Harbord, Marcus William Nixon; (2002) Investigation of acute inflammation in Crohn's disease and chronic granulomatous disease. Doctoral thesis (Ph.D.), University College London (United Kingdom).

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Abstract

Neutrophil function is defective in Crohn's disease and chronic granulomatous disease (CGD). Patients with CGD develop a colitis that is indistinguishable from Crohn's disease. In order to develop a model to assess treatment strategies, colitis was studied in CGD mice. CGD mice did not develop colitis spontaneously. Colitis induced by dextran sodium sulphate augmented with human faecal flora produced self-limiting chronic inflammation. Chronic colitis did develop after oral administration of Diclofenac. Crystals developed in the lungs of CGD mice. They were shown to be composed of the protein Yml. This was located in neutrophil granules and gastric epithelial cells and demonstrated to have weak -hexosaminidase activity. In order to investigate inflammation in Crohn's disease, a method was developed to induce acute inflammation in humans using cantharidin blisters. Neutrophil migration into blisters was reduced in Crohn's disease, independent of blister fluid chemoldnes and cytokines. The respiratory burst of blister fluid macrophages was increased in Crohn's disease after stimulation with opsonised bacteria. Neutrophils isolated from venous blood of Crohn's disease patients demonstrated normal oxygen consumption. Digestion of radiolabelled bacteria by neutrophils was assessed in a small number of Crohn's disease patients and found to be normal. Experimental evidence suggested haploinsufficiency of p47phox as a possible cause of Crohn's disease. DNA from patients with inflammatory bowel disease was screened for this mutation. No excess in the p47phox haplotype was found. However, reduction in the p47phox gene to p47phox -pseudogene ratio was associated with Crohn's disease. Augmentation of neutrophil function by Granulocyte Colony Stimulating Factor (G- CSF) was assessed in Crohn's disease. Serum G-CSF was raised slightly in Crohn's disease. Two days G-CSF administration in vivo caused a reduction in venous neutrophil oxygen consumption and enhanced neutrophil penetration of cantharidin blisters, equally in control and Crohn's disease subjects. Therapy with G-CSF for one month may have improved the clinical condition of a minority of patients with Crohn's disease.

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