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Aliving Case of Pulmonary Ossification Associated With CASE REPORT A Living Case of Pulmonary Ossification Associated with Osteoclast Formation from Alveolar Macrophage in the Presence of T-cell Cytokines Takao TSUJI*, Seiichi NAKAMURA,Iwao KOMURO, Masashi MlKAMI, Michiko BABAand Michio TANAKA Abstract and both are composed of mature lamellar bone. Pulmonary ossification has usually been found at autopsy, because the A 61-year-old womanhad been coughing up blood- disease is very rare and usually occurs without symptoms. Its tinged sputum since May 1998. Chest radiography and pathogenesis is not fully understood. Here we report a living computed tomography (CT) scans revealed a solitary patient with an antemortemdiagnosis of pulmonary mass (3 cm in greatest dimension) in the right lower field, dendriform ossification, and present in vitro data suggesting accompanied by a surrounding area of ground glass and that osteoclasts derived from pulmonarymacrophages may reticular appearance. Surgical lung biopsy was per- be involved in the development of pulmonary ossification. formed to the surrounding area. The pathological diag- As to the etiology of pulmonary ossification, we assume that nosis was pulmonary ossification of the dendriform type. osteoclasts mayplay an important role. Osteoclasts are nec- Alveolar macrophages obtained from her lung differenti- essary for bone remodeling and absorption, and are gener- ated into tartrate-resistant acid phosphatase (TRAP)- ated from progenitors of monocytes/macrophages. It is positive multinucleated giant cells (MGCs) in the generally accepted that alveolar macrophagesand osteoclasts presence of autologous T cells or of macrophage colony are differentiated from myeloid precursor cells, including stimulating factor (M-CSF) and interleukin-4 (IL-4). This monocytes/macrophages (1, 2). Akagawa et al showed that results suggest the possibility that monocytes/macro- TRAP-positive osteoclast-like MGCs are generated from phages mayhave the ability to form osteoclasts in the humanmonocytes in the presence of M-CSFand IL-4 (3). presence of cytokines that maybe involved in the devel- Therefore, we hypothesized that transformation from pulmo- opmentof pulmonary ossification. nary macrophages to osteoclasts in the lung leads to pulmo- (Internal Medicine 42: 834-838, 2003) nary ossification, and consequently evaluated the response of alveolar macrophages obtained from the patient's BALFin Key words: pulmonary ossification, a living case, T-cell vitro. cytokines, M-CSF, IL-4 Case Report Patien t Introduction A 61-year-old womanwith no history of smoking had been coughing up blood-tinged sputum for a month. Her Ossification in the lung may occur in association with a medical history revealed no mitral valve disease, and no variety of diseases. Independently of ossification associated chronic inflammatory diseases, but she had diabetes that had with another primary disease, another form of benign ossifi- been treated with insulin for some years. Physical examina- cation in the lung has been reported; it is knownas idiopathic tion revealed no abnormalities except for fine crackles on the pulmonary ossification. Generally, there are two types of right lung. Hematological and blood chemistry values in- pulmonary ossification, dendriform type and nodular type, cluding serum Ca, P, and PTH, were normal. Chest radiogra- From the Department of Pneumology, Tokyo Metropolitan Hiro-o General Hospital, Tokyo and *the First Department of Medicine, Tokyo Women's Medical University, School of Medicine, Tokyo Received for publication September 18, 2002; Accepted for publication April 16, 2003 Reprint requests should be addressed to Dr. Takao Tsuji, the First Department of Medicine, Tokyo Women's Medical University, School of Medicine, 8-1 Kawata-cho, Shinjuku-ku, Tokyo 162-8666 834 Internal Medicine Vol. 42, No. 9 (September 2003) A Living Case of Pulmonary Ossification Figure 2. Chest CT scan taken in May1998 reveals a solitary mass 3 cm in greatest dimension in the right lower lobe, ac- companied by a surrounding area of ground glass and reticu- lar appearance. Figure 1. Chest radiography taken in May 1998 reveals a solitary mass about 3 cm in greatest dimension in the right lower field. phy and computed tomography (CT) scans revealed a soli- tary mass (3 cmin greatest dimension), accompanied by a surrounding area of ground glass and reticular appearance, in the right lower field (Figs. 1, 2). Sputum culture was normal flora and cytology showed no abnormal findings. Transbronchial lung biopsy (TBLB) and bronchial alveolar lavage (BAL) were performed. Histopathological findings showed no evidence of malignancy, with only mild fibrosis and a mild increase of lymphocyte cell counts in BALfluid (BALF). A solitary mass was subsequently