Substance P is an early mediator of peritoneal fibrinolytic pathway genes and promotes intra-abdominal adhesion formation

Background: The substance P (SP) or neurokinin-1 receptor pathway has been implicated in intra-abdominal adhesion formation, in large part through its effects on peritoneal fibrinolysis. This study investigates the role of SP as an early mediator of the messenger RNA (mRNA) expression of key components of the peritoneal fibrinolytic system and other fundamental adhesiogenic pathways. Materials and methods: Intra-abdominal adhesions were surgically induced in 28 rats using the ischemic button model. mRNA levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), hypoxia-inducible factors (HIFs) 1α and 2α, and vascular endothelial growth factor A (VEGF-A) were measured in adhesive button tissue taken at time 0 and 1, 3, 6, 12, and 24 h after surgery in rats receiving an intraoperative peritoneal bolus (25 mg/kg) of a neurokinin-1 receptor antagonist (NK-1RA) or saline. Peritoneal fluid fibrinolytic activity was measured in peritoneal lavages taken at the same time points. Results: SP levels increased (P ≤ 0.05) within 1 h postoperatively followed by an increase (P ≤ 0.05) in tPA mRNA expression from 3 to 6 h after surgery along with a striking increase (P ≤ 0.05) in PAI-1 mRNA expression from 3 to 12 h. NK-1RA administration further increased (P ≤ 0.05) tPA mRNA expression and significantly blunted the increase in PAI-1 mRNA levels. The NK-1RA increased (P ≤ 0.05) fitbrinolytic activity in peritoneal fluid at 3, 12, and 24 h after surgery. HIF-1α and VEGF-A mRNA expressions increased from 3 to 12 h (P ≤ 0.05) and from 1 to 3 h (P ≤ 0.05) after surgery, respectively, whereas HIF-2α mRNA expression steadily decreased. NK-1RA delayed the rise in HIF-1α mRNA and ablated the changes in HIF-2α and VEGF-A mRNAs. Conclusions: SP is a pleiotropic early regulator of mRNA levels of key adhesiogenic mediators after surgery, suggesting that it may be a viable therapeutic target.