Experimental blunt chest trauma impairs fracture healing in rats

In poly‐traumatic patients a blunt chest trauma is an important trigger of the posttraumatic systemic inflammatory response. There is clinical evidence that fracture healing is delayed in such patients, however, experimental data are lacking. Therefore, we investigated the influence of a thoracic trauma on fracture healing in a rat model. Male Wistar rats received either a blunt chest trauma combined with a femur osteotomy or an isolated osteotomy. A more rigid or a more flexible external fixator was used for fracture stabilization to analyze whether the thoracic trauma influences regular healing and mechanically induced delayed bone healing differently. The blunt chest trauma induced a significant increase of IL‐6 serum levels after 6 and 24 h, suggesting the induction of a systemic inflammation, whereas the isolated fracture had no effect. Under a more rigid fixation the thoracic trauma considerably impaired fracture healing after 35 days, reflected by a significantly reduced flexural rigidity (three‐point‐bending test), as well as a significantly diminished callus volume, moment of inertia, and relative bone surface (µCT analysis). In confirming the clinical evidence, this study reports for the first time that a blunt chest trauma considerably impaired bone healing, possibly via the interaction of the induced systemic inflammation with local inflammatory processes. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:734–739, 2011     

Conversion from external fixator to intramedullary nail causes a second hit and impairs fracture healing in a severe trauma model

In poly‐traumatic patients, second hits are known to potentiate the posttraumatic systemic inflammatory response, thus increasing the risk of multi‐organ dysfunction. In accordance with “damage control orthopaedic surgery” principles, fractures are initially treated with external fixators, which are replaced by internal osteosynthesis once the immunological status of the patient is considered stable. Recently, we demonstrated that a severe trauma impaired the healing of fractures stabilized by external fixation during the entire healing period. The question arose, whether switching to intramedullary nailing increases the inflammatory response in terms of a second hit, leading to a further impairment of bone healing. Wistar rats received a femoral osteotomy stabilized by an external fixator. Simultaneously half of the rats underwent an additional thoracic trauma. After 4 days, the external fixator was replaced by an intramedullary nail in half of the rats of the two groups. The inflammatory response was evaluated by measuring serum C5a levels. Fracture healing was determined by three‐point‐bending, µCT, and histomorphometry. The thoracic trauma significantly increased C5a concentrations 6, 24, and 72 h after the second surgical intervention. After 40 days, conversion to intramedullary nailing considerably decreased the flexural rigidity of the callus, with no significant differences between rats with or without thoracic trauma. After 47 days, flexural rigidity in rats subjected to conversion remained decreased compared to animals solely treated by external fixation, particularly in combination with blunt chest trauma. The results indicate that accumulation of second hits after multiple injuries could lead to aggravation of the fracture healing outcome. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31: 465–471, 2013     

Temporal profile of inflammatory response to fracture and hemorrhagic shock: Proposal of a novel long‐term survival murine multiple trauma model

Hemorrhagic shock (hS) interacts with the posttraumatic immune response and fracture healing in multiple trauma. Due to the lack of a long‐term survival multiple trauma animal models, no standardized analysis of fracture healing referring the impact of multiple trauma on fracture healing was performed. We propose a new long‐term survival (21 days) murine multiple trauma model combining hS (microsurgical cannulation of carotid artery, withdrawl of blood and continuously blood pressure measurement), femoral (osteotomy/external fixation) and tibial fracture (3‐point bending technique/antegrade nail). The posttraumatic immune response was measured via IL‐6, sIL‐6R ELISA. The hS was investigated via macrohemodynamics, blood gas analysis, wet‐dry lung ration and histologic analysis of the shock organs. We proposed a new murine long‐term survival (21 days) multiple trauma model mimicking clinical relevant injury patterns and previously published human posttraumatic immune response. Based on blood gas analysis and histologic analysis of shock organs we characterized and standardized our murine multiple trauma model. Furthermore, we revealed hemorrhagic shock as a causative factor that triggers sIL‐6R formation underscoring the fundamental pathophysiologic role of the transsignaling mechanism in multiple trauma. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:965–970, 2015.     

Are polymorphisms of molecules involved in bone healing correlated to aseptic femoral and tibial shaft non‐unions?

