Clarithromycin prevents smoke-induced emphysema in mice.

RATIONALE: Modulating the low-grade chronic inflammation in chronic obstructive pulmonary disease remains challenging. Clarithromycin (CAM), a macrolide antibiotic, reportedly ameliorates chronic inflammation via mechanisms independent of its antibacterial activity. OBJECTIVES: The aim of this study was to examine whether CAM can prevent or reduce emphysema induced by chronic cigarette smoke exposure. METHODS: Mice were exposed to cigarette smoke daily for 6 months and treated with orally administered CAM at doses of 25 to 100 mg/kg twice a day throughout the course of the experiment to test the preventive effects. The administration of CAM at 50 or 100 mg/kg was performed during the second half of a 6-month exposure period to assess the therapeutic effects. Histologic analysis was performed to evaluate the effect of CAM. MEASUREMENTS AND MAIN RESULTS: CAM treatment for 6 months decreased airspace enlargement and the destruction of the alveolar walls and impaired the accumulation of macrophages in bronchoalveolar lavage fluid in a dose-related fashion. The administration of clarithromycin at 100 mg/kg in the therapeutic protocol reduced emphysema compared with the smoke-exposed group without treatment. An immunohistologic analysis revealed that CAM reduced the number of F4/80-positive macrophages in the lung parenchyma. In an in vitro test, CAM at 5 to 20 microM directly suppressed the activation of macrophages stimulated with tumor necrosis factor-alpha. CONCLUSIONS: Our data demonstrated that CAM at a clinically achievable dose prevented cigarette smoke-induced emphysema by modulating lung inflammation. This study supports the possibility that low-dose CAM treatment might provide a new therapeutic strategy for chronic obstructive pulmonary diseases.

The TSC1 gene product hamartin interacts with NADE.

Hamartomatous brain lesions are a hallmark of brain pathology of tuberous sclerosis complex (TSC). To elucidate the mechanism of tumor development in the brain of TSC, we identified NADE (p75NTR-associated cell death executor) as an interactor for TSC1 gene product hamartin using a yeast two-hybrid system. In a pull-down assay, endogenous NADE was purified with the immobilized coiled-coil domain (CCD) of hamartin from the PC12h cell lysate. Immunofluorescence and immunoprecipitation confirmed the interaction of hamartin and NADE in cultured neurons and mouse brain lysate. Hamartin constitutively associated with NADE to prevent its proteasomal degradation. Suppression of hamartin with TSC1 small interfering RNA (siRNA) caused reduction of NADE and failed to lead to NGF-induced apoptosis in PC12h cells. These results indicate that hamartin binds to NADE to regulate neuronal cell function and loss of this association is likely to contribute to the brain pathology in TSC.