ROLE OF MAST-CELLS, NEUTROPHILS AND NITRIC-OXIDE IN ENDOTOXIN-INDUCEDDAMAGE TO THE NEONATAL RAT COLON

1 The mechanisms involved in mediating bacterial endotoxin lipopolysac charide (LPS)-induced injury in the colon of neonatal rat pups aged 10 -12 days was examined. 2 Administration of LPS (3 mg kg(-1), i.p.) cau sed a time-related increase in the plasma concentration of rat mast ce ll 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. 3 In addition, doxant razole (5 mg kg(-1), i.p.) inhibited mast cell degranulation in respon se to LPS in sections of neonatal rat colon, but ketotifen (5 mg kg(-1 ), i.p.) was without effect. 4 The increase in plasma RMCP-II concentr ation in response to LPS treatment preceded increases in tissue myelop eroxidase (MPO) activity, inducible nitric oxide synthase (iNOS) activ ity and tissue lipid peroxidation. These events were all attenuated by pretreatment with doxantrazole (5 mg kg(-1), i.p.), antineutrophil se rum (100 mu l kg(-1) i.p.), dexamethasone (2 mg kg(-1), i.p.) and the selective iNOS inhibitor, aminoguanidine (25 mg kg(-1), i.p.). 5 In ad dition, lipid peroxidation was inhibited by pre-administration of the antioxidant enzymes superoxide dismutase (2000 u kg(-1), i.p.) and cat alase (2000 u kg(-1), i.p.), the xanthine oxidase inhibitor allopurino l (100 mg kg(-1), i.p.) and the peroxyl scavenger deferoxamine (10 mg kg(-1), i.p.), suggesting the involvement of reactive oxygen metabolit es in the colonic injury. 6 These findings suggest that the sequence o f events resulting in colonic damage in the neonatal rat following adm inistration of LPS include mast cell degranulation, neutrophil infiltr ation, elevation in iNOS activity and subsequent lipid peroxidation.