Neutrophil generation

Oxatomide (l- 3- [4-(diphenylmethyl)-l-piperazinyl] propyl)-l,3-dihydro-2H-benzimidazol-2-one) is an antiallergy drug. Akamatsu has reported that oxatomide decreases neutrophil-generated superoxide anion and hydrogen peroxide formation in a dose-dependent manner. The authors hypothesize that the drug is inhibiting NADPH-dependent oxygen metabolism within the neutrophil (Akamatsu et al., 1993). 

Reactive nitrogen species are another factor of free radical damage in rheumatoid arthritis, although their role is less studied than that of oxygen radicals. Stichtenoth and Frolich [242] pointed out that the inhibition of nitric oxide synthesis had beneficial effects in humans. Mazzetti et al. [243] found that IL-1(3 stimulated NO production in RA chondrocytes. We demonstrated that NO synthase of RA neutrophils generated the enhanced amount of peroxynitrite [234]. Nitric oxide and oxygen radicals are also important inducers of death of human osteoarthritic synoviocytes [244]. 

The properties of GM-CSF and the GM-CSF receptor are given in section 2.2.4. GM-CSF acts on mature neutrophils over the concentration range 1-100 pM. It does not stimulate the generation of oxidant secretion in cells in suspension, but rather primes their ability to generate oxidants when the neutrophils are exposed to a second stimulus primed neutrophils generate greater levels of oxidants compared to unprimed neutrophils (see 7.2 for... 

IL-6 induces terminal maturation of B cells, promotes the growth of hy-bridoma/myeloma cells and T cells, and acts upon haematopoietic progenitors in synergy with IL-1 and IL-3. It also induces the production of acute-phase proteins by liver cells. In addition to its production by neutrophils, IL-6 is also synthesised by monocytes, T and B cells, fibroblasts, cardiac myxoma cells, some bladder carcinomas, cervical cancer cells and glioblastomas. Stimulated neutrophils generate about ten times less IL-6 (on a per-cell basis) than do monocytes. 

Several cytokines are in clinical use that support immune responses, such as IL-2, DFNs, or colony-stimulating factors. IL-2 supports the proliferation and effector ftmction of T-lymphocytes in immune compromised patients such as after prolonged dialysis or HIV infection. IFNs support antiviral responses or antitumoral activities of phagocytes, NK cells, and cytotoxic T-lymphocytes. Colony-stimulatory factors enforce the formation of mature blood cells from progenitor cells, e.g., after chemo- or radiotherapy (G-CSF to generate neutrophils, TPO to generate platelets, EPO to generate erythrocytes). 

The neutrophil is an interesting system in which to study signal transduction and response generation for a number of reasons ... 

Stevens, C.R., Bucurenci, N., Abbott, S.E., Sahinoglu, T, Blake, D.R, Naughton, D. and Grootveld, M. (1992). Application of methionine as a detector molecule for the assessment of oxygen radical generation by human neutrophils and endothelial cells. Free Rad. Res. Commun. 17, 143-154. 

M. (1982). Auto-oxidative damage in Beh het s disease-endothelial cell damage following the elevated oxygen radicals generated by stimulated neutrophils. Clin. Exp. Imunol. 49, 247-255. 

Meltzer, S., Goldberg, B., Lad, P. and Easton, J. (1989). Superoxide generation and its modulation by adenosine in neutrophils of subjects with asthma. J. Allergy Clin. Immunol. 83, 960-966. 

Thomas, P.D., Mao, G.D., Rabinovitch, A. and Posnansky, M.J. (1993). Inhibition of superoxide generating NADPH oxidase of human neutrophils by lazaroids. Biochem. Pharmacol. 45, 241-251. 

Tumour necrosis factor provokes superoxide anion generation from neutrophils. Biochem. Biophys. Res. Commun. 137, 1094-1100. 

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