Effects of azithromycin and tanomastat on experimental bronchiolitis obliterans.

OBJECTIVE: Azithromycin has become a standard of care in therapy of bronchiolitis obliterans following lung transplantation. Matrix metalloprotease-9 broncho-alveolar lavage levels increase in airway neutrophilia and bronchiolitis obliterans. Interleukin-17 may play a role in lung allograft rejection, and interleukin-12 is downregulated in bronchiolitis obliterans. Whether these mechanisms can be targeted by azithromycin remains unclear. METHODS: Bronchiolitis obliterans was induced by transplantation of Fischer F344 rat left lungs to Wistar Kyoto rats. Allografts with azithromycin therapy from day 1 to 28 or 56 and mono- or combination therapy with the broad-spectrum matrix metalloprotease inhibitor tanomastat from day 1 to 56 were compared to control allografts and isografts. Graft histology was assessed, and tissue cytokine expression studied using Western blotting and immunofluorescence. RESULTS: The chronic airway rejection score in the azithromycin group did not change between 4 and 8 weeks after transplantation, whereas it significantly worsened in control allografts (P = .041). Azithromycin+tanomastat prevented complete allograft fibrosis, which occurred in 40% of control allografts. Azithromycin reduced interleukin-17 expression (P = .049) and the number of IL-17(+)/CD8(+) lymphocytes at 4 weeks, and active matrix metalloprotease-9 at 8 weeks (P = .017), and increased interleukin-12 expression (P = .025) at 8 weeks following transplantation versus control allografts. CONCLUSIONS: The expression of interleukin-17 and matrix metalloprotease-9 in bronchiolitis obliterans may be attenuated by azithromycin, and the decrease in interleukin-12 expression was prevented by azithromycin. Combination of azithromycin with a matrix metalloprotease inhibitor is worth studying further because it prevented complete allograft fibrosis in this study.

The impact of colony-stimulating factor-1 on fracture healing: an experimental study.

The role of colony stimulating factor-1 (CSF-1) in the regulation of osteoclasts and bone remodeling suggests that CSF-1 may also be involved in regulation of bone healing. The ability of CSF-1 to promote healing of bone defects was tested in a rabbit model. Twenty-four New Zeeland rabbits were included in the study. Animals were assigned to two groups: the control group (n = 12) was treated by plate fixation. The animals in the second group (n = 12) were also stabilized by conventional plating and received additionally CSF-1 for 2 weeks systemically. Histologic, histomorphometric, and radiologic examinations were performed to evaluate the healing process at 4, 8, and 12 weeks following surgery. Animals that were treated by CSF-1 produced a significantly higher amount of mineralized bone over the first 8 weeks after fracture compared to the control animals. Furthermore, a higher number of osteoclasts was found in CSF-1-treated animals within the first 8 weeks, compared to the controls. The present data emphasize for the first time the importance of CSF-1 in the bone healing. The use of CSF-1 in addition to conventional fixation might be a novel approach for the treatment of bone defects.

Combination of anorganic bovine-derived hydroxyapatite with binding peptide does not enhance bone healing in a critical-size defect in a rabbit model.

Anorganic bovine-derived hydroxyapatite (ABM) in combination with binding peptid (P-15) has demonstrated the capacity to improve the healing of periodontal defects. This study evaluated the benefit of ABM/P-15 to promote healing of cortical long bone defects in a rabbit model. A 5-mm segmental bone defect was created in the femur and fixed with a plate. There were two treatment groups: no implant (n = 12) and ABM/P-15 (n = 12). At 4, 8, and 12 weeks, healing of the defect was evaluated with radiographs and histomorphometric examination of the treated femora. After 4 weeks, radiographs showed bone formation without signs of complete consolidation in three of four animals in the control group and two of four ABM/P-15 treated animals. At the later course of the treatment, no radiologic difference was evident between the treatment groups. Histomorphometric evaluation revealed an area of 1.29 +/- 0.11 mm(2) and 0.97 +/- 0.21 mm(2) of newly produced bone in animals of the control group and ABM/P-15 group after 4 weeks. After 8 and 12 weeks, animals in the control group had an area of 2.44 +/- 0.62 mm(2) and 2.5 +/- 0.2 mm(2) of newly produced bone within the osteotomy gap compared to 1.6 +/- 0.65 mm(2) and 1.56 +/- 0.27 mm(2) in the ABM/P-15 group (p = 0.0004). An enhanced or accelerated ingrowth of bone, as reported in previous studies, was not observed. Our results imply that the ABM/P-15 is not a suitable graft for the treatment of critical-sized segmental defects in long bones.