 h after both LPS and SDX exposure. At 24 h no further rise in ET-1 levels was observed in the LPS model, while a substantial increase in the ET-1 concentration was measured in the SDX group (p<0.05). The TNF-alpha concentrations in BALF rose considerably at 3 h in the LPS group, but was nearly abolished at 24 h. In SDX challenged animals however, an increase in BALF-TNF-alpha did not occur until 24 h postchallenge. In conclusion, intratracheal instillation of lipopolysaccharide, leading to a purely neutrophilic lung inflammation, does not induce synthesis of endothelin-1. This is in contrast to observations during an eosinophilic airway inflammation, indicating a specific role of endothelin-1 in lung inflammations dominated by eosinophils. In contrast to in vitro experiments, no evidence for induction of endothelin-1 synthesis was observed by high levels of tumour necrosis factor-alpha in vivo.

Topics: Animals; Blotting, Northern; Bronchial Provocation Tests; Bronchitis; Bronchoalveolar Lavage Fluid; Dextrans; Disease Models, Animal; Endothelin-1; Eosinophilia; Lipopolysaccharides; Lung; Male; Probability; Rats; Rats, Wistar; Reference Values; Statistics, Nonparametric; Tumor Necrosis Factor-alpha