Toxic neutrophils

At around this time, the synthetic formylated oligopeptides, thought to be analogous to bacterial-derived products, were being characterised. Remarkably, it was shown that the pretreatment of normal neutrophils in vitro with 2 x 10 8 M fMet-Leu-Phe for 15 min could alter the function of these cells so that they resembled toxic neutrophils. The conclusion, therefore, was that factors induced by the bacterial infection (either derived from the bacteria themselves or else generated by the host in response to the infection) could up-regulate the function of mature, circulating neutrophils. 

Mangafodipir administration in animals has been associated with slight eosinopenia and eosinophilia and reduction of toxic neutrophils following exposure to doses several times the recommended clinical dose (Larsen and Grant 1997). No adverse immunological effects have been observed in clinical trials (Earls and Bluemke 1999). Immunological effects are not a concern for individuals exposed to mangafodipir. 

Bronchial Asthma. Figure 2 Mechanisms of bronchial hyperresponsiveness. Toxic products from eosinophils [cationic peptides, reactive oxygen species (ROS)] cause epithelial injury. Nerve endings become easily accessible to mediators from mast cells, eosinophils [eosinophil-derived neurotoxin (EDN)], and neutrophils, and to airborne toxicants such as S02. Activation of nerve endings stimulates effector cells like mucosal glands and airway smooth muscle either directly or by cholinergic reflexes. 

Williams, J.G. and Hallett, M.B. (1989).Effect of sulphasalazine and its active metabolite, 5-aminosalicylic acid, on toxic oxygen metabolite production by neutrophils. Gut 30, 1581-1587. 

Closely monitor patients for efficacy and toxicity while they are receiving hydroxyurea. Monitor mean corpuscular volume (MCV) because it increases as the level of HbF increases. If the MCV does not increase with hydroxyurea use, the marrow may be unable to respond, the dose may not be adequate, or the patient may be noncompliant.27 HbF levels also can be monitored to assess response. Assess blood counts every 2 weeks during dose titration and then every 4 to 6 weeks once the dose is stabilized. Temporary discontinuation of therapy is warranted if the hemoglobin level is less than 5 g/dL (50 g/L or 3.1 mmol/L), the absolute neutrophil count is less than 2000/mm3 (2 x 109/L), platelets are less than 80,000/mm3 (80 x 109/L), or reticulocytes are less than 80,000/mm3 (80 x 109/L) if the hemoglobin is less than 9 g/dL (90 g/L or 5.6 mmol/L). Monitor for increases in serum creatinine and transaminases. Once the patient has recovered, hydroxyurea may be restarted with a dose that is 2.5 to 5 mg/kg less than the dose associated with the patient s toxicity. Doses then may be increased by 2.5 to 5 mg/kg daily after 12 weeks with no toxicity. 

Numerous studies have demonstrated that degradation products of (3-carotene exhibit deleterious effects in cellular systems (Alija et al., 2004, 2006 Hurst et al., 2005 Salerno et al., 2005 Siems et al., 2003). A mixture of (3-carotene degradation products exerts pro-apoptotic effects and cytotoxicity to human neutrophils (Salerno et al., 2005 Siems et al., 2003), and enhances the geno-toxic effects of oxidative stress in primary rat hepatocytes (Alija et al., 2004, 2006), as well as dramatically reduces mitochondrial activity in a human leukaemic cell line, K562, and RPE 28 SV4 cell line derived from stably transformed fetal human retinal pigmented epithelial cells (Hurst et al., 2005). As a result of degradation or enzymatic cleavage of (3-carotene, retinoids are formed, which are powerful modulators of cell proliferation, differentiation, and apoptosis (Blomhoff and Blomhoff, 2006). 

Animal studies indicate that the pathogenesis of NSAID small intestinal toxicity involves multiple interactions dependent on enterohepatic circulation, epithelial permeability, neutrophil infiltration and bacterial infection [233]. Several investigations [234-238] have suggested that bacterial flora may play a role in the pathogenesis of NSAID bowel injury and Robert and Asano [239] did show more than 25 years ago that germ-free rats are resis-... 

The superoxide anion (O2 ) exhibits numerous physiological toxic effects including endothelial cell damage, increased microvascular permeability, formation of chemotactic factors such as leukotriene B4, recruitment of neutrophils at sites of inflammation, lipid peroxidation and oxidation, release of cytokines, DNA singlestrand damage, and formation of peroxynitrite anion (ONOO-), a potent cytotoxic and proinflammatory molecule generated according to equation 7.210 ... 

Before we discuss how neutrophils (and other professional phagocytes) generate O2 and other oxygen metabolites during the respiratory burst, let us first consider why they produce such compounds. If these metabolites are produced in order to kill phagocytosed microorganisms, why and how are they toxic The answer comes from an examination of the chemistry of the oxygen molecule itself. 

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