Background: Sepsis is a life-threatening condition caused by infection. Substance P (SP), encoded by the preprotachykinin A (PPTA) gene, acts as an inflammatory mediator in sepsis. Fenestrated liver sinusoidal endothelial... [ view full abstract ]
Background: Sepsis is a life-threatening condition caused by infection. Substance P (SP), encoded by the preprotachykinin A (PPTA) gene, acts as an inflammatory mediator in sepsis. Fenestrated liver sinusoidal endothelial cells (LSECs), forming the “liver sieve”, regulate the metabolism of circulating inflammatory mediators. We have recently shown that sepsis is associated with disruption of the liver sieve.
Objective: To determine whether SP plays a role in the disruption of the liver sieve in caecal-ligation and puncture (CLP)-induced sepsis in mice.
Materials & methods: Adult wild-type (WT) and PPTA-deficient (PPTA-KO) mice were assigned into control (sham) or experimental (sepsis) groups. Sepsis was induced by CLP, and after 8 hours, mice were sacrificed and liver samples were processed for scanning electron microscopy. Diameter, frequency, porosity and gap area of the liver sieve were calculated.
Results: Sepsis induced damage to the LSEC fenestrae, as seen by a reduction in frequency (6.40±2.49 vs 10.63±1.54, p<0.05) and porosity (11.05±3.23 vs 18.44±2.18%, p<0.01) and increased gaps (0.12 ± 0.02 vs 0.06±0.01, p<0.05) compared to sham control in WT mice. However, LSEC morphology was preserved in PPTA-KO sepsis mice, with maintenance of patent fenestrations (frequency: 9.05±0.94 vs 10.63±1.54; porosity: 15.71±2.19 vs 18.44±2.18%) and fewer gaps (0.09±0.01 vs 0.06±0.01) when compared to WT mice.
Conclusion: These results suggest that SP, encoded by the PPTA gene, plays an important role in the liver sieve disruption in sepsis.
Keywords: Substance P, Preprotachykinin A, Sepsis, Liver Sieve, Inflammation.
Acknowledgements: University of Otago and University of Sydney.
