Polymorphonuclear Leukocyte Dysfunction Research Articles

Risk of Infection with Intravenous Iron Therapy

To review the potential risks of administering intravenous iron to patients with infection. Literature was accessed through MEDLINE (1977-June 2007) and Google Scholar, using the terms intravenous iron, iron sucrose, ferric gluconate, iron dextran, and infection. In addition, reference citations from publications identified were reviewed. All English-language articles identified from the data sources were evaluated. Studies that provided data relevant to the objective were used, including in vitro and animal studies. The role of iron in bacterial growth and the pathophysiology of cellular immunity create legitimate, yet theoretical, concerns that active infection may be exacerbated by the administration of intravenous iron. Human data relating to this issue are limited. A few small, human studies in a population with chronic kidney disease suggest a possible increased risk of developing an infection associated with intravenous iron; however, prospective human data directly linking intravenous iron to exacerbation of existing infection or infection-related mortality are lacking. In vitro data suggest that increased transferrin saturation related to iron administration may result in polymorphonuclear leukocyte dysfunction and decreased inhibition of bacterial growth. Sparse animal data have linked intravenous iron therapy with morbidity and mortality in sepsis models. Despite the limited human data, careful consideration of risk versus benefit should be used when administering intravenous iron to patients with ongoing infection. Additional clinical data are needed to determine whether intravenous iron administration worsens outcomes of patients with infection.

In vitro effect of advanced glycation end-products on human polymorphonuclear superoxide production.

Advanced glycation end-products (AGEs) are elevated in the sera of diabetic patients. The latter are prone to severe bacterial infections. Advanced glycation end-products have been shown to modulate immune competent cell activities. In this study we examined the in vitro effect of advanced glycation end-products on superoxide anion generation by human polymorphonuclear leukocytes. Advanced glycation end-products were prepared by incubation of bovine serum albumin (BSA) with glucose for 90 days. Superoxide production was measured as the superoxide dismutase-inhibitable reduction of ferricytochrome c. The effect of advanced glycation end-products on superoxide production was evaluated in both baseline (nonstimulated) and stimulated (by either formyl-methionyl-leucyl-phenylalanine, or phorbol-myristate-acetate) polymorphonuclear leukocytes. The baseline superoxide production of polymorphonuclear leukocytes was significantly increased by advanced glycation end-products in a dose-dependent manner. In contrast, in stimulated polymorphonuclear leukocytes advanced glycation end-products significantly inhibited superoxide production, again in a dose-dependent manner. This inhibitory effect of advanced glycation end-products was observed after dialyzing AGE-BSA, thereby eliminating the possible influence of reactive carbohydrates. No modification of superoxide production was seen with BSA and only a mild inhibitory effect of glucose at high concentrations. Advanced glycation end-products depress superoxide production by stimulated polymorphonuclear leukocytes. As superoxide plays an essential role in bactericidal activity, this polymorphonuclear leukocyte dysfunction may be a contributory factor to the increased prevalence and severity of bacterial infection seen in diabetic patients.

Dysfunction of polymorphonuclear leukocytes in uremia: Role of parathyroid hormone

Dysfunction of polymorphonuclear leukocytes in uremia: Role of parathyroid hormone

Dysfunction of polymorphonuclear leukocytes in uremia: Role of parathyroid hormone

Polymorphonuclear leukocytes (PMNLs) from uremic patients have elevated basal levels of cytosolic calcium ([Ca2+]i), reduced calcium signal after activation of Fc(gamma) RIII receptor, and impaired phagocytosis. Chronic excess of parathyroid hormone (PTH) in uremia mediates its effect on PMNL's metabolism and function through the sustained elevation of their [Ca2+]i. Because calcium channel blockers interfere with this effect of PTH on PMNLs, treatment of patients on hemodialysis with verapamil, nifedipine, or amlodipine was associated with an improvement in metabolism and phagocytosis of PMNLs in humans. The therapy with calcium channel blockers should be continued in order to maintain its beneficial effects.

Are granulocyte inhibitory proteins contributing to enhanced susceptibility to infections in uraemia?

Infectious complications are still a major cause of morbidity and mortality in patients undergoing regular dialysis treatment. This increased morbidity and mortality of patients with uraemia has been attributed to the dysfunction of polymorphonuclear leukocytes (PMNLs). Uraemia contributes to impaired PMNL function by means of disarrangements in cellular biochemistry and biology. Reduced chemotaxis, adherence, oxidative activity, and glucose consumption in response to phagocytic challenge have been reported. Several compounds present in uraemic serum have been isolated and characterized to inhibit the biological activity of PMNLs. A first granulocyte inhibitory protein (GIP I) responsible for the PMNL dysfunction in uraemia has been isolated and characterized. The polypeptide, with a molecular weight of 28 000 Da, inhibits the uptake of deoxyglucose, chemotaxis, oxidative metabolism, and intracellular bacterial killing by PMNLs. A second granulocyte inhibitory protein (GIP II), with a molecular weight of 9500 Da, has been isolated from plasma ultrafiltrates obtained from haemodialysis patients. It interferes with similar functions of PMNLs. GIP I displays homology with light chain protein and GIP II with beta 2-microglobulin, respectively. Both proteins were also isolated from peritoneal dialysis effluents. Isolated kappa and lambda light chain monomers and dimers from haemodialysis and peritoneal dialysis patients also inhibit several PMNL functions. Recently, a PMNL degranulation inhibiting protein (DIP) was purified from plasma ultrafiltrates obtained from patients undergoing regular haemodialysis therapy. DIP shows homology with angiogenin and inhibits spontaneous as well as stimulated PMNL degranulation. These proteins may explain at least in part the enhanced susceptibility to infections in haemodialysis and peritoneal dialysis patients.

Effect of priming polymorphonuclear leukocytes with cytokines (granulocyte-macrophage colony-stimulating factor [GM-CSF] and G-CSF) on the host resistance to Streptococcus pneumoniae in chinchillas infected with influenza A virus

Patients infected with influenza A virus (IAV) are at increased risk for bacterial superinfections, and this occurs in association with depressed polymorphonuclear leukocyte (PMNL) function. Recently, we reported that in vitro exposure of human PMNL to granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses IAV-induced cell dysfunction. The present study used an established animal model of IAV infection to examine whether G-CSF and/or GM-CSF can overcome IAV- induced PMNL dysfunction and thereby prevent secondary infections. Preliminary studies determined a dosing schedule of these cytokines that caused significant priming of chinchilla PMNL. In subsequent studies, animals were inoculated intranasally with IAV (day 1) followed 3 days later by Streptococcus pneumoniae, and administered daily intraperitoneal injections with a cytokine or placebo on days 3 through 9. Animals had blood obtained on multiple occasions for PMNL studies, and were followed-up for evidence of pneumococcal disease. Both cytokines caused significant priming of the PMNL chemiluminescence response and this was associated with reversal of the IAV-induced PMNL dysfunction. However, neither cytokine decreased the incidence of pneumococcal disease.

Effect of Priming Polymorphonuclear Leukocytes With Cