Effects on neutrophils

Concentrations of 10 4-10 6 M histamine enhance neutrophil chemokinesis in response to zymosan-activated serum, casein and fMet-Leu-Phe, whereas 

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Lipoxygenases catalyse the regio-specific and stereoselective oxygenation of unsaturated fatty acids. The mammalian enzymes have been detected in human platelets, lung, kidney, testes and white blood cells. The leukotrienes, derived from the enzymatic action of the enzyme on arachidonic acid, have effects on neutrophil migration and aggregation, release of lysosomal enzymes, capillary permeability, induction of pain and smooth muscle contraction (Salmon, 1986). 

An intravenous infusion of PAF causes rapid (within 60 s) intravascular platelet aggregation, thrombocytopenia and platelet factor 4 release, as well as a profound and reversible neutropenia, due to enhanced aggregation and adherence of these cells. In vitro, PAF effects on neutrophils are dependent upon extracellular Ca2+ and Mg2+ and occur within 60 s of addition. The addition of inhibitors of 5-lipoxygenase activity (e.g. ETYA, 5,8,11,14-eicosatetraenoic acid and NDGA, nordihydroguaiaretic acid) - but not those... 

TNF-a is chemotactic for monocytes and neutrophils. Its effects on neutrophils are numerous for example, it can prime degranulation and reactive oxidant production, enhance phagocytosis and ADCC and up-regulate the expression of some surface receptors, such as CR3. Whilst low concentrations of TNF-a are required to prime the cells subsequent to stimulation by other agonists, such as fMet-Leu-Phe, higher concentrations of TNF-a alone can activate low levels of oxidant production. This activity is even more pronounced if the neutrophils are adhered to surfaces. 

Topical metronidazole is effective in the treatment of rosacea. The mechanism of action is unknown, but it may relate to the inhibitory effects of metronidazole on Demodex brevis alternately, the drug may act as an anti-inflammatory agent by direct effect on neutrophil cellular function. Oral metronidazole has been shown to be a carcinogen in susceptible rodent species, and topical use during pregnancy and by nursing mothers and children is therefore not recommended. 

Although the two growth factors have similar effects on neutrophil counts, G-CSF is used more frequently because it is better tolerated. G-CSF can cause bone pain, which clears when the drug is discontinued. GM-CSF can cause more severe side effects, particularly at higher doses. These include fevers, malaise, arthralgias, myalgias, and a capillary leak syndrome characterized by peripheral edema and pleural or pericardial effusions. Allergic reactions may occur but are infrequent. Splenic rupture is a rare but serious complication of the use of G-CSF for PBSC. 

Tosi, M.F., Stark, S.M., Smith, C.W., Hamedani, A., Gruenert, D.C. and Infeld, W. (1992). Induction of ICAM-I expression on human airway epithelial cells by inflammatory cytokines effects on neutrophil-epithelial cell adhesion. Am. J. Respir. Cell. Mol. Biol. 7, 214-221. 

A number of other mechanisms may contribute to the development of NSAID-induced mucosal injury. Neutrophil adherence may damage the vascular endothelium and may lead to a reduction in mucosal blood flow, or may liberate oxygen-derived free radicals and proteases. Leukotrienes, products of lipoxygenase metabolism, are inflammatory substances that may contribute to mucosal injury through stimulatory effects on neutrophil adherence (see Fig. 33-3). 

Akamatsu H, Komura J, Asada Y, Niwa Y. Mechanism of antiinflammatory action of glycyrrhizin effect on neutrophil functions incuding reactive oxygen species generation. Planta Med 1991 57 119— 21. 

The Listeria monocytogenes host resistance model is controlled primarily in the liver and spleen. The Listeria monocytogenes systemic infection assay is useful primarily to evaluate adverse effects on neutrophils and Kupffer cells of the liver and splenic macrophages and neutrophils. NK cells and T lymphocytes also play a role in bacterial clearance. The Listeria monocytogenes host... 

Umeki, S. (1993). Anti-inflanunatory action of erythromycin. Its inhibitory effect on neutrophil NADPH oxidase activity. Chest 104, 1191-1193. 

The principal use of HU has been as a myelosuppressive agent in myeloproliferative syndromes, particularly in essential thrombocythemia with platelet counts >1.5 million cells/mrrP or history of arterial or venous thrombosis. It dramatically lowers the risk of thrombosis by lowering the platelet count, through its effect on neutrophil and red cell counts, and by reducing L-selectin expression and increasing NO production of neutrophils. 

The above observations clearly indicate that IL-4 is an important neutrophil activator in vitro. Recently, one study was conducted in order to assess the capacity of IL-4 and IL-IO to block neutrophil activation in an ex vivo human model system, and to confirm their effect on neutrophil function in an animal model of arthritis [75]. In the rat adjuvant arthritis model, treatment with systemic murine IL-4 (mIL-4 and mIL-10) was found to be effective against even the most severely diseased [75]. IL-4 (and IL-10) was effective in lowering the absolute neutrophil cell number recovered and the neutrophil activation state in the joint synovia. Both cytokines reduced the phagocytic activation of human neutrophils in response to proinflammatory cytokines. Collectively, the results demonstrate that IL-4 (and IL-10) can exert powerful regulatory effects on neutrophil function that translate into a therapeutic response in a disease model of arthritis. The authors concluded that treatment with IL-4 (or IL-10) alone or in combination might therefore be very usefiil in the management of patients with rheumatoid arthritis [75]. 

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