Substance P promotes production of the inflammatory mediator leukotriene B4 during acute pancreatitis, which causes neutrophils to reverse-migrate into the bloodstream and damage the lungs.
2 druggable targets identifiedBoth the substance P receptor (NK-1) and the LTB4 receptor (BLT1) can be blocked to reduce pancreatitis-associated lung injury in mice
What the researchers found
In two mouse models of acute pancreatitis (caerulein/LPS and L-arginine), LTB4 and its receptor BLT1 were markedly upregulated. Blocking BLT1 with the antagonist LY293111 achieved three effects: attenuated pancreatitis severity, decreased neutrophil reverse transendothelial migration (rTEM) into the circulation, and alleviated acute lung injury severity.
In vitro, substance P treatment of pancreatic acinar cells increased LTB4 production through activation of protein kinase Cα (PKCα) and MAP kinases (ERK, p38, JNK). Blocking substance P's neurokinin-1 receptor with CP96345 significantly reduced pancreatitis severity and LTB4 levels. The complete pathway: substance P → NK-1 receptor → PKCα/MAPK → LTB4 production → BLT1 activation → neutrophil reverse migration → lung injury.
Why it matters
Acute lung injury is one of the most dangerous complications of severe pancreatitis, contributing significantly to mortality. This study reveals a specific and potentially druggable pathway: substance P drives LTB4-mediated neutrophil reverse migration that damages the lungs. Since both NK-1 receptor antagonists and LTB4 receptor blockers already exist as drugs, this pathway could be targeted to prevent lung damage in pancreatitis patients — a setting where few effective treatments currently exist.
How the study worked
Two in vivo acute pancreatitis models were used in BALB/c mice: caerulein plus lipopolysaccharide, and L-arginine. LTB4 levels and BLT1 expression were measured. The BLT1 antagonist LY293111 was used to block leukotriene signaling. Neutrophil reverse transendothelial migration was assessed. In vitro, pancreatic acinar cells were treated with substance P and analyzed for LTB4 production and PKCα/MAPK phosphorylation. The NK-1 receptor antagonist CP96345 was tested for its ability to reduce pancreatitis severity and LTB4 levels.
What this study cannot tell us
All experiments were conducted in mice, and the pancreatitis models (caerulein/LPS and L-arginine) are standardized but do not perfectly replicate the most common human cause — gallstone pancreatitis. The in vitro work used isolated pancreatic acinar cells, removing the complex multicellular environment of the pancreas. Specific quantitative measures of disease severity reduction are not detailed in the abstract. The study focused on acute effects; whether blocking this pathway remains effective in more severe or prolonged pancreatitis is unknown.
How to read the evidence
This is a preclinical study using two different mouse models of pancreatitis combined with in vitro mechanistic work. The use of multiple models and pharmacological blockade at different pathway steps provides strong mechanistic evidence, but no human data exists for this specific application.
When this study was published
Published in 2018, this study describes a relatively novel mechanism (neutrophil reverse migration) that continues to gain attention in critical care and inflammation research.
The bigger picture
Substance P is one of the most studied neuropeptides in pain and inflammation research. This work adds an important new dimension — showing how substance P contributes to distant organ injury through a specific inflammatory cascade. The concept of neutrophil reverse migration (neutrophils leaving an inflammation site and causing damage elsewhere) is a relatively new and increasingly recognized mechanism of multi-organ failure in critical illness. Understanding this process could have implications beyond pancreatitis, including sepsis, trauma, and other conditions where secondary lung injury occurs.
Questions still open
- Could NK-1 receptor antagonists (like aprepitant, already approved for nausea) be repurposed to prevent lung injury in acute pancreatitis patients?
- Does neutrophil reverse transendothelial migration contribute to lung injury in other critical illnesses like sepsis and major trauma?
- Is the substance P-LTB4 pathway also involved in other organ damage (kidney, liver) during severe pancreatitis?
Common questions
What is substance P and how does it cause inflammation?
What is neutrophil reverse migration and why is it dangerous?
Read the original research
Substance P-regulated leukotriene B4 production promotes acute pancreatitis-associated lung injury through neutrophil reverse migration.
International immunopharmacology, 57, 147-156
Citation
Li, Bin; Han, Xiao; Ye, Xin; Ni, Jianbo; Wu, Jianghong; Dai, Juanjuan; Wu, Zengkai; Chen, Congying; Wan, Rong; Wang, Xingpeng; Hu, Guoyong. (2018). Substance P-regulated leukotriene B4 production promotes acute pancreatitis-associated lung injury through neutrophil reverse migration.. International immunopharmacology, 57, 147-156. https://doi.org/10.1016/j.intimp.2018.02.017