Neutral endopeptidase (EC 3.4.24.11) downregulates the onset of intestinal inflammation in the nematode infected mouse.
OBJECTIVE
Substance P (SP) release from sensory nerves induces neurogenic inflammation. Neutral endopeptidase (NEP) degrades SP, thereby limiting its proinflammatory effects. Intestinal inflammation following Trichinella spiralis infection markedly downregulates NEP, resulting in diminished SP degradation, with unknown functional consequences. We hypothesised that diminished expression of NEP would exacerbate T spiralis induced enteritis.


METHODS
NEP knockout (NEP-/-) and wild-type (NEP+/+) mice were infected with T spiralis and studied at 6, 12, 24, and 48 hours post infection (PI). Tissue inflammation was quantified by computerised cell counting and myeloperoxidase activity (MPO). The leucocyte adhesion molecule, intercellular adhesion molecule 1 (ICAM-1), and SP were assessed by immunohistochemistry.


RESULTS
Before infection, the lack of NEP was not associated with changes in mucosal cellularity or MPO activity. Twelve hours PI, NEP-/- mice showed a 2.5-fold increase in MPO activity at a time when values in NEP+/+ mice were still within normal limits. MPO activity and cellularity peaked at 24 hours PI. This was accompanied by increased staining for both ICAM-1 and SP in NEP-/- mice. Infusion of rhNEP to NEP-/- mice significantly reduced MPO activity 24 hours PI.


CONCLUSIONS
These findings demonstrate that NEP downregulates the early onset of nematode intestinal inflammation and that increased bioavailability of SP and overexpression of ICAM-1 in NEP-/- mice likely play a role in the earlier onset of intestinal inflammation.
Barbara
G
G
Intestinal Disease Research Program and Gastrointestinal Division, Health Sciences Center, McMaster University, Hamilton, Ontario, Canada.
De Giorgio
R
R
Stanghellini
V
V
Corinaldesi
R
R
Cremon
C
C
Gerard
N
N
Gerard
C
C
Grady
E F
EF
Bunnett
N W
NW
Blennerhassett
P A
PA
Collins
S M
SM
D000818:Animals; D001920:Bradykinin / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007411:Intestinal Diseases, Parasitic / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000276:immunology / Q000469:parasitology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015260:Neprilysin / Q000235:genetics / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism*; D017160:Trichinella spiralis; D014235:Trichinellosis / Q000378:metabolism*
D018799:Intercellular Adhesion Molecule-1; D013373:Substance P; D015260:Neprilysin; D001920:Bradykinin