Fracture healing is a well‐organized process between several molecules and mediators. As known from other diseases, genetic polymorphisms may exhibit different expression patterns in these mediators. Concerning fracture healing, this may lead to an extended healing process or non‐union. We investigated the incidence of polymorphisms in patients with aseptic non‐unions after femoral and tibial shaft fractures as compared to patients with uneventful healing. Exclusion criteria were smoking, diabetes, bilateral fractures, systemic corticoid therapy, and septic non‐unions. Analysis of allele frequencies and genotype distribution of various mediators were carried out following PCR. Clinical parameters such as injury severity and in‐hospital were analyzed. Fifty patients following non‐union (group NU) were enrolled, the control group consisted of 44 patients (group H). A significant association of a PDGF haplotype and non‐unions following fracture could be observed. There was a significantly increased in‐hospital time and amount of surgical procedures in group NU. Polymorphisms within the PDGF gene seem to be a genetic risk factor for the development of non‐unions of the lower extremity following fracture. The early identification of high risk patients could result in an adapted therapeutical strategy and might contribute to a significant decrease of posttraumatic non‐unions. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1724–1731, 2011     

The effect of both a thoracic trauma and a soft-tissue trauma on fracture healing in a rat model

Background and purpose

There is some clinical evidence that fracture healing is impaired in multiply injured patients. Nothing is known, however, about the effects of various types of injuries and their contribution to a possible disturbance of the fracture-healing process. We investigated the effect of a thoracic trauma and an additional soft-tissue trauma on fracture healing in a rat tibia model.

Methods

3 groups of rats were operated: group A with a simple fracture of the tibia and fibula, group B with a fracture and an additional thoracic trauma, and group C with a fracture, thoracic trauma, and an additional soft-tissue trauma. The fracture and the soft-tissue injury were produced by a special guillotine-like device and the thoracic trauma by a blast wave generator.After one day, the serum level of IL-6 was quantified, and at the end of the study (28 days) the mechanical properties and the callus volume of the healed tibia were determined.

Results

Increasing the severity of the injury caused IL-6 levels to more than double 1 day after injury. It halved the load to failure in mechanical tests and led to reduced callus volume after 28 days of healing.

Interpretation

Fracture healing is impaired when additional thoracic trauma and soft tissue trauma occurs.Fractures are often associated with other forms of trauma such as additional soft-tissue trauma, blunt chest trauma, or head trauma. Multiply injured patients most often suffer from injuries of the extremities, with two-thirds having fractures and soft-tissue trauma, followed by injuries of the thorax and head (Shorr et al. 1987, Bardenheuer et al. 2000). Multiply injured patients with blunt chest trauma are known to have higher rates of multi-organ failure and mortality (Trupka et al. 1998, Stensballe et al. 2009), while there is some evidence that additional traumas can affect fracture healing. A higher rate of reoperations after fracture fixation was found in multiply injured patients with tibial fractures in comparison to those with isolated fractures (Bhandari et al. 2003). One possible reason might be accumulation of inflammatory factors and the interaction between the inflammatory processes induced by the different injuries.A blunt chest trauma leads to a rapid systemic inflammatory reaction (Knoferl et al. 2003). Several cytokines (e.g. IL-6, TNF-a, and IL-10) are released systemically within the first few hours after trauma; IL-6 levels appear to correlate best with the severity of thoracic trauma (Knoferl et al. 2003, Liener et al. 2011, Seitz et al. 2011). The same cytokines play an important role during fracture healing, where they regulate inflammation, enchondral bone formation, and remodeling (Cho et al. 2001, Giannoudis et al. 2008). IL-6 was found to be maximally expressed at the early phase of fracture healing whereas IL-1 showed only a moderate change, at a very low level (Cho et al. 2001).A previous study on fracture healing in rats showed that additional soft tissue damage induced substantially elevated serum levels of IL-6 within 6 hours of injury (Kobbe et al. 2008). Other studies have, however, shown that the effect of a moderate additional soft-tissue trauma only has a temporary (Claes et al. 2006) and small effect on the final fracture-healing outcome (Utvag et al. 2003). To our knowledge, nothing is known about the effect of a blunt thoracic trauma or even a combination of soft-tissue trauma and blunt thoracic trauma on fracture healing.We tested the hypothesis that these additional traumas would disturb the normal healing process of a fracture. We performed an animal experiment that focused on clinically relevant outcome parameters: bending stiffness, strength of the healed bone, and the amount of callus formation.     

