Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice

Norifumi Ohashi, Tomohide Hori, Florence Chen, Sura Jermanus, Akimasa Nakao, Shinji Uemoto, Justin H Nguyen

Research output: Contribution to journalArticle

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Abstract

AIM: To investigate the role of matrix metalloproteinase (MMP)-9 in the pathogenesis of postoperative liver failure (PLF) after extended hepatectomy (EH). METHODS: An insufficient volume of the remnant liver (RL) results in higher morbidity and mortality, and a murine model with 80%-hepatectomy was used. All investigations were performed 6 h after EH. Mice were first divided into two groups based on the postoperative course (i.e., the PLF caused or did not), and MMP-9 expression was measured by Western blotting. The source of MMP-9 was then determined by immunohistological stainings. Tissue inhibitor of metalloproteinase (TIMP)-1 is the endogenous inhibitor of MMP-9, and MMP-9 behavior was assessed by the experiments in wild-type, MMP-9(-/-) and TIMP-1(-/-) mice by Western blotting and gelatin zymography. The behavior of neutrophils was also assessed by immunohistological stainings. An anti-MMP-9 monoclonal antibody and a broadspectrum MMP inhibitor were used to examine the role of MMP-9. RESULTS: Symptomatic mice showed more severe PLF (histopathological assessments: 2.97 ± 0.92 vs 0.11 ± 0.08, P <0.05) and a higher expression of MMP-9 (71085 ± 18274 vs 192856 ± 22263, P <0.01). Nonnative leukocytes appeared to be the main source of MMP-9, because MMP-9 expression corresponding with CD11b positive-cell was observed in the findings of immunohistological stainings. In the histopathological findings, the PLF was improved in MMP-9(-/-) mice (1.65% ± 0.23% vs 0.65% ± 0.19%, P <0.01) and it was worse in TIMP-1(-/-) mice (1.65% ± 0.23% vs 1.78% ± 0.31%, P <0.01). Moreover, neutrophil migration was disturbed in MMP-9(-/-) mice in the immunohistological stainings. Two methods of MMP-9 inhibition revealed reduced PLF, and neutrophil migration was strongly disturbed in MMP-9-blocked mice in the histopathological assessments (9.6 ± 1.9 vs 4.2 ± 1.2, P <0.05, and 9.9 ± 1.5 vs 5.7 ± 1.1, P <0.05). CONCLUSION: MMP-9 is important for the process of PLF. The initial injury is associated with MMP-9 derived from neutrophils, and MMP-9 blockade reduces PLF. MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.

Original languageEnglish (US)
Pages (from-to)3027-3042
Number of pages16
JournalWorld Journal of Gastroenterology
Volume19
Issue number20
DOIs
StatePublished - 2013

Fingerprint

Matrix Metalloproteinase 9
Hepatectomy
Wounds and Injuries
Liver Failure
Neutrophils
Staining and Labeling
Tissue Inhibitor of Metalloproteinase-1
Matrix Metalloproteinase Inhibitors
Western Blotting
Liver
Gelatin

Keywords

  • Hepatectomy
  • Matrix metalloproteinase
  • Portal hypertension
  • Shear stress
  • Sinusoidal injury

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice. / Ohashi, Norifumi; Hori, Tomohide; Chen, Florence; Jermanus, Sura; Nakao, Akimasa; Uemoto, Shinji; Nguyen, Justin H.

In: World Journal of Gastroenterology, Vol. 19, No. 20, 2013, p. 3027-3042.

Research output: Contribution to journalArticle

Ohashi, Norifumi ; Hori, Tomohide ; Chen, Florence ; Jermanus, Sura ; Nakao, Akimasa ; Uemoto, Shinji ; Nguyen, Justin H. / Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice. In: World Journal of Gastroenterology. 2013 ; Vol. 19, No. 20. pp. 3027-3042.
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abstract = "AIM: To investigate the role of matrix metalloproteinase (MMP)-9 in the pathogenesis of postoperative liver failure (PLF) after extended hepatectomy (EH). METHODS: An insufficient volume of the remnant liver (RL) results in higher morbidity and mortality, and a murine model with 80{\%}-hepatectomy was used. All investigations were performed 6 h after EH. Mice were first divided into two groups based on the postoperative course (i.e., the PLF caused or did not), and MMP-9 expression was measured by Western blotting. The source of MMP-9 was then determined by immunohistological stainings. Tissue inhibitor of metalloproteinase (TIMP)-1 is the endogenous inhibitor of MMP-9, and MMP-9 behavior was assessed by the experiments in wild-type, MMP-9(-/-) and TIMP-1(-/-) mice by Western blotting and gelatin zymography. The behavior of neutrophils was also assessed by immunohistological stainings. An anti-MMP-9 monoclonal antibody and a broadspectrum MMP inhibitor were used to examine the role of MMP-9. RESULTS: Symptomatic mice showed more severe PLF (histopathological assessments: 2.97 ± 0.92 vs 0.11 ± 0.08, P <0.05) and a higher expression of MMP-9 (71085 ± 18274 vs 192856 ± 22263, P <0.01). Nonnative leukocytes appeared to be the main source of MMP-9, because MMP-9 expression corresponding with CD11b positive-cell was observed in the findings of immunohistological stainings. In the histopathological findings, the PLF was improved in MMP-9(-/-) mice (1.65{\%} ± 0.23{\%} vs 0.65{\%} ± 0.19{\%}, P <0.01) and it was worse in TIMP-1(-/-) mice (1.65{\%} ± 0.23{\%} vs 1.78{\%} ± 0.31{\%}, P <0.01). Moreover, neutrophil migration was disturbed in MMP-9(-/-) mice in the immunohistological stainings. Two methods of MMP-9 inhibition revealed reduced PLF, and neutrophil migration was strongly disturbed in MMP-9-blocked mice in the histopathological assessments (9.6 ± 1.9 vs 4.2 ± 1.2, P <0.05, and 9.9 ± 1.5 vs 5.7 ± 1.1, P <0.05). CONCLUSION: MMP-9 is important for the process of PLF. The initial injury is associated with MMP-9 derived from neutrophils, and MMP-9 blockade reduces PLF. MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.",
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T1 - Matrix metalloproteinase-9 in the initial injury after hepatectomy in mice

