Fumiaki Aoki

Pioglitazone, a Peroxisome Proliferator-Activated Receptor Gamma Ligand, Suppresses Bleomycin-Induced Acute Lung Injury and Fibrosis

Background: Peroxisome proliferator-activated receptor-γ (PPARγ) ligands have been shown to possess potent anti-inflammatory actions. Idiopathic interstitial pneumonia is defined as a specific form of chronic fibrosing lung disease characterized by progressive fibrosis which leads to deterioration and destruction of the lungs. Objective: To investigate whether the PPARγ ligand pioglitazone (PGZ) inhibited bleomycin (BLM)-induced acute lung injury and subsequent fibrosis. Methods: BLM was administered intratracheally to Wistar rats which were then treated with PGZ. Rat alveolar macrophages were stimulated with BLM for 6 h with or without PGZ pretreatment for 18 h. MRC-5 cells (human lung fibroblasts) were treated with PGZ for 18 h. After the treatment, the cells were stimulated with transforming growth factor- β (TGF-β) for 6 h. Results: PGZ inhibited BLM-induced acute lung injury and subsequent lung fibrosis when it was administered from day –7. PGZ treatment suppressed the accumulation of inflammatory cells in lungs and the concentration of tumor necrosis factor-α (TNF-α) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-α production in alveolar macrophages. Furthermore, PGZ inhibited fibrotic changes and an increase in hydroxyproline content in lungs after instillation of BLM, even when PGZ was administered in the period from day 7 to day 28. Northern blot analyses revealed that PGZ inhibited TGF-β-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells. Conclusion: These results suggest that activation of PPARγ ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-α, procollagen I and CTGF expression. Beneficial effects of this PPARγ ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARγ as a molecular target in fibroproliferative lung diseases.

Alendronate inhalation ameliorates elastase-induced pulmonary emphysema in mice by induction of apoptosis of alveolar macrophages

Alveolar macrophages play a crucial role in the pathogenesis of emphysema, for which there is currently no effective treatment. Bisphosphonates are widely used to treat osteoclast-mediated bone diseases. Here we show that delivery of the nitrogen-containing bisphosphonate alendronate via aerosol inhalation ameliorates elastase-induced emphysema in mice. Inhaled, but not orally ingested, alendronate inhibits airspace enlargement after elastase instillation, and induces apoptosis of macrophages in bronchoalveolar fluid via caspase-3- and mevalonate-dependent pathways. Cytometric analysis indicates that the F4/80(+)CD11b(high)CD11c(mild) population characterizing inflammatory macrophages, and the F4/80(+)CD11b(mild)CD11c(high) population defining resident alveolar macrophages take up substantial amounts of the bisphosphonate imaging agent OsteoSense680 after aerosol inhalation. We further show that alendronate inhibits macrophage migratory and phagocytotic activities and blunts the inflammatory response of alveolar macrophages by inhibiting nuclear factor-κB signalling. Given that the alendronate inhalation effectively induces apoptosis in both recruited and resident alveolar macrophages, we suggest this strategy may have therapeutic potential for the treatment of emphysema.

Conophylline suppresses hepatic stellate cells and attenuates thioacetamide-induced liver fibrosis in rats

Conophylline (CnP) is a vinca alkaloid purified from a tropical plant and inhibits activation of pancreatic stellate cells. We investigated the effect of CnP on hepatic stellate cells (HSC) in vitro. We also examined whether CnP attenuates hepatic fibrosis in vivo.

Bilateral Empyema Mimicking Cardiac Tamponade

Accessible online at: www.karger.com/journals/res A 68-year-old lean female was admitted because of severe dyspnea and fainting. On admission, she was pale and sometimes coughed up purulent sputum. Her vital signs were as follows: blood pressure 99/66 mm Hg, pulse 110/min, body temperature 38.2°C. The jugular veins were dilated, but no edema was present. Chest radiograph revealed a markedly enlarged ‘cardiac’ shadow and a patchy infiltration (fig. 1). An electrocardiogram showed sinus tachycardia and flattened T waves in the lateral chest leads. Laboratory investigations revealed leukocytosis, positive inflammatory reactions, mild anemia, elevation of serum transaminases, and mild hypoxemia, but serum autoantibodies including antinuclear antibody, rheumatoid factor, SS-A and SS-B were negative. Ultrasound echographic study disclosed liver congestion and retention of a large amount of fluid around the heart. From these findings, she was initially diagnosed to have cardiac tamponade and pneumonia. Plain computed tomography (CT) of the chest demonstrated plenty of fluid surrounding the heart (fig. 2A). However, after contrast enhancement CT clearly depicted the pericardium inside the effusion, in addition to the anterior conjugation line of pleurae (fig. 2B). The fluid space consisted of bilateral thoracic cavities. The effusion obtained by thoracentesis was chocolate colored, and contained 8,000 cells/mm3, most of which were polymorphonuclear neutrophils. Pseudomonas aeruginosa was cultured from both sputum and left pleural effusion. Another CT after clinical improvement following treatment with intravenous imipenem and chest drainage showed focal pleural thickening and cylindrical bronchiectasis. We proposed that pneumonia had developed from chronic Pseudomonas infection in the bronchiectatic lesions, leading to unilateral empyema, which penetrated into the other pleural cavity through the anterior conjunction. The fluid that localized around the heart compressed the pericardium owing to the pleural adhesion, and induced fainting, hypotension and liver congestion.