Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice

S. Yoshida, N. Minematsu, Shotaro Chubachi, H. Nakamura, M. Miyazak, K. Tsuduki, S. Takahashi, T. Miyasho, T. Iwabuchi, R. Takamiya, H. Tateno, M. Mouded, S. D. Shapiro, K. Asano, Tomoko Betsuyaku

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Abstract

Efferocytosis is believed to be a key regulator for lung inflammation in chronic obstructive pulmonary disease. In this study we pharmacologically inhibited efferocytosis with annexin V and attempted to determine its impact on the progression of pulmonary emphysema in mouse. We first demonstrated in vitro and in vivo efferocytosis experiments using annexin V, an inhibitor for phosphatidylserinemediated efferocytosis. We then inhibited efferocytosis in porcine pancreatic elastase (PPE)-treated mice. PPE-treated mice were instilled annexin V intranasally starting from day 8 until day 20. Mean linear intercept (Lm) was measured, and cell apoptosis was assessed in lung specimen obtained on day 21. Cell profile, apoptosis, and mRNA expression of matrix metalloproteinases (MMPs) and growth factors were evaluated in bronchoalveolar lavage (BAL) cells on day 15. Annexin V attenuated macrophage efferocytosis both in vitro and in vivo. PPE-treated mice had a significant higher Lm, and annexin V further increased that by 32%. More number of macrophages was found in BAL fluid in this group. Interestingly, cell apoptosis was not increased by annexin V treatment both in lung specimens and BAL fluid, but macrophages from mice treated with both PPE and annexin V expressed higher MMP-2 mRNA levels and had a trend for higher MMP-12 mRNA expression. mRNA expression of keratinocyte growth factor tended to be downregulated. We showed that inhibited efferocytosis with annexin V worsened elastase-induced pulmonary emphysema in mice, which was, at least partly, attributed to a lack of phenotypic change in macrophages toward anti-inflammatory one.

Original languageEnglish
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume303
Issue number10
DOIs
Publication statusPublished - 2012 Nov 15

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Pulmonary Emphysema
Pancreatic Elastase
Annexin A5
Macrophages
Bronchoalveolar Lavage Fluid
Swine
Messenger RNA
Apoptosis
Matrix Metalloproteinase 12
Fibroblast Growth Factor 7
Matrix Metalloproteinase 2
Bronchoalveolar Lavage
Matrix Metalloproteinases
Chronic Obstructive Pulmonary Disease
Intercellular Signaling Peptides and Proteins
Pneumonia
Anti-Inflammatory Agents
Down-Regulation
Lung

Keywords

  • COPD
  • Macrophage phenotype
  • Matrix metalloproteinase
  • Phosphatidylserine

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology
  • Physiology

Cite this

Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice. / Yoshida, S.; Minematsu, N.; Chubachi, Shotaro; Nakamura, H.; Miyazak, M.; Tsuduki, K.; Takahashi, S.; Miyasho, T.; Iwabuchi, T.; Takamiya, R.; Tateno, H.; Mouded, M.; Shapiro, S. D.; Asano, K.; Betsuyaku, Tomoko.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 303, No. 10, 15.11.2012.

Research output: Contribution to journalArticle

Yoshida, S, Minematsu, N, Chubachi, S, Nakamura, H, Miyazak, M, Tsuduki, K, Takahashi, S, Miyasho, T, Iwabuchi, T, Takamiya, R, Tateno, H, Mouded, M, Shapiro, SD, Asano, K & Betsuyaku, T 2012, 'Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice', American Journal of Physiology - Lung Cellular and Molecular Physiology, vol. 303, no. 10. https://doi.org/10.1152/ajplung.00066.2012
Yoshida, S. ; Minematsu, N. ; Chubachi, Shotaro ; Nakamura, H. ; Miyazak, M. ; Tsuduki, K. ; Takahashi, S. ; Miyasho, T. ; Iwabuchi, T. ; Takamiya, R. ; Tateno, H. ; Mouded, M. ; Shapiro, S. D. ; Asano, K. ; Betsuyaku, Tomoko. / Annexin V decreases PS-mediated macrophage efferocytosis and deteriorates elastase-induced pulmonary emphysema in mice. In: American Journal of Physiology - Lung Cellular and Molecular Physiology. 2012 ; Vol. 303, No. 10.
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abstract = "Efferocytosis is believed to be a key regulator for lung inflammation in chronic obstructive pulmonary disease. In this study we pharmacologically inhibited efferocytosis with annexin V and attempted to determine its impact on the progression of pulmonary emphysema in mouse. We first demonstrated in vitro and in vivo efferocytosis experiments using annexin V, an inhibitor for phosphatidylserinemediated efferocytosis. We then inhibited efferocytosis in porcine pancreatic elastase (PPE)-treated mice. PPE-treated mice were instilled annexin V intranasally starting from day 8 until day 20. Mean linear intercept (Lm) was measured, and cell apoptosis was assessed in lung specimen obtained on day 21. Cell profile, apoptosis, and mRNA expression of matrix metalloproteinases (MMPs) and growth factors were evaluated in bronchoalveolar lavage (BAL) cells on day 15. Annexin V attenuated macrophage efferocytosis both in vitro and in vivo. PPE-treated mice had a significant higher Lm, and annexin V further increased that by 32{\%}. More number of macrophages was found in BAL fluid in this group. Interestingly, cell apoptosis was not increased by annexin V treatment both in lung specimens and BAL fluid, but macrophages from mice treated with both PPE and annexin V expressed higher MMP-2 mRNA levels and had a trend for higher MMP-12 mRNA expression. mRNA expression of keratinocyte growth factor tended to be downregulated. We showed that inhibited efferocytosis with annexin V worsened elastase-induced pulmonary emphysema in mice, which was, at least partly, attributed to a lack of phenotypic change in macrophages toward anti-inflammatory one.",
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AU - Miyazak, M.

AU - Tsuduki, K.

AU - Takahashi, S.

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AU - Takamiya, R.

AU - Tateno, H.

AU - Mouded, M.

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N2 - Efferocytosis is believed to be a key regulator for lung inflammation in chronic obstructive pulmonary disease. In this study we pharmacologically inhibited efferocytosis with annexin V and attempted to determine its impact on the progression of pulmonary emphysema in mouse. We first demonstrated in vitro and in vivo efferocytosis experiments using annexin V, an inhibitor for phosphatidylserinemediated efferocytosis. We then inhibited efferocytosis in porcine pancreatic elastase (PPE)-treated mice. PPE-treated mice were instilled annexin V intranasally starting from day 8 until day 20. Mean linear intercept (Lm) was measured, and cell apoptosis was assessed in lung specimen obtained on day 21. Cell profile, apoptosis, and mRNA expression of matrix metalloproteinases (MMPs) and growth factors were evaluated in bronchoalveolar lavage (BAL) cells on day 15. Annexin V attenuated macrophage efferocytosis both in vitro and in vivo. PPE-treated mice had a significant higher Lm, and annexin V further increased that by 32%. More number of macrophages was found in BAL fluid in this group. Interestingly, cell apoptosis was not increased by annexin V treatment both in lung specimens and BAL fluid, but macrophages from mice treated with both PPE and annexin V expressed higher MMP-2 mRNA levels and had a trend for higher MMP-12 mRNA expression. mRNA expression of keratinocyte growth factor tended to be downregulated. We showed that inhibited efferocytosis with annexin V worsened elastase-induced pulmonary emphysema in mice, which was, at least partly, attributed to a lack of phenotypic change in macrophages toward anti-inflammatory one.

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