Complement Mediated Renal Inflammation Induced by Donor Brain Death: Role of Renal C5a‐C5aR Interaction

Kidneys retrieved from brain‐dead donors have impaired allograft function after transplantation compared to kidneys from living donors. Donor brain death (BD) triggers inflammatory responses, including both systemic and local complement activation. The mechanism by which systemic activated complement contributes to allograft injury remains to be elucidated. The aim of this study was to investigate systemic C5a release after BD in human donors and direct effects of C5a on human renal tissue. C5a levels were measured in plasma from living and brain‐dead donors. Renal C5aR gene and protein expression in living and brain‐dead donors was investigated in renal pretransplantation biopsies. The direct effect of C5a on human renal tissue was investigated by stimulating human kidney slices with C5a using a newly developed precision‐cut method. Elevated C5a levels were found in plasma from brain‐dead donors in concert with induced C5aR expression in donor kidney biopsies. Exposure of precision‐cut human kidney slices to C5a induced gene expression of pro‐inflammatory cytokines IL‐1 beta, IL‐6 and IL‐8. In conclusion, these findings suggest that systemic generation of C5a mediates renal inflammation in brain‐dead donor grafts via tubular C5a‐C5aR interaction. This study also introduces a novel in vitro technique to analyze renal cells in their biological environment.     

Role of Videothoracoscopy in Chest Trauma

Background. The aim of this study was to evaluate videothoracoscopic procedures in the setting of chest trauma.Methods. We retrospectively analyzed our experience of videothoracoscopy in patients with either blunt trauma or penetrating thoracic injuries.Results. Forty-three procedures involving 42 patients were performed between July 1990 and April 1996. Indications for videothoracoscopy included suspected diaphragmatic injury (14 patients), clotted hemothorax (12), continued hemothorax (6), persistent pneumothorax (5), intrathoracic foreign body (4), posttraumatic chylothorax (1), and posttraumatic empyema (1 patient). Ten patients (24%) required conversion to thoracotomy. Two patients suffered postoperative pneumonia. There was one perioperative death. Mean hospital stay was 17 days; 21 days for patients with blunt trauma and 13 days for patients with penetrating injuries. There was no procedure-related complication. Videothoracoscopy allowed precocious discharge of patients suffering penetrating injuries and allowed faster recovery in the majority of patients suffering severe blunt trauma.Conclusions. Videothoracoscopy appears to be a safe, accurate, and useful approach in selected patients with chest trauma. It is ideal for the assessment of diaphragmatic injuries, for control of chest wall bleeding, for early removal of clotted hemothorax, for treatment of empyema, for treatment of chylothorax, for treatment of persistent pneumothorax, and for removal of intrathoracic foreign body. However, we do not recommend the use of this technique in the setting of suspected great vessel or cardiac injury.(Ann Thorac Surg 1997;63:327–33)© 1997 by The Society of Thoracic Surgeons     

An animal model for open femur fracture and osteomyelitis: Part I

Infection is an everyday problem in orthopaedics and is quite common in open fracture management. To study this process and provide a basis to prevent infection, we developed a model that includes trauma (blunt fracture in the fashion of Bonnarens and Einhorn), surgical stabilization (standardized intramedullary K‐wire fixation), and infection (Staphylococcus aureus inoculum). In this two‐part study, we found that 10² colony‐forming units of inoculum produced an optimal infection rate of 90–100%, which substantially challenged the immune system without overwhelming sepsis. We hypothesized that, in traumatic fractures, there is a specific immunological response that may lead to an increased rate of infection. In Part 2, we demonstrated immunosuppression (decreased Interleukin‐12 levels) at days 6, 10, and 12 after fracture fixation versus nonfractured control groups (p < 0.05). This study describes a rat model of femur factures with osteomyelitis that allows investigation of posttraumatic immunosuppression. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:38–42, 2010     

Local application of VEGF compensates callus deficiency after acute soft tissue trauma—results using a limb‐shortening distraction procedure in rabbit tibia

