The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS.

Abstract

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.

• Authors: Masahiko Fukatsu, Hiroshi Ohkawara, Xintao Wang, Lobna Alkebsi, Miki Furukawa, Hirotaka Mori, Miwa Fukami, Shin-Ichi Fukami, Takahiro Sano, Hiroshi Takahashi, Kayo Harada-Shirado, Satoshi Kimura, Koichi Sugimoto, Kazuei Ogawa, Takayuki Ikezoe
• Journal: Science signaling (Sci Signal) Vol. 15 Issue 724 Pg. eabd2533 (03 08 2022) ISSN: 1937-9145 [Electronic] United States
• PMID: 35258998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lipopolysaccharides

Topics

• Animals
• Endothelial Cells (metabolism)
• Humans
• Lipopolysaccharides (pharmacology)
• Lung (metabolism)
• Mice
• Mice, Inbred C57BL
• Respiratory Distress Syndrome (chemically induced, drug therapy)
• Sepsis (metabolism)