Elastolytic activity and alveolar epithelial type-1 cell damage after chronic LPS inhalation: Effects of dexamethasone and rolipram

• Published in: Toxicology and applied pharmacology 2005-09, Vol.207 (3), p.257-265
• Main Authors: Johnson, Frederick J., Reynolds, Lucy J., Toward, Toby J.
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ADENOSINE; Administration, Inhalation; Alveolar type-1 cell; AMINES; AMP; Animals; Anti-Inflammatory Agents - pharmacology; AZO DYES; Biological and medical sciences; Biomarkers; Bronchoalveolar Lavage Fluid - cytology; CARBON MONOXIDE; CHEMILUMINESCENCE; Chronic LPS; Corticosteroid; DEXAMETHASONE; Dexamethasone - pharmacology; DMSO; Elasticity - drug effects; Elastolytic activity; Epithelial Cells - drug effects; FORMALDEHYDE; GLYCOPROTEINS; GUINEA PIGS; INFLAMMATION; INHALATION; Leukocytes - drug effects; Lipopolysaccharides - toxicity; LUNGS; MACROPHAGES; Male; Medical sciences; MONOCLONAL ANTIBODIES; NECROSIS; Neutrophilia; NEUTROPHILS; OXYGEN; PATHOLOGY; Phosphodiesterase Inhibitors - pharmacology; Phosphodiesterase-4 inhibition; Pulmonary Alveoli - cytology; Pulmonary Alveoli - drug effects; RATS; RESPIRATORY SYSTEM DISEASES; Rolipram - pharmacology; SULFONIC ACIDS; Toxicology
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2005.01.006

This study investigated whether a correlation between leukocyte-derived elastolytic activity, alveolar epithelial type-1 cell damage, and leukocyte infiltration of the airways existed in guinea-pigs chronically exposed to inhaled lipopolysaccharide (LPS). The airway pathology of this model, notably the neutrophilia, resembles chronic obstructive pulmonary disease (COPD). The effect of the corticosteroid, dexamethasone, or the phosphodiesterase-4 (PDE4)-inhibitor, rolipram, on these features was studied. Conscious guinea-pigs were exposed for 1 h to single or repeated (nine) doses of LPS (30 μg ml −1). Dexamethasone (20 mg kg −1, ip) or rolipram (1 mg kg −1, ip) was administered 24 and 0.5 h before the first exposure and daily thereafter. Bronchoalveolar lavage fluid (BALF) was removed and elastolytic activity determined as the elastase-like release of Congo Red from impregnated elastin. The presence of the specific epithelial cell type-1 protein (40–42 kDa) RT1 40 in BALF was identified by Western blotting using a rat monoclonal antibody and semi-quantified by dot-blot analysis. The antibody was found to identify guinea-pig RT1 40. BALF inflammatory cells, particularly neutrophils and macrophages, and elastolytic activity were increased in chronic LPS-exposed guinea-pigs, the latter by 90%. Chronic LPS exposure also increased (10.5-fold) RT1 40 levels, indicating significant alveolar epithelial type-1 cell damage. Dexamethasone or rolipram treatment reduced the influx of inflammatory cells, the elastolytic activity (by 40% and 38%, respectively), and RT1 40 levels (by 50% and 57%, respectively). In conclusion, chronic LPS-exposed guinea-pigs, like COPD, exhibit elastolytic lung damage. This was prevented by a PDE4 inhibitor and supports their development for suppressing this leukocyte-mediated pathology.