AU - Ohashi, Norifumi

AU - Hori, Tomohide

AU - Chen, Florence

AU - Jermanus, Sura

AU - Nakao, Akimasa

AU - Uemoto, Shinji

AU - Nguyen, Justin H

PY - 2013

Y1 - 2013

N2 - AIM: To investigate the role of matrix metalloproteinase (MMP)-9 in the pathogenesis of postoperative liver failure (PLF) after extended hepatectomy (EH). METHODS: An insufficient volume of the remnant liver (RL) results in higher morbidity and mortality, and a murine model with 80%-hepatectomy was used. All investigations were performed 6 h after EH. Mice were first divided into two groups based on the postoperative course (i.e., the PLF caused or did not), and MMP-9 expression was measured by Western blotting. The source of MMP-9 was then determined by immunohistological stainings. Tissue inhibitor of metalloproteinase (TIMP)-1 is the endogenous inhibitor of MMP-9, and MMP-9 behavior was assessed by the experiments in wild-type, MMP-9(-/-) and TIMP-1(-/-) mice by Western blotting and gelatin zymography. The behavior of neutrophils was also assessed by immunohistological stainings. An anti-MMP-9 monoclonal antibody and a broadspectrum MMP inhibitor were used to examine the role of MMP-9. RESULTS: Symptomatic mice showed more severe PLF (histopathological assessments: 2.97 ± 0.92 vs 0.11 ± 0.08, P <0.05) and a higher expression of MMP-9 (71085 ± 18274 vs 192856 ± 22263, P <0.01). Nonnative leukocytes appeared to be the main source of MMP-9, because MMP-9 expression corresponding with CD11b positive-cell was observed in the findings of immunohistological stainings. In the histopathological findings, the PLF was improved in MMP-9(-/-) mice (1.65% ± 0.23% vs 0.65% ± 0.19%, P <0.01) and it was worse in TIMP-1(-/-) mice (1.65% ± 0.23% vs 1.78% ± 0.31%, P <0.01). Moreover, neutrophil migration was disturbed in MMP-9(-/-) mice in the immunohistological stainings. Two methods of MMP-9 inhibition revealed reduced PLF, and neutrophil migration was strongly disturbed in MMP-9-blocked mice in the histopathological assessments (9.6 ± 1.9 vs 4.2 ± 1.2, P <0.05, and 9.9 ± 1.5 vs 5.7 ± 1.1, P <0.05). CONCLUSION: MMP-9 is important for the process of PLF. The initial injury is associated with MMP-9 derived from neutrophils, and MMP-9 blockade reduces PLF. MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.

AB - AIM: To investigate the role of matrix metalloproteinase (MMP)-9 in the pathogenesis of postoperative liver failure (PLF) after extended hepatectomy (EH). METHODS: An insufficient volume of the remnant liver (RL) results in higher morbidity and mortality, and a murine model with 80%-hepatectomy was used. All investigations were performed 6 h after EH. Mice were first divided into two groups based on the postoperative course (i.e., the PLF caused or did not), and MMP-9 expression was measured by Western blotting. The source of MMP-9 was then determined by immunohistological stainings. Tissue inhibitor of metalloproteinase (TIMP)-1 is the endogenous inhibitor of MMP-9, and MMP-9 behavior was assessed by the experiments in wild-type, MMP-9(-/-) and TIMP-1(-/-) mice by Western blotting and gelatin zymography. The behavior of neutrophils was also assessed by immunohistological stainings. An anti-MMP-9 monoclonal antibody and a broadspectrum MMP inhibitor were used to examine the role of MMP-9. RESULTS: Symptomatic mice showed more severe PLF (histopathological assessments: 2.97 ± 0.92 vs 0.11 ± 0.08, P <0.05) and a higher expression of MMP-9 (71085 ± 18274 vs 192856 ± 22263, P <0.01). Nonnative leukocytes appeared to be the main source of MMP-9, because MMP-9 expression corresponding with CD11b positive-cell was observed in the findings of immunohistological stainings. In the histopathological findings, the PLF was improved in MMP-9(-/-) mice (1.65% ± 0.23% vs 0.65% ± 0.19%, P <0.01) and it was worse in TIMP-1(-/-) mice (1.65% ± 0.23% vs 1.78% ± 0.31%, P <0.01). Moreover, neutrophil migration was disturbed in MMP-9(-/-) mice in the immunohistological stainings. Two methods of MMP-9 inhibition revealed reduced PLF, and neutrophil migration was strongly disturbed in MMP-9-blocked mice in the histopathological assessments (9.6 ± 1.9 vs 4.2 ± 1.2, P <0.05, and 9.9 ± 1.5 vs 5.7 ± 1.1, P <0.05). CONCLUSION: MMP-9 is important for the process of PLF. The initial injury is associated with MMP-9 derived from neutrophils, and MMP-9 blockade reduces PLF. MMP-9 may be a potential target to prevent PLF after EH and to overcome an insufficient RL.

KW - Hepatectomy

KW - Matrix metalloproteinase

KW - Portal hypertension

KW - Shear stress

KW - Sinusoidal injury

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