Acute soft tissue trauma influences callus formation and fracture healing. Several studies showed a relationship between angiogenesis and bone formation during distraction osteogenesis. The purpose of this study was to investigate the influence of controlled release of vascular endothelial growth factor (VEGF) on callus formation in a limb‐shortening distraction procedure after acute compartment syndrome. Acute soft tissue trauma with critical increased compartment pressure was generated in 22 rabbits, and the limb was shortened simulating fracture site debridement. In the test group (n = 11), a VEGF‐coated collagen matrix was locally applied around the fracture, while no collagen was applied in the control group (n = 11). Following 10 days in limb shortening, a gradual distraction of 0.5 mm/12 h was performed using an external fixation device and followed up for 40 days. Osseous consolidation occurred in all animals. Average callus diameter (1.54 ± 0.8 vs. 1.27 ± 0.14 mm) and torsional strength (72% vs. 46% of normal) were significantly higher in the test versus the control group. Blood vessel formation increased with a significantly higher number of vessels (6.3 vs. 3.81/mm²) and larger cross‐sectional area (>40 µm, 90.5% vs. 86%) in the test versus control group. The results showed that locally applied VEGF stimulates fracture healing after acute soft tissue trauma and might be an option for fracture treatment in cases with severe soft tissue damage. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29: 1093–1098, 2011     

Scapular fractures and concomitant injuries

Objective: The association of scapular fractures with other life-threatening injuries including blunt thoracic aortic injury is widely recognized.Few studies have investigated this presumed association...     

Effects of cartilage impact with and without fracture on chondrocyte viability and the release of inflammatory markers

Post‐traumatic arthritis (PTA) frequently develops after intra‐articular fracture of weight bearing joints. Loss of cartilage viability and post‐injury inflammation have both been implicated as possible contributing factors to PTA progression. To further investigate chondrocyte response to impact and fracture, we developed a blunt impact model applying 70%, 80%, or 90% surface‐to‐surface compressive strain with or without induction of an articular fracture in a cartilage explant model. Following mechanical loading, chondrocyte viability, and apoptosis were assessed. Culture media were evaluated for the release of double‐stranded DNA (dsDNA) and immunostimulatory activity via nuclear factor kappa B (NF‐κB) activity in Toll‐like receptor (TLR) ‐expressing Ramos‐Blue reporter cells. High compressive strains, with or without articular fracture, resulted in significantly reduced chondrocyte viability. Blunt impact at 70% strain induced a loss in viability over time through a combination of apoptosis and necrosis, whereas blunt impact above 80% strain caused predominantly necrosis. In the fracture model, a high level of primarily necrotic chondrocyte death occurred along the fracture edges. At sites away from the fracture, viability was not significantly different than controls. Interestingly, both dsDNA release and NF‐κB activity in Ramos‐Blue cells increased with blunt impact, but was only significantly increased in the media from fractured cores. This study indicates that the mechanism of trauma determines the type of chondrocyte death and the potential for post‐injury inflammation. (c) 2013 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 31:1283–1292, 2013     

Strongly enhanced levels of sclerostin during human fracture healing

Sclerostin (SOST), an antagonist of Wnt signaling, is an important negative regulator of bone formation. However, no data on the role of SOST in the human fracture healing have been published so far. This study addressed this issue. Seventy‐five patients with long bone fractures were included into the study and divided in two groups. The first group contained 69 patients with normal fracture healing. Six patients with impaired fracture healing formed the second group. Thirty‐four volunteers donated blood samples as control. Serum samples were collected over a period of 1 year following a standardized time schedule. In addition, SOST levels were measured in fracture hematoma and serum of 16 patients with bone fractures. Fracture hematoma contained significantly higher SOST concentrations compared to patient's serum. SOST levels in fracture hematoma and in patient's serum were both significantly higher than in the serum of controls. Highly elevated SOST serum concentrations were found in patients with physiological fracture healing. SOST levels were decreased in patients with impaired fracture healing. However, this difference was not statistically significant. This is the first study to provide evidence of strongly enhanced SOST levels in patients with bone fracture. The results indicate local and systemic involvement of SOST in humans during fracture healing. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1549–1555, 2012     

Low intensity pulsed ultrasound enhances fracture healing in both ovariectomy‐induced osteoporotic and age‐matched normal bones

Low intensity pulsed ultrasound (LIPUS) was proven to enhance fracture healing effectively. Similar effect of LIPUS on accelerating the osteoporotic fracture healing was therefore hypothesized. The normal and osteoporotic fracture healings under this non‐invasive biophysical intervention of LIPUS were compared and investigated. Closed femoral fracture procedures were performed on 120 Sprague–Dawley rats, in which 60 of them were ovariectomized (OVX). The rats were randomly assigned into four groups: sham OVX with treatment (Sham‐T), sham OVX control (Sham‐C), OVX with treatment (OVX‐T) and OXV control (OVX‐C). LIPUS treatment was 20 min a day, 5 days a week for durations of 2, 4, or 8 weeks. Results from weekly radiography, histomorphometry, micro‐computed tomography and mechanical test showed both the treatment groups were with better healing responses than their control groups. Moreover, between the normal and the osteoporotic treatment groups, a significantly higher (p = 0.015) callus width (week 4), higher ratio of increment in bone volume to tissue volume ratio value (7.4% more), faster response of endochondral ossification and a higher stiffness measurement were observed in the osteoporotic treatment group. These comparable results on healing responses imply that LIPUS can be applied clinically to enhance both normal and osteoporotic fracture healing. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:129–136, 2012     

