Role of mast cells, neutrophils and nitric oxide in endotoxin-induced damage to the neonatal rat colon

TY - JOUR

T1 - Role of mast cells, neutrophils and nitric oxide in endotoxin-induced damage to the neonatal rat colon

AU - Brown, J. F.

AU - Chafee, K. A.

AU - Tepperman, B. L.

PY - 1998/1/1

Y1 - 1998/1/1

N2 - The mechanisms involved in mediating bacterial endotoxin lipopolysaccharide (LPS)-induced injury in the colon of neonatal rat pups aged 10-12 days was examined. Administration of LPS (3 mg kg-1, i.p.) caused a time-related increase in the plasma concentration of rat mast cell protease-II (RMCP-II) which was attenuated dose-dependently, by the non-selective mast cell stabilizer doxantrazole (0.05-5 mg kg-1, i.p.). The selective connective tissue mast cell stabilizer ketotifen (5-25 mg kg-1, i.p.) was without effect at the lower dose and had only a limited inhibitory effect at the higher dose. In addition, doxantrazole (5 mg kg-1, i.p.) inhibited mast cell degranulation in response to LPS in sections of neonatal rat colon, but ketotifen (5 mg kg-1, i.p.) was without effect.The increase in plasma RMCP-II concentration in response to LPS treatment preceded increases in tissue myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS) activity and tissue lipid peroxidation. These events were all attenuated by pretreatment with doxantrazole (5 mg kg-1, i.p.), antineutrophil serum (100 μl kg-1, i.p.), dexamethasone (2 mg kg-1, i.p.) and the selective iNOS inhibitor, aminoguanidine (25 mg kg-1, i.p.). In addition, lipid peroxidation was inhibited by pre-administration of the antioxidant enzymes superoxide dismutase (2000 u kg-1, i.p.) and catalase (2000 u kg-1, i.p.), the xanthine oxidase inhibitor allopurinol (100 mg kg-1, i.p.) and the peroxyl scavenger deferoxamine (10 mg kg-1, i.p.), suggesting the involvement of reactive oxygen metabolites in the colonic injury. These findings suggest that the sequence of events resulting in colonic damage in the neonatal rat following administration of LPS include mast cell degranulation, neutrophil infiltration, elevation in iNOS activity and subsequent lipid peroxidation.

AB - The mechanisms involved in mediating bacterial endotoxin lipopolysaccharide (LPS)-induced injury in the colon of neonatal rat pups aged 10-12 days was examined. Administration of LPS (3 mg kg-1, i.p.) caused a time-related increase in the plasma concentration of rat mast cell protease-II (RMCP-II) which was attenuated dose-dependently, by the non-selective mast cell stabilizer doxantrazole (0.05-5 mg kg-1, i.p.). The selective connective tissue mast cell stabilizer ketotifen (5-25 mg kg-1, i.p.) was without effect at the lower dose and had only a limited inhibitory effect at the higher dose. In addition, doxantrazole (5 mg kg-1, i.p.) inhibited mast cell degranulation in response to LPS in sections of neonatal rat colon, but ketotifen (5 mg kg-1, i.p.) was without effect.The increase in plasma RMCP-II concentration in response to LPS treatment preceded increases in tissue myeloperoxidase (MPO) activity, inducible nitric oxide synthase (iNOS) activity and tissue lipid peroxidation. These events were all attenuated by pretreatment with doxantrazole (5 mg kg-1, i.p.), antineutrophil serum (100 μl kg-1, i.p.), dexamethasone (2 mg kg-1, i.p.) and the selective iNOS inhibitor, aminoguanidine (25 mg kg-1, i.p.). In addition, lipid peroxidation was inhibited by pre-administration of the antioxidant enzymes superoxide dismutase (2000 u kg-1, i.p.) and catalase (2000 u kg-1, i.p.), the xanthine oxidase inhibitor allopurinol (100 mg kg-1, i.p.) and the peroxyl scavenger deferoxamine (10 mg kg-1, i.p.), suggesting the involvement of reactive oxygen metabolites in the colonic injury. These findings suggest that the sequence of events resulting in colonic damage in the neonatal rat following administration of LPS include mast cell degranulation, neutrophil infiltration, elevation in iNOS activity and subsequent lipid peroxidation.

KW - Aminoguanidine

KW - Colonic injury

KW - doxantrazole

KW - inducible nitric oxide synthase

KW - Lipopolysaccharide

KW - Myeloperoxidase

KW - Neonatal rats

KW - Rat mast cell protease II

UR - http://www.scopus.com/inward/record.url?scp=0031984074&partnerID=8YFLogxK

U2 - 10.1038/sj.bjp.0701576

DO - 10.1038/sj.bjp.0701576

M3 - Article

C2 - 9484851

AN - SCOPUS:0031984074

VL - 123

SP - 31

EP - 38

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 1476-5381

IS - 1

ER -