Plasminogen is essential for granulation tissue formation during the recovery process after liver injury in mice

Kawao, Naoyuki; Nagai, Nobuo; Ishida, Chiharu; Okada, Kiyotaka; Okumoto, Katsumi; Suzuki, Yasuhiro; Umemura, Kazuo; Ueshima, Shigeru; Matsuo, Osamu

doi:10.1111/j.1538-7836.2010.03870.x

Cited by 12 publications

(39 citation statements)

References 26 publications

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“…The plasminogen knockout mice ( Plg −/−) and their wild-type littermates ( Plg +/+) with mixed backgrounds of C57BL/6J (75%) and 129/SvJ (25%) were used for generating the PIT-LD models [5], [6]. Male SHRSP/Kpo rats (Experimental Animal Facility at Kinki University School of Medicine) were used as a spontaneous stroke model.…”

Section: Methodsmentioning

confidence: 99%

“…The MCAO, PIT-BD and PIT-LD models were generated as previously described [3], [6]. Briefly, these mouse models were generated as follows.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous studies, for instance, surgical manipulation to create the model was required on dozens of animals for each experiment, and the brains or livers of several treated animals and matched controls were sampled at defined time-points after surgical induction of the disease (e.g., on days 1, 4, 7 and 14). The organs from each animal were subsequently fixed, sectioned, stained, and examined histologically to measure the injured area of each organ from its serial sections [3], [6]. The lesion volumes were roughly estimated from the lesion area and thickness of each section.…”

Section: Introductionmentioning

confidence: 99%

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In Vivo Diagnostic Imaging Using Micro-CT: Sequential and Comparative Evaluation of Rodent Models for Hepatic/Brain Ischemia and Stroke

et al. 2012

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BackgroundThere is an increasing need for animal disease models for pathophysiological research and efficient drug screening. However, one of the technical barriers to the effective use of the models is the difficulty of non-invasive and sequential monitoring of the same animals. Micro-CT is a powerful tool for serial diagnostic imaging of animal models. However, soft tissue contrast resolution, particularly in the brain, is insufficient for detailed analysis, unlike the current applications of CT in the clinical arena. We address the soft tissue contrast resolution issue in this report.MethodologyWe performed contrast-enhanced CT (CECT) on mouse models of experimental cerebral infarction and hepatic ischemia. Pathological changes in each lesion were quantified for two weeks by measuring the lesion volume or the ratio of high attenuation area (%HAA), indicative of increased vascular permeability. We also compared brain images of stroke rats and ischemic mice acquired with micro-CT to those acquired with 11.7-T micro-MRI. Histopathological analysis was performed to confirm the diagnosis by CECT.Principal FindingsIn the models of cerebral infarction, vascular permeability was increased from three days through one week after surgical initiation, which was also confirmed by Evans blue dye leakage. Measurement of volume and %HAA of the liver lesions demonstrated differences in the recovery process between mice with distinct genetic backgrounds. Comparison of CT and MR images acquired from the same stroke rats or ischemic mice indicated that accuracy of volumetric measurement, as well as spatial and contrast resolutions of CT images, was comparable to that obtained with MRI. The imaging results were also consistent with the histological data.ConclusionsThis study demonstrates that the CECT scanning method is useful in rodents for both quantitative and qualitative evaluations of pathologic lesions in tissues/organs including the brain, and is also suitable for longitudinal observation of the same animals.

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Section: Methodsmentioning

confidence: 99%

“…The MCAO, PIT-BD and PIT-LD models were generated as previously described [3], [6]. Briefly, these mouse models were generated as follows.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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In Vivo Diagnostic Imaging Using Micro-CT: Sequential and Comparative Evaluation of Rodent Models for Hepatic/Brain Ischemia and Stroke

et al. 2012

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“…The sections were processed for hematoxylin and eosin staining. Immunostaining with ALP, osterix, BrdU, or CD31 was performed as described previously (25,26,29). Briefly, the sections were incubated with anti-ALP antibody at a dilution of 1:100, anti-osterix antibody at a dilution of 1:200, anti-BrdU antibody at a dilution of 1:300, or anti-CD31 antibody at a dilution of 1:100, followed by incubation with the appropriate secondary antibody conjugated with horseradish peroxidase.…”

