Effects on neutrophil function

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 

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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 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]. 

Lastly, we will describe how these methods have been used to characterize the effects of hexachlorocyclohexanes on neutrophil functions. Although we are limiting this to a discussion of neutrophils, these approaches are completely generalizable to other cell types and have already been applied to some. We hope this summary will be useful to workers who wish to extend these techniques to the cell systems of interest to them. 

Politis I, Bizelis I, Tsiaras A and Baldi A (2004), Effect of vitamin E supplementation on neutrophil function, milk composition and plasmin activity in dairy cows in a commercial herd , Journal of Dairy Research, 71, 273-278. 

Another reason for complexity of cell-activation mechanisms resides in the end response of neutrophils - that is, the delivery of cytotoxic products. Whilst these products are highly lethal towards pathogens, they can also attack and destroy host tissues, and this can have deleterious effects on tissue function. Complex intracellular signalling mechanisms to activate these cytotoxic pathways also guards against non-specific activation, which could lead to host tissue damage. 

Pfizer s tenidap (CP-66,248) (157), another enolic compound, was also more potent (500-fold) toward CO over 5-LO inhibition in human ISN (0.032 /iM and 18 /iM, respectively) [379-381]. Efficacy in rheumatoid arthritis clinical trials has been reported [380,382] in patients, serum levels of acute phase proteins and synovial fluid levels of IL-1 were reduced by tenidap, in contrast to the lack of this effect with NSAIDs. Besides CO/5-LO inhibition, a variety of in vitro activities have been reported, including a number of effects on monocyte functions and differentiation [379], inhibition of neutrophil degranulation [382], inhibition of the activation of neutrophil collagenase [383], inhibition of leukocyte-endothelial cell adhesion [384], and inhibition of LTB4-induced neutrophil chemotaxis [385]. Al-... 

Another drug that has been found to have anticytokine activity is pentoxifylline. It was initially characterized as a haemorheologic agent for the treatment of peripheral vascular diseases [141]. In addition, it was also found to be capable of inhibiting the pro-inflammatory actions of IL-1 and TNEa on neutrophil function and cytokine production by monocytic cells [142]. Its mechanism of action is the inhibition of phosphodiesterases, leading to increased intracellular levels of cyclic adenosine monophosphate [143]. Besides its effects on the cytokine network, pentoxifylline also exerted an anti-fibrogenic action in cultures of fibroblasts and in animal models of fibrosis [144] and could therefore be an attractive candidate for targeting hepatic inflammation. 

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. 

D12. Dwenger, A., Funck, M., Lueken, B., Schweitzer, G., and Lehmann, U., Effect of ascorbic acid on neutrophil functions and hypoxanthine-xanthine oxidase-generated, oxygen derived radicals. Eur. J. Clin. Chem. Clin. Biochem. 30, 187-191 (1992). 

Archana, R. and Namasivayam, A. 1999. The effect of acute noise stress on neutrophil functions. Indian J Physiol Pharmacol 43 491 —495. 

Figure 6 Oxidative stress in COPD. Oxidative stress plays a key role In the pathophysiology of COPD and amplifies the inflammatory and destructive process. ROS from cigarette smoke or from inflammatory cells (particularly macrophages and neutrophils) result in several damaging effects in COPD, which include decreased antiprotease defenses, such as al -antitrypsin (AD and secretory leukoprotease inhibitor (SLPI), activation of NF-kB resulting in increased secretion of the cytokines CXCL8 and TNF-as, increased production of isoprostanes, and direct effects on airway function. In addition, recent evidence suggests that oxidative stress induces steroid resistance.

Krause R, Patruta S, Daxbock F, Fladerer P, Wenisch C. The effect of fosfomycin on neutrophil function. J Antimicrob Chemother 2001 47(2) 141-6. 

KIO. Kaplan, S. S., and Basford, R. E., Effect of vitamin B12 and folic acid deficiencies on neutrophil function. Blood 47, 801-805 (1976). 

Weiss WP, Hogan JS. Effects of dietary vitamin C on neutrophil function and responses to intramammary infusion of lipopolysaccharide in periparturient dairy cows. J Dairy Sci 2007 90 731-9. 

Livingston, D. H., Appel, S. H., Sonnenfeld, G., and Malangoni, M. A. The effect of tumor necrosis factor-alpha and interferon-gamma on neutrophil function. J. Surg. Res. 46, 322-326... 

The antiinflammatory effect of GZ has been known for several years and has been reviewed by Pisha and Pezutto, 1994 [82]. In order to elucidate the antiinflammatory mechanisms of action, Akamatsu et al., 1991 [89] have assessed the effects of GZ on neutrophil functions. They showed that this saponin didn t affect chemotaxis and phagocytosis and was not a reactive oxygen species (ROS) scavenger. It rather exerted an antiinflammatory action by inhibiting the generation of ROS by neutrophils, the most potent inflammatory mediator at the site of inflammation [89]. 

As shown by Alarcon de la Lastra et al. [100] using a model of gastric injury induced by ischemia-reperfusion in rats, pretreatment with silymarin, the hepatoprotective principle of Silybum marianum L. prevented post-ischemic injury. These protective effects were specifically related to reduction of MPO activity as index of polymorphonuclear leukocyte infiltration after injury. These findings indicated that inhibitory effects of silymarin on neutrophil function seem to contribute significantly to its gastroprotective actions. 

Hoglund M, Hakansson L, Venge P Effects of in vivo administration of G-CSF on neutrophil functions in healthy volunteers. Eur J Haematol 1997 58 195-202. 

Effect of glucose-6-phosphate dehydrogenase deficiency on neutrophil function. 

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