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- Title
The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS.
- Authors
Fukatsu, Masahiko; Ohkawara, Hiroshi; Wang, Xintao; Alkebsi, Lobna; Furukawa, Miki; Mori, Hirotaka; Fukami, Miwa; Fukami, Shin-ichi; Sano, Takahiro; Takahashi, Hiroshi; Harada-Shirado, Kayo; Kimura, Satoshi; Sugimoto, Koichi; Ogawa, Kazuei; Ikezoe, Takayuki
- 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. Targeting Mer in lungs: Patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) exhibit tissue edema, alveolar collapse, and respiratory failure. After sepsis, patients with ALI/ARDS exhibit immune cell infiltration in the lungs and excessive amounts of pro-inflammatory cytokines, and treatment options are limited. Noting that the protein Gas6, which is a ligand of the receptor tyrosine kinase Mer, is increased in abundance in the plasma of patients with septic ALI/ARDS, Fukatsu et al. examined the effects of the Mer inhibitor UNC2250 on disease in mice subjected to inhalation of LPS, a model of ALI. The authors found that blocking Gas6-Mer signaling resulted in less inflammation, immune cell infiltration, and lung damage in the lungs in mice, resulting in decreased mortality, as well as inhibiting immune cell proliferation in vitro. Together, these findings suggest that therapeutically targeting Mer may help to treat the inflammatory responses in ALI/ARDS.
- Subjects
RESPIRATORY distress syndrome; ADULT respiratory distress syndrome; INFLAMMATION; SEPSIS; INHIBITION of cellular proliferation; PROTEIN-tyrosine kinases; CD14 antigen
- Publication
Science Signaling, 2022, Vol 15, Issue 724, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.abd2533