Zoledronate induces bisphosphonate-related osteonecrosis of the jaw in osteopenic sheep.

OBJECTIVES: Bisphosphonate-related osteonecrosis of the jaw (BP-ONJ) occurs in 1 % of patients with medication-induced osteoporosis treated with bisphosphonates. Sheep are an established large animal model for investigating osteoporotic skeletal changes. Zoledronate significantly reduces tissue mineral variability in ovariectomized sheep. The aim of this study was to analyze bone healing after tooth extraction in sheep with induced osteopenia and zoledronate administration. MATERIALS AND METHODS: Eight adult ewes were randomly divided into two groups of four animals. All sheep underwent ovariectomy and a low-calcium diet. Dexamethasone was administered weekly for 16 weeks. Zoledronate was then given every third week for a further 16 weeks in four sheep; these infusions were repeated after extraction of two lower premolars. Four sheep without zoledronate administrations served as controls. RESULTS: Due to general health conditions, two sheep of the zoledronate group had to be excluded before surgery. The remaining two sheep of this group developed BP-ONJ lesions at the extraction site and various other sites in both jaws. Control group animals showed uneventful wound healing. Histology of the alveolar processes as well as lumbar spine revealed larger portions of old bone and smaller portions of new bone in the zoledronate group. CONCLUSIONS: This animal study showed uneventful wound healing after tooth extraction in osteopenic sheep whereas zoledronate treatment leads to development of BP-ONJ-like lesions. CLINICAL RELEVANCE: As bisphosphonate administration is a standard treatment for glucocorticoid-induced osteoporosis, this model can be used for further research in pathogenesis and management of bisphosphonate-related adverse events.

The chemokine ligand CXCL16 is an indicator of bacterial infection in necrotizing pancreatitis.

OBJECTIVES: Current guidelines tell us that intervention in severe necrotizing pancreatitis ought to be performed as late as possible. However, when pancreatic necrosis becomes infected, the necrotic tissue needs to be removed. Unfortunately, bacterial infection can only be proven by invasive methods. METHODS: Necrotizing pancreatitis with sterile or infected necrosis was induced in mice. Mice serum samples were examined by antibody-based protein array. After identifying candidate proteins that showed strong regulation, the serum concentration of these proteins was examined by sandwich ELISA. Then, human serum samples were collected from patients with mild pancreatitis, severe pancreatitis with and without pancreatic necrosis and patients with microbiologically proven infection of pancreatic necrosis. These serum samples were then analyzed by sandwich ELISA. RESULTS: In mice 6 proteins were strongly up-regulated and were further investigated by ELISAs. Of these proteins, CXCL16 and TRANCE (RANKL) concentrations were analyzed in human serum samples. CXCL16 and TRANCE were increased in patients with pancreatic necrosis and abdominal infection. Receiver operated characteristics showed that CXCL16 was superior in predicting infected pancreatic necrosis when compared to C-reactive protein and TRANCE. CONCLUSIONS: Serum CXCL16 is increased in severe pancreatitis with infected pancreatic necrosis and identifies patients who benefit from surgical necrosectomy.

Dissecting the effect of moxifloxacin in mice with infected necrosis in taurocholate induced necrotizing pancreatitis.

OBJECTIVES: To investigate the limited benefit of antibiotics in ameliorating the outcome of acute necrotizing pancreatitis, we analyzed antibiotic therapy in primarily infected necrotizing pancreatitis in mice with respect to the local pancreatic pathology as well as systemic, pancreatitis induced adverse events. METHODS: Sterile pancreatic necrosis (SN) was induced by retrograde injection of 4% taurocholate in the common bile duct of Balb/c mice. Primarily infected pancreatic necrosis (IN) was induced by co-injecting 10(8) CFU/ml Escherichia coli. 10 mg/kg of moxifloxacin was administered prior to pancreatitis induction (AN). After 24 h, animals were sacrificed to examine serum as well as organs for signs of SIRS. RESULTS: Moxifloxacin significantly reduced bacterial count in pancreatic lysates of animals with infected pancreatic necrosis (IN 4.1·10(7) ± 2.4·10(7) vs. AN 4.9·10(4) ± 2.6·10(4) CFU/g; p < 0.001). However, it did not alter pancreatic histology or pulmonary damage (Histology score: IN 23.8 ± 2.7 vs. AN 22.6 ± 1.7). Moxifloxacin reduced systemic immunoactivation (Serum IL-6: IN 330.5 ± 336.6 vs. 38.7 ± 25.5 pg/ml; p < 0.001), hypoglycemia (serum glucose: IN 105.8 ± 12.7 vs. AN 155.7 ± 39.5 mg/dl; p < 0.001), and serum aspartate aminotransferase (IN 606 ± 89.7 vs. AN 255 ± 52.1; p < 0.05). These parameters were significantly increased in animals with necrotizing pancreatitis. CONCLUSION: In the experimental setting, initial antibiotic therapy with moxifloxacin in acute infected necrotizing pancreatitis in mice does not have a beneficial impact on pancreatic pathology or pulmonary damage. However, other systemic complications induced by infected necrosis in acute pancreatitis are reduced by the administration of moxifloxacin.

Infected pancreatic necrosis increases the severity of experimental necrotizing pancreatitis in mice.

OBJECTIVE: Infection of pancreatic necrosis in necrotizing pancreatitis increases the lethality of patients with acute pancreatitis. To examine mechanisms underlying this clinical observation, we developed and tested a model, in which primary infection of necrosis is achieved in taurocholate-induced pancreatitis in mice. METHODS: Sterile necrosis of acute necrotizing pancreatitis was induced by retrograde injection of 4% taurocholate into the common bile duct of Balb/c mice. Primary infection of pancreatic necrosis was induced by coinjecting 10 colony-forming units of Escherichia coli. Animals were killed after 6, 12, 24, 48, and 120 hours, and pancreatic damage and pancreatitis-associated systemic inflammatory response were assessed. RESULTS: Mice with pancreatic acinar cell necrosis had an increased bacterial concentration in all tissues and showed sustained bacteremia. Acute pancreatitis was induced only by coinjection of taurocholate and not by bacterial infection alone. Infection of pancreatic necrosis increased pancreatic damage and the pulmonary vascular leak. Serum glucose concentrations serving as a parameter of hepatic function were reduced in mice with infected pancreatic necrosis. CONCLUSIONS: Primary infection of pancreatic necrosis with E. coli increases both pancreatic damage and pulmonary and hepatic complications in acute necrotizing pancreatitis in mice.