Adrenomedullin Ameliorates Pulmonary Fibrosis by Regulating TGF-ß-Smads Signaling and Myofibroblast Differentiation.

Pulmonary fibrosis is an irreversible, potentially fatal disease. Adrenomedullin (AM) is a multifunctional peptide whose activity is regulated by receptor activity-modifying protein 2 (RAMP2). In the present study, we used the bleomycin (BLM)-induced mouse pulmonary fibrosis model to investigate the pathophysiological significance of the AM-RAMP2 system in the lung. In heterozygous AM knockout mice (AM+/-), hydroxyproline content and Ashcroft scores reflecting the fibrosis severity were significantly higher than in wild-type mice (WT). During the acute phase after BLM administration, FACS analysis showed significant increases in eosinophil, monocyte, and neutrophil infiltration into the lungs of AM+/-. During the chronic phase, fibrosis-related molecules were upregulated in AM+/-. Notably, nearly identical changes were observed in RAMP2+/-. AM administration reduced fibrosis severity. In the lungs of BLM-administered AM+/-, the activation level of Smad3, a receptor-activated Smad, was higher than in WT. In addition, Smad7, an antagonistic Smad, was downregulated and microRNA-21, which targets Smad7, was upregulated compared to WT. Isolated AM+/- lung fibroblasts showed less proliferation and migration capacity than WT fibroblasts. Stimulation with TGF-ß increased the numbers of α-SMA-positive myofibroblasts, which were more prominent among AM+/- cells. TGF-ß-stimulated AM+/- myofibroblasts were larger and exhibited greater contractility and extracellular matrix production than WT cells. These cells were α-SMA (+), F-actin (+), and Ki-67(-) and appeared to be nonproliferating myofibroblasts (non-p-MyoFbs), which contribute to the severity of fibrosis. Our findings suggest that in addition to suppressing inflammation, the AM-RAMP2 system ameliorates pulmonary fibrosis by suppressing TGF-ß-Smad3 signaling, microRNA-21 activity and differentiation into non-p-MyoFbs.

[A case of primary pulmonary nocardiosis with multiple pulmonary nodules successfully treated with moxifloxacin].

A 18-year-old man was admitted with fever. His chest radiograph and CT scan showed consolidation shadow in the right middle lobe and multiple nodules in both lungs. He was treated with meropenem and minocycline. After this antibiotic therapy, the consolidation shadow disappeared and the multiple nodules were slightly reduced in their size. Since filamentous bacteria suspicious of Nocardia grew transiently in the initial sputum culture, we started to treat him with oral sulfametoxazole-trimethoprim. However, because agranulocytosis was caused by sulfametoxazole-trimethoprim therapy, we had to change the anti-bacterial therapy to minocycline. Minocycline was not effective, and the nodules enlarged. For accurate diagnosis, we employed video-assisted thoracic surgery (VATS) to investigate the histological and bacterial analyses of the pulmonary nodules. Histological findings of the pulmonary nodule obtained by VATS revealed granuloma with central necrosis associated with neutrophilic micro-abscess. Filamentous gram-positive bacteria in pulmonary nodule tissue was stained positively with both Grocott and Ziehl-Neelsen staining. Taking these findings together, we diagnosed primary pulmonary nocardiosis. Three months after initiating moxifloxacin, the size of the multiple pulmonary nodules was markedly reduced. Our experience with this case suggests that moxifloxacin can be recommended for the treatment of pulmonary nocardiosis.

Fat-soluble and water-soluble vitamin contents of breast milk from Japanese women.

To determine the concentrations of fat-soluble and water-soluble vitamins in the maternal milk of Japanese women, we collected human milk samples from more than 4,000 mothers living throughout Japan between December 1998 and September 1999, and defined as group A the 691 samples among these that met the following conditions: breast milk of mothers who were under 40 y of age, who did not smoke habitually and/or use vitamin supplements, and whose babies showed no symptoms of atopy and had birth weights of 2.5 kg or more. We then analyzed the contents of vitamins individually. Large differences were observed among the contents of individual human milk samples. The mean contents of each component were as follows: vitamin A, 159.0 +/- 95.2 IU/100 mL; vitamin E, 0.325 +/- 0.165 alpha-TE mg/100mL; vitamin D3 (cholecalciferol), 8.0 +/- 10.7 ng/100mL; vitamin B1 (thiamin), 12.3 +/- 3.2 microg/100 mL; vitamin B2, 38.4 +/- 12.7 microg/100 mL; vitamin B6, 5.7 +/- 2.5 microg/100 mL; vitamin B12, 0.04 +/- 0.02 microg/100 mL; vitamin C, 5.1 +/- 1.9 mg/100 mL; biotin, 0.50 +/- 0.23 microg/100 mL; choline, 9.2 +/- 1.8 mg/100 mL; folic acid, 6.2 +/- 2.9 microg/100 mL; inositol, 12.6 +/- 3.6 mg/100 mL; niacin (nicotinamide), 32.9 +/- 20.4 microg/100 mL and pantothenic acid, 0.27 +/- 0.09 mg/100 mL. The concentrations of derivatives and/or related compounds of vitamin A (retinol, beta-carotene), vitamin E (alpha-, beta-, gamma-, and delta-tocopherol), and B2 (riboflavin, FMN, and FAD) were determined separately. The contents of each were found to vary greatly as the duration of lactation increased. The present results indicate that it is necessary to evaluate individual differences in human milk in order to perform valid research regarding infant formula.