Sildenafil accelerates fracture healing in mice

Sildenafil, a cyclic guanosine monophosphate (cGMP)‐dependent phospodiesterase‐5 inhibitor, has been shown to be a potent stimulator of angiogenesis through upregulation of pro‐angiogenic factors and control of cGMP concentration. Herein, we determined whether sildenafil also influences angiogenic growth factor expression and bone formation during the process of fracture healing. Bone healing was studied in a murine closed femur fracture model using radiological, biomechanical, histomorphometric, and protein biochemical analysis at 2 and 5 weeks after fracture. Thirty mice received 5 mg/kg body weight sildenafil p.o. daily. Controls (n = 30) received equivalent amounts of vehicle. After 2 weeks of fracture healing sildenafil significantly increased osseous fracture bridging, as determined radiologically and histologically. This resulted in an increased biomechanical stiffness compared to controls. A smaller callus area with a slightly reduced amount of cartilaginous tissue indicated an accelerated healing process. After 5 weeks the differences were found blunted, demonstrating successful healing in both groups. Western blot analysis showed a significantly higher expression of the pro‐angiogenic and osteogenic cysteine‐rich protein (CYR) 61, confirming the increase of bone formation. We show for the first time that sildenafil treatment accelerates fracture healing by enhancing bone formation, most probably by a CYR61‐associated pathway. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:867–873     

Differential gene expression and immunolocalization of insulin‐like growth factors and insulin‐like growth factor binding proteins between experimental nonunions and standard healing fractures

Insulin‐like growth factors (IGF‐I/II) are important growth factors in bone, and their actions are regulated by six IGF binding proteins (IGFBPs). However, little is known about their exact functions in fracture healing. The aim of this study was to compare the gene expression and immunolocalization of IGFs and IGFBPs between standard healing fractures and nonunions using rat experimental models. Standard healing fractures and nonunions produced by periosteal cauterization at the fracture site were created in rat femurs. At postfracture days 3, 7, 10, 14, 21, and 28, total RNA was extracted from the callus of the healing fractures and the fibrous tissue of the nonunions, and gene expression were analyzed by real‐time PCR. Additionally, immunolocalization of these proteins was studied by immunohistochemistry at postfracture days 7, 14, and 21. In nonunions, the gene expression of IGF‐I/II and IGFBP‐6 was significantly higher, and that of IGFBP‐5 was significantly lower at several time points. The immunolocalization of IGF‐I/II and IGFBP‐5 was widely distributed in both models. In contrast, that of IGFBP‐6 was barely detected in the fracture callus. In conclusion, our results suggest that IGFs/IGFBPs may have important roles not only in fracture healing but also in nonunion formation. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 29:1820–1826, 2011     

Elcatonin injections suppress systemic bone resorption without affecting cortical bone regeneration after drill‐hole injuries in mice

It is assumed that there are systemic changes in mineral metabolism during fracture healing that may cause a predisposition to sequential fractures in osteoporotic patients who suffered from previous fractures. Initial therapies for patients with osteoporotic fractures are important to prevent disabilities in daily life consequent to bone and muscle atrophies, and sequential fractures, although systemic and local bone metabolism during fracture healing have not been well understood. We evaluated the effects of bone injury and elcatonin injection as an initial therapy on systemic and local bone turnover and bone wound healing. Two drill holes were made in the diaphysis of the left femur and tibia of 12‐week‐old male C57BL/6J mice. They were treated with three doses of elcatonin or a vehicle thrice a week until the end of the 28‐day experiment. Urinary crosslinked C‐telopeptide of type I collagen (CTX) increased and the bone mineral densities (BMDs) in the lumbar vertebrae decreased in the vehicle‐treated mice. Elcatonin injection prevented increases in urinary CTX and reduction of the BMDs. In the noninjured femoral metaphysis, osteoclast surface increased until day 28, whereas elcatonin suppressed it. In the fracture site, elcatonin facilitated osteoblast proliferation and did not delay the healing of the bone defect. Bone injuries accelerated bone turnover systemically and locally, and the elcatonin injections suppressed the systemic acceleration of bone resorption without a delay of filling regenerated cortical bone in the bone defect. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1652–1658, 2009     

