Pioglitazone, a peroxisome proliferator-activated receptor gamma ligand, suppresses bleomycin-induced acute lung injury and fibrosis.

BACKGROUND: Peroxisome proliferator-activated receptor-gamma (PPARgamma) 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 PPARgamma 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- beta (TGF-beta) 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-alpha (TNF-alpha) in bronchoalveolar lavage fluid on day 3. PGZ also inhibited BLM-induced TNF-alpha 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-beta-induced procollagen I and connective tissue growth factor (CTGF) expression in MRC-5 cells. CONCLUSION: These results suggest that activation of PPARgamma ameliorates BLM-induced acute inflammatory responses and fibrotic changes at least partly through suppression of TNF-alpha, procollagen I and CTGF expression. Beneficial effects of this PPARgamma ligand on inflammatory and fibrotic processes open new perspectives for a potential role of PPARgamma as a molecular target in fibroproliferative lung diseases.

[A case of small cell lung carcinoma complicated by Lambert-Eaton myasthenic syndrome].

A 54-year old man was admitted with general fatigue, muscle weakness and dyspnea on effort. Medical examinations led to a diagnosis of small cell lung carcinoma (SCLC) with Lambert-Eaton myasthenic syndrome (LEMS). Marked improvement of SCLC and symptoms of LEMS were recognized twice during chemoradiotherapy. On his third admission, he showed muscle weakness, dysaethesia, and neurodysfunction of the bladder and rectum. We initially considered these symptoms to be due to spinal metastasis because MRI findings showed multiple spinal metastases. However, electoromyogram and nerve conduction study demonstrated that his muscle weakness resulted from LEMS though dysethesia and neurodysfunction of bladder and rectum were caused by spinal metastasis. We believe that it is important to perform electomyogram and nerve conduction studies, not only radiographic findings, to detect the "hidden" symptoms of LEMS.

[Case of HLA-DR8 positive sarcoidosis following polymyositis and Sjögren's syndrome].

A 69-year-old woman had been found to have idiopathic interstitial pneumonia (fibrotic NSIP) in 1997. Proximal muscle weakness appeared in April 2005. Chest CT revealed hilar and mediastinal lymphadenopathy. Polymyositis and Sjögren's syndrome were subsequently diagnosed. We assumed that the interstitial pneumonia had preceded polymyositis and Sjögren's syndrome. A muscle biopsy and transbronchial needle aspiration biopsy demonstrated noncaseating epithelioid cell granulomas. A diagnosis of sarcoidosis complicated with polymyositis and Sjögren's syndrome was made from these findings. Moreover, her HLA genotype contained DR8. HLA-DR8 is considered to be associated with polymyositis, Sjögren's syndrome, and sarcoidosis in Japanese patients. This case suggests the possibility that there are common immunological and genetical pathogenetic mechanisms in autoimmune diseases and sarcoidosis.

[Case of allergic bronchopulmonary aspergillosis successfully treated with itraconazole].

A 58-year-old woman had a productive cough but not from bronchial asthma. A chest radiograph revealed infiltrative shadows in right middlelung field on September, 2004. Aspergillus fumigatus was detected in a sputum culture. She was treated with oral itraconazole. After the treatment, infiltrative shadows on her chest radiograph disappeared. On October 2005, her peripheral blood showed eosinophilla, a high serum level of total immunoglobulin E (IgE), and a chest radiograph revealed new infiltrative shadows in both lung fields. A chest computed tomography revealed multiple nodular shadows and central bronchiectasis. We detected a mucoid plug which showed a large number of eosinophils pathologically by bronchoscopy. Aspergillus niger was detected in a bronchial lavage fluid. We therefore made a diagnosis of allergic bronchopulmonary aspergillosis (ABPA). The decreases of peripheral blood eosinophils and a serum IgE level were recognized and multiple nodular shadows disappeared by reinstitution of itraconazole. However, a chest computed tomography revealed new infiltrative shadows. Therefore, we treated her with the concomitant administration of oral itraconazole and inhaled corticosteroid. All laboratory data and image findings were improved. It is critical to consider the both aspects of allergy and infection in the treatment for ABPA.

[A case of miliary tuberculosis showing acute respiratory failure during pregnancy].

A 36-year-old Philippine woman had had fever and general fatigue from September, 2006 (11th week of pregnancy). She was admitted with high fever, general fatigue and dyspnea on October 16, 2006 (13th week of pregnancy). A chest radiograph on admission showed bilateral miliary shadows and ground glass shadows. She already had severe hypoxia on admission. As acid-fast bacilli were positive in urine (Gaffky 8) and sputum (Gaffky 1), we diagnosed as miliary tuberculosis and pulmonary tuberculosis complicated with acute respiratory distress syndrome (ARDS). We treated her with antituberculosis chemotherapy, corticosteroid, sivelestat sodium hydrate, direct hemoperfusion using a polymyxin B immobilized column, and mechanical ventilation, but she died due to respiratory failure. We emphasize that in this case pregnancy has the risk of to causing disease progression of miliary tuberculosis and we should treat immediately and intensively for miliary tuberculosis complicated with ARDS.

[Case of acute interstitial pneumonia that responded to therapy but relapsed six months later].

A 66-year-old man was admitted because of general fatigue. A chest computed tomography showed bilateral alveolar consolidation and ground glass opacities. Although we treated him with broad-spectrum antibiotics, his symptoms and chest image findings did not improve. Thoracoscopic lung biopsy (rS2, S9) was performed. The specimens showed obstructive type intraluminar organization and interstitial inflammatory thickening. Membranous organization was seen in a limited area. The etiology of the illness could not be identified. We diagnosed acute interstitial pneumonia (AIP) because the specimens showed diffuse alveolar damage pattern (DAD/P) and because of unknown etiology. The symptoms and chest image findings were improved on treatment with corticosteroid and cyclophosphamide. However, he was readmitted because of dyspnea 6 months later after the thoracoscopic lung biopsy. Chest computed tomography showed bilateral diffuse ground glass opacities and reticular opacities in both lower lobes. We employed mechanical ventilation, antibiotics, sivelestat sodium hydrate and steroid pulse therapy, but he died without any response to treatment. The findings of autopsy revealed DAD/P accompanied by a new lesion mainly composed of membranous organization and hyaline membrane. We believe this case is valuable when considering the variety of responses to treatment of AIP and prognosis.

[A case of Wegener's granulomatosis associated with the syndrome of inappropriate secretion of ADH].

A 68 year-old woman was admitted with fever, productive cough and sore throat. A chest radiograph and a chest computed tomography showed multiple nodules in both lungs. Thoracoscopic lung biopsy was performed. The specimens showed vasculitis and geographic basophilic necrosis with palisading histiocytes, giant cells, and neutrophils. Wegener's granulomatosis was diagnosed. On the 5th hospital day, the serum sodium level was 128 mEq/l. Since secretion of antidiuretic hormone had continued despite a low plasma osmolarity, we diagnosed the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and initiated oral prednisolone and cyclophosphamide. As a result, the symptoms and image findings were improved, and serum sodium level became normal. This case was considered to be SIADH secondary to Wegener's granulomatosis.