Systemic protection through remote ischemic preconditioning is spread by platelet-dependent signaling in mice.
Remote ischemic preconditioning (RIPC), the repetitive transient mechanical obstruction of vessels at a limb remote to the operative site, is a novel strategy to mitigate distant organ injury associated with surgery. In the clinic, RIPC has demonstrated efficacy in protecting various organs against ischemia reperfusion (IR), but a common mechanism underlying the systemic protection has not been identified. Here, we reasoned that protection may rely on adaptive physiological responses toward local stress, as is incurred through RIPC. Standardized mouse models of partial hepatic IR and of RIPC to the femoral vascular bundle were applied. The roles of platelets, peripheral serotonin, and circulating vascular endothelial growth factor (Vegf) were studied in thrombocytopenic mice, Tph1(-) (/) (-) mice, and through neutralizing antibodies, respectively. Models of interleukin-10 (Il10) and matrix metalloproteinase 8 (Mmp8) deficiency were used to assess downstream effectors of organ protection. The protection against hepatic IR through RIPC was dependent on platelet-derived serotonin. Downstream of serotonin, systemic protection was spread through up-regulation of circulating Vegf. Both RIPC and serotonin-Vegf induced differential gene expression in target organs, with Il10 and Mmp8 displaying consistent up-regulation across all organs investigated. Concerted inhibition of both molecules abolished the protective effects of RIPC. RIPC was able to mitigate pancreatitis, indicating that it can protect beyond ischemic insults.


CONCLUSIONS
We have identified a platelet-serotonin-Vegf-Il10/Mmp8 axis that mediates the protective effects of RIPC. The systemic action, the conservation of RIPC effects among mice and humans, and the protection beyond ischemic insults suggest that the platelet-dependent axis has evolved as a preemptive response to local stress, priming the body against impending harm.
Laboratory of the Swiss Hepato-Pancreatico-Biliary (HPB) Center, Department of Surgery, University Hospital Zurich, Zurich, Switzerland.
Christian E
CE
Oberkofler
Perparim
P
Limani
Jae-Hwi
JH
Jang
Andreas
A
Rickenbacher
Kuno
K
Lehmann
Dimitri A
DA
Raptis
Udo
U
Ungethuem
Yinghua
Y
Tian
Kamile
K
Grabliauskaite
Rok
R
Humar
Rolf
R
Graf
Bostjan
B
Humar
Pierre-Alain
PA
Clavien
D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D004195:Disease Models, Animal; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019194:Ischemic Preconditioning / Q000379:methods*; D008099:Liver / Q000098:blood supply*; D020784:Matrix Metalloproteinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015427:Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D012701:Serotonin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013921:Thrombocytopenia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014365:Tryptophan Hydroxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000172:deficiency / Q000235:genetics / Q000378:metabolism
D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D012701:Serotonin; C487801:Tph1 protein, mouse; D014365:Tryptophan Hydroxylase; C576328:MMP8 protein, mouse; D020784:Matrix Metalloproteinase 8