TY - JOUR
T1 - SPRED2 deficiency may lead to lung ischemia–reperfusion injury via ERK1/2 signaling pathway activation
AU - Okada, Masanori
AU - Yamane, Masaomi
AU - Yamamoto, Sumiharu
AU - Otani, Shinji
AU - Miyoshi, Kentaroh
AU - Sugimoto, Seiichiro
AU - Matsukawa, Akihiro
AU - Toyooka, Shinichi
AU - Oto, Takahiro
AU - Miyoshi, Shinichiro
N1 - Funding Information:
We used C57BL/6 wild-type (WT) and Spred2−/−mice (7–10 weeks old, approximately 25–35 g). Spred2−/− mice were generated as previously described [27, 28]. These mice were bred and maintained in specific pathogen-free conditions at the Department of Animal Resources, Okayama University (Okayama, Japan). The Animal Care Committee at Okayama University reviewed and approved all aspects of our experimental protocol before experimentation. All experimental mice received humane care in accordance with the “Principles of Laboratory Animal Care” of the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals”, prepared by the National Academy of Science and published by the National Institutes of Health (NIH).
Publisher Copyright:
© 2018, Springer Nature Singapore Pte Ltd.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Purpose: Inflammatory changes during lung ischemia–reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. Methods: C57BL/6 wild-type (WT) and Spred2−/− mice were used in the left hilar clamp model. Experimental groups underwent 30 min of left hilar clamping followed by 1 h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2−/− mice with reperfused lungs. Results: The partial pressures of oxygen of the Spred2−/− mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2−/− mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2−/− mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). Conclusion: The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI.
AB - Purpose: Inflammatory changes during lung ischemia–reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. Methods: C57BL/6 wild-type (WT) and Spred2−/− mice were used in the left hilar clamp model. Experimental groups underwent 30 min of left hilar clamping followed by 1 h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2−/− mice with reperfused lungs. Results: The partial pressures of oxygen of the Spred2−/− mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2−/− mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2−/− mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). Conclusion: The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI.
KW - Extracellular signal-regulated kinase
KW - Ischemia reperfusion injury
KW - Lung transplantation
KW - Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (Spreds)
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U2 - 10.1007/s00595-018-1696-x
DO - 10.1007/s00595-018-1696-x
M3 - Article
C2 - 30022248
AN - SCOPUS:85050208584
VL - 48
SP - 1089
EP - 1095
JO - Japanese Journal of Surgery
JF - Japanese Journal of Surgery
SN - 0941-1291
IS - 12
ER -