decreasing in size on chest CT, and this mass was considered inflammatory Figure 3. Histopathological findings (HE x4) show fibrosis and mature lamellar bones whose marrow elements contain change like organizing pneumonia. But the surrounding area mature fat. of ground glass and reticular appearance remained; this area was considered interstitial change like interstitial pneumo- nitis. Finally, transluminal lung biopsy of the surrounding area of ground glass and reticular appearance wasperformed is a portion of the lesion in which fibrosis maytransform into by video-assisted thoracoscopic surgery (surgical lung bi- ossification in the future (Fig. 4) and there is fibrosis in the opsy). Pathological findings were fibrosis and mature other bilateral lung fields. Other general body surveys, in- lamellar bones whose marrow elements had mature fat (Fig. cluding head and abdominal CT and bone X-P, were almost 3). These bones were distributed diffusely, and ranged in size normal. The blood-tinged sputum improved spontaneously from 100 nm to 6 mm. The pathological diagnosis was pul- without medication. At three years after discharge from the monary ossification dendriform type. TBLBwas perfomed hospital, her cough and blood-tinged sputum have remained bilaterally on another lobe on a separate occasion, but patho- improved. logical findings were slight fibrosis only, indicating that pul- monary ossification was localized in the right lower lobe. Materials and Methods However,wecannot rule out the possibility that the area of ground glass and reticular appearance in the right lower lobe RPMI 1,640 medium (Nissui Seiyaku Co., Ltd., Tokyo, is only an early stage of systemic ossification, because there Japan) was supplemented with 3 mg/ml glutamine (Sigma Internal Medicine Vol. 42, No. 9 (September 2003) 835 TSUJI et al Figure 4. Histopathological findings (HE x40) show the por- tion in which fibrosis maytransform into ossification. Figure 5. Development in the presence ofM-CSFand IL-4 of Aldrich Japan K.K, Tokyo, Japan), 100 U/ml penicillin G TRAP-positive multinucleated giant cells from alveolar macrophages obtained from the patient (8 weeks, magnifica- potassium (Banyu Seiyaku Co., Ltd., Tokyo, Japan), 100 |ig/ tion xlOO). ml streptomycin (Meiji Seika Co., Ltd., Tokyo, Japan), 10% of autoclaved NaHCO3and finally 10%heat-inactivated fetal calf serum (FCS: Z. L. Bockneck Laboratories, Inc., Ontario, Canada). FCS and distilled water were shown to contain 3 pg and less than 1 pg of lipopolysaccaride per ml by the Limullus amebocyte lysate test, respectively. Recombinant human M-CSF (2xlO8U/mg) was kindly supplied by Morinaga Milk Industry Co., Ltd., Tokyo, Japan. Recombi- nant human IL-4 (lxl07U/mg) was obtained from Genzyme Corp, Minneapolis, USA. Human alveolar macrophages were obtained from the patient and healthy volunteers (non- smokers without pathogenesis) by bronchoalveolar lavage. The patient and healthy volunteers consented to permit the use of alveolar macrophagein part of this study by informed consent. Alveolar macrophages were incubated in plastic dishes for 1 hour at 37°C in a CO2 incubator, and non- adherent cells were removed by repeated washing. Morethan 97% of the recovered cells were judged to be alveolar macrophages based on morphology, nonspecific esterase staining (cells were stained for a-naphthyl butyrate esterase), CD14 positivity and their ability to phagocytize latex parti- cles. Autologeuous T cells were obtained from the non- Figure 6. Development by cocultivation with autologous T adherent cells through the nylon wool column. Human cells of TRAP-positive multinucleated giant cells from alveo- alveolar macrophages (2.5xlO5 per ml in 12 well tissue cul- lar macrophages obtained from the patient (8 weeks, magnifi- ture plates) were cultured with M-CSF (104U/ml) in the cation xlOO). presence of IL-4 (103U/ml) for 8 weeks or cocultured with autologous T-cells (macrophage: T cell=l : 20) for 8 weeks. After culture, the cells were fixed and stained with Diff- and stained using a commercial kit (Sigma Diagnostics, St Quick (Kokusai Siyaku Co., Ltd., Kobe, Japan) and counted Louis, MO)according to the manufacturer's instructions. on an inverted microscope. Cells with 3 or more nuclei per TRAP-positive cells appeared dark red. cell were defined as MGCs.The results are expressed as the meanMGCscounts and standard deviations of triplicate wells. Numberof MGCswas counted in 500 total cells at triplicate wells. Before culture, no limited MGCwere ob- served in culture plate. For TRAP activity, cells were fixed 836 Internal Medicine Vol. 42, No. 9 (September 2003) A Living Case of Pulmonary Ossification dendriform type is often associated with lung scarring and interstitial fibrosis. Radiographically, the dendriform type manifests as
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