Section: Methodsmentioning

confidence: 99%

“…The mice received eight intraperitoneal injections of BrdU at 100 mg/kg every 12 h immediately after the production of the femoral bone defect, and they were euthanized on day 4 (25,28). Double-staining for BrdU and osterix was performed as described above.…”

Section: Methodsmentioning

confidence: 99%

Tissue-type plasminogen activator deficiency delays bone repair: roles of osteoblastic proliferation and vascular endothelial growth factor

Kawao

Tamura

Okumoto

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Further development in research of bone regeneration is necessary to meet the clinical demand for bone reconstruction. Recently, we reported that plasminogen is crucial for bone repair through enhancement of vessel formation. However, the details of the role of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) in the bone repair process still remain unknown. Herein, we examined the effects of plasminogen activators on bone repair after a femoral bone defect using tPA-deficient ( tPA−/−) and uPA-deficient ( uPA−/−) mice. Bone repair of the femur was delayed in tPA−/− mice, unlike that in wild-type ( tPA+/+) mice. Conversely, the bone repair was comparable between wild-type ( uPA+/+) and uPA−/− mice. The number of proliferative osteoblasts was decreased at the site of bone damage in tPA−/− mice. Moreover, the proliferation of primary calvarial osteoblasts was reduced in tPA−/− mice. Recombinant tPA facilitated the proliferation of mouse osteoblastic MC3T3-E1 cells. The proliferation enhanced by tPA was antagonized by the inhibition of endogenous annexin 2 by siRNA and by the inhibition of extracellular signal-regulated kinase (ERK)1/2 phosphorylation in MC3T3-E1 cells. Vessel formation as well as the levels of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1α (HIF-1α) were decreased at the damaged site in tPA−/− mice. Our results provide novel evidence that tPA is crucial for bone repair through the facilitation of osteoblast proliferation related to annexin 2 and ERK1/2 as well as enhancement of vessel formation related to VEGF and HIF-1α at the site of bone damage.

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Plasminogen Plays a Crucial Role in Bone Repair

Kawao

Tamura

Okumoto

et al. 2013

Journal of Bone and Mineral Research

105

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The further development in research of bone regeneration is necessary to meet the clinical demand for bone reconstruction. Plasminogen is a critical factor of the tissue fibrinolytic system, which mediates tissue repair in the skin and liver. However, the role of the fibrinolytic system in bone regeneration remains unknown. Herein, we investigated bone repair and ectopic bone formation using plasminogen-deficient (Plg -/-) mice. Bone repair of the femur is delayed in Plg -/-mice, unlike that in the wild-type (Plg þ/þ ) mice. The deposition of cartilage matrix and osteoblast formation were both decreased in Plg -/-mice. Vessel formation, macrophage accumulation, and the levels of vascular endothelial growth factor (VEGF) and transforming growth factor-b (TGF-b) were decreased at the site of bone damage in Plg -/-mice. Conversely, heterotopic ossification was not significantly different between Plg þ/þ and Plg -/-mice. Moreover, angiogenesis, macrophage accumulation, and the levels of VEGF and TGF-b were comparable between Plg þ/þ and Plg -/-mice in heterotopic ossification. Our data provide novel evidence that plasminogen is essential for bone repair. The present study indicates that plasminogen contributes to angiogenesis related to macrophage accumulation, TGF-b, and VEGF, thereby leading to the enhancement of bone repair.

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Plasminogen is essential for granulation tissue formation during the recovery process after liver injury in mice

Cited by 12 publications

References 26 publications

In Vivo Diagnostic Imaging Using Micro-CT: Sequential and Comparative Evaluation of Rodent Models for Hepatic/Brain Ischemia and Stroke

In Vivo Diagnostic Imaging Using Micro-CT: Sequential and Comparative Evaluation of Rodent Models for Hepatic/Brain Ischemia and Stroke

Tissue-type plasminogen activator deficiency delays bone repair: roles of osteoblastic proliferation and vascular endothelial growth factor

Plasminogen Plays a Crucial Role in Bone Repair

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