Hemorrhagic shock alters fracture callus composition and activates the IL6 and RANKL/OPG pathway in mice

Bundkirchen, Katrin; Macke, Christian; Angrisani, Nina; Schäck, Luisa Marilena; Noack, Sandra; Fehr, Michael; Krettek, Christian; Neunaber, Claudia

doi:10.1097/ta.0000000000001952

Cited by 13 publications

(12 citation statements)

References 24 publications

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“…Specifically, we saw that the initiation of bone formation (maximum in week 2–3), indicating the onset of the reparative phase, triggered bone resorption (maximum in week 3–4) with maximum osseous callus volumes in week 3. These observations are in line with cross-sectional histomorphometric analyses in similar defect models, where maximum callus area was seen in weeks 2 and 3 37–39 . From week 4 to week 6, bone formation and resorption continuously decreased to levels (BFR ≤1%/day; BRR ≤0.8%/day) seen in normal bone remodeling of trabecular and cortical bone in mice 14,40–43 , indicating proceeding towards the end of the healing process.…”

Section: Discussionsupporting

confidence: 89%

Evaluation of longitudinal time-lapsed in vivo micro-CT for monitoring fracture healing in mouse femur defect models

Wehrle

Betts

Kuhn

et al. 2019

Sci Rep

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Longitudinal in vivo micro-computed tomography (micro-CT) is of interest to non-invasively capture the healing process of individual animals in preclinical fracture healing studies. However, it is not known whether longitudinal imaging itself has an impact on callus formation and remodeling. In this study, a scan group received weekly micro-CT measurements (week 0–6), whereas controls were only scanned post-operatively and at week 5 and 6. Registration of consecutive scans using a branching scheme (bridged vs. unbridged defect) combined with a two-threshold approach enabled assessment of localized bone turnover and mineralization kinetics relevant for monitoring callus remodeling. Weekly micro-CT application did not significantly change any of the assessed callus parameters in the defect and periosteal volumes. This was supported by histomorphometry showing only small amounts of cartilage residuals in both groups, indicating progression towards the end of the healing period. Also, immunohistochemical staining of Sclerostin, previously associated with mediating adverse radiation effects on bone, did not reveal differences between groups. The established longitudinal in vivo micro-CT-based approach allows monitoring of healing phases in mouse femur defect models without significant effects of anesthesia, handling and radiation on callus properties. Therefore, this study supports application of longitudinal in vivo micro-CT for healing-phase-specific monitoring of fracture repair in mice.

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Section: Discussionsupporting

confidence: 89%

Evaluation of longitudinal time-lapsed in vivo micro-CT for monitoring fracture healing in mouse femur defect models

Wehrle

Betts

Kuhn

et al. 2019

Sci Rep

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show abstract

“…Specifically, we saw that the initiation of bone formation (maximum in week 2-3), indicating the onset of the reparative phase, triggered bone resorption (maximum in week 3-4) with maximum osseous callus volumes in week 3. These observations are in line with cross-sectional histomorphometric analyses in similar defect models, where maximum callus area was seen in weeks 2 and 3 37–39 . From week 4 to week 6, bone formation and resorption continuously decreased to levels (BFR ≤ 1%/day; BRR ≤ 0.8%/day) seen in normal bone remodeling of trabecular and cortical bone in mice 14,40–43 , indicating proceeding towards the end of the healing process.…”

Section: Discussionsupporting

confidence: 89%

Evaluation of longitudinal time-lapsedin vivomicro-CT for monitoring fracture healing in mouse femur defect models

Wehrle

Betts

Kuhn

et al. 2019

Preprint

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“…All surgical procedures were performed under deep inhalation anesthesia using isoflurane (Baxter Deutschland GmbH, Unterschleißheim, Germany) as described before ( 20 , 21 ). Interdigital reflexes were proofed regularly and the surgery began when this reflex was negative.…”

Section: Methodsmentioning

confidence: 99%

Acute Intoxication With Alcohol Reduces Trauma-Induced Proinflammatory Response and Barrier Breakdown in the Lung via the Wnt/β-Catenin Signaling Pathway

Noack

Bundkirchen

et al. 2022

Front. Immunol.

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BackgroundTrauma is the third leading cause of mortality worldwide. Upon admission, up to 50% of traumatized patients are acutely intoxicated with alcohol, which might lead to aberrant immune responses. An excessive and uncontrolled inflammatory response to injury is associated with damage to trauma-distant organs. We hypothesize that, along with inflammation-induced apoptosis, the activation of the Wnt/β-catenin signaling pathway would cause breakdown of the lung barrier and the development of lung injury after trauma. It remains unclear whether ethanol intoxication (EI) prior to trauma and hemorrhagic shock will attenuate inflammation and organ injury.MethodsIn this study, 14 male C57BL/6J mice were randomly assigned to two groups and exposed either to EtOH or to NaCl as a control by an oral gavage before receiving a femur fracture (Fx) and hemorrhagic shock, followed by resuscitation (THFx). Fourteen sham animals received either EtOH or NaCl and underwent surgical procedures without THFx induction. After 24 h, oil red O staining of fatty vacuoles in the liver was performed. Histological lung injury score (LIS) was assessed to analyze the trauma-induced RLI. Gene expression of Cxcl1, Il-1β, Muc5ac, Tnf, and Tnfrsf10b as well as CXCL1, IL-1β, and TNF protein levels in the lung tissue and bronchoalveolar lavage fluid were determined by RT-qPCR, ELISA, and immunohistological analyses. Infiltrating polymorphonuclear leukocytes (PMNLs) were examined via immunostaining. Apoptosis was detected by activated caspase-3 expression in the lung tissue. To confirm active Wnt signaling after trauma, gene expression of Wnt3a and its inhibitor sclerostin (Sost) was determined. Protein expression of A20 and RIPK4 as possible modulators of the Wnt signaling pathway was analyzed via immunofluorescence.ResultsSignificant fatty changes in the liver confirmed the acute EI. Histopathology and decreased Muc5ac expression revealed an increased lung barrier breakdown and concomitant lung injury after THFx versus sham. EI prior trauma decreased lung injury. THFx increased not only the gene expression of pro-inflammatory markers but also the pulmonary infiltration with PMNL and apoptosis versus sham, while EI prior to THFx reduced those changes significantly. EI increased the THFx-reduced gene expression of Sost and reduced the THFx-induced expression of Wnt3a. While A20, RIPK4, and membranous β-catenin were significantly reduced after trauma, they were enhanced upon EI.ConclusionThese findings suggest that acute EI alleviates the uncontrolled inflammatory response and lung barrier breakdown after trauma by suppressing the Wnt/β-catenin signaling pathway.

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Hemorrhagic shock alters fracture callus composition and activates the IL6 and RANKL/OPG pathway in mice

Abstract: Hemorrhagic shock has a retarding effect on fracture healing in the early phase of fracture healing and leads to activation of the IL6 and RANKL/OPG signaling pathways.

Cited by 13 publications

References 24 publications

Evaluation of longitudinal time-lapsed in vivo micro-CT for monitoring fracture healing in mouse femur defect models

Evaluation of longitudinal time-lapsed in vivo micro-CT for monitoring fracture healing in mouse femur defect models

Evaluation of longitudinal time-lapsedin vivomicro-CT for monitoring fracture healing in mouse femur defect models

Acute Intoxication With Alcohol Reduces Trauma-Induced Proinflammatory Response and Barrier Breakdown in the Lung via the Wnt/β-Catenin Signaling Pathway

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