The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS
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- Masahiko Fukatsu
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Hiroshi Ohkawara
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Xintao Wang
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Lobna Alkebsi
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Miki Furukawa
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Hirotaka Mori
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Miwa Fukami
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Shin-ichi Fukami
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Takahiro Sano
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Hiroshi Takahashi
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Kayo Harada-Shirado
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Satoshi Kimura
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Koichi Sugimoto
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan.
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- Kazuei Ogawa
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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- Takayuki Ikezoe
- Department of Hematology, Fukushima Medical University, Fukushima, Japan.
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説明
<jats:p>The pathogenesis of sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has not yet been fully elucidated. Growth arrest–specific 6 (Gas6) has marked effects on hemostasis and reduces inflammation through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Here, we found that plasma concentrations of Gas6 and soluble Mer were greater in patients with severe sepsis or septic ALI/ARDS compared with those in normal healthy donors. To determine whether the Gas6-Mer axis was critical in the pathogenesis of ALI/ARDS, we investigated the effects of intravenous administration of the selective Mer inhibitor UNC2250 on lipopolysaccharide (LPS)–induced ALI in mouse models subjected to inhalation of LPS. UNC2250 markedly inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of Gas6 and Mer proteins, severe lung damage, and increased amounts of reactive oxygen species (ROS) in LPS-induced ALI in mice. In human pulmonary aortic endothelial cells, LPS induced decreases in the amounts of endothelial nitric oxide synthase, thrombomodulin, and vascular endothelial–cadherin, which was blocked by treatment with UNC2250. UNC2250 also inhibited the LPS-dependent increases in cell proliferation and enhanced apoptosis in HL-60 cells, a human neutrophil–like cell line, and RAW264.7 cells, a mouse monocyte/macrophage cell line. These data provide insights into the potential multiple beneficial effects of the Mer inhibitor UNC2250 as a therapeutic reagent to treat inflammatory responses in ALI/ARDS.</jats:p>
収録刊行物
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- Science Signaling
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Science Signaling 15 (724), 2022-03-08
American Association for the Advancement of Science (AAAS)