Delayed Chylothorax Following Blunt Chest Trauma

Chylothorax is a very rare disease, and its diagnosis following blunt chest trauma is exceptional. Only a small number of cases have been reported in the literature. We report a case of a male patient involved in a car accident presenting a delayed chylothorax after blunt chest trauma with a bilateral serial rib fracture and fracture of the ninth thoracic vertebrae. The therapy includes thorax drainage, dietary modifications with total parenteral nutrition and, in severe cases, PEEP ventilation. Hematological monitoring is mandatory to detect metabolic abnormalities resulting from chyle loss. Surgical treatment is only required in cases of persistent or increasing intrathoracal chyle flow. Thoracoscopic ligation of the thoracic duct is then required.     

Chylothorax after blunt chest trauma: a report of 2 cases

Chylothorax is a rare complication of blunt chest trauma and is associated with fracture-dislocation of the thoracic spine in only 20% of these cases. Two cases of chylothorax after blunt chest injury are described in this paper; 1 was related to a fracture of the third thoracic vertebra. Closed chest drainage and total parenteral nutrition led to resolution of the condition within 3 weeks in both cases. In general, traumatic chylothorax should be managed conservatively for at least 4 weeks before surgical intervention is considered.     

Inhibition of beta‐catenin signaling by Pb leads to incomplete fracture healing

There is strong evidence in the clinical literature to suggest that elevated lead (Pb) exposure impairs fracture healing. Since Pb has been demonstrated to inhibit bone formation, and Wnt signaling is an important anabolic pathway in chondrocyte maturation and endochondral ossification, we investigated the impact of Wnt therapy on Pb‐exposed mice undergoing bone repair in a mouse tibial fracture model. We established that tibial fracture calluses from Pb‐treated mice were smaller and contained less mineralized tissue than vehicle controls. This resulted in the persistence of immature cartilage in the callus and decreased β‐catenin levels. Reduction of β‐catenin protein was concurrent with systemic elevation of LRP5/6 antagonists DKK1 and sclerostin in Pb‐exposed mice throughout fracture healing. β‐catenin stimulation by the GSK3 inhibitor BIO reversed these molecular changes and restored the amount of mineralized callus. Overall, Pb is identified as a potent inhibitor of endochondral ossification in vivo with correlated effects on bone healing with noted deficits in β‐catenin signaling, suggesting the Wnt/β‐catenin as a pivotal pathway in the influence of Pb on fracture repair. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1397–1405, 2014.     

Role of hemorrhage in the induction of systemic inflammation and remote organ damage: Analysis of combined pseudo‐fracture and hemorrhagic shock

This study was performed to analyze the role of hemorrhage‐induced hypotension in the induction of systemic inflammation and remote organ dysfunction. Male C57/BL6 mice (6‐ to 10‐week old and 20–30 g) were used. Animals were either subjected to pseudo‐fracture [PF; standardized soft‐tissue injury and injection of crushed bone, PF group: n = 9], or PF combined with hemorrhagic shock (HS + PF group: n = 6). Endpoint was 6 h. Systemic inflammation was assessed by IL‐6 and IL‐10 levels. Myeloperoxidase (MPO) and NF‐κB activity in the lung and liver tissue were obtained to assess remote organ damage. The increases of systemic cytokines are similar for animals subjected to PF and PF + HS (IL‐6: 189 pg/ml ± 32.5 vs. 160 pg/ml ± 5.3; IL‐10: 60.3 pg/ml ± 15.8 vs. 88 pg/ml ± 32.4). Furthermore, the features (ALT; NF‐κB) of liver injury are equally elevated in mice subjected to PF (76.9 U/L ± 4.5) and HS + PF (80 U/L ± 5.5). Lung injury, addressed by MPO activity was more severe in group HS + PF (2.95 ng/ml ± 0.32) than in group PF (1.21 ng/ml ± 0.2). Both PF and additional HS cause a systemic inflammatory response. In addition, hemorrhage seems to be associated with remote affects on the lung. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 29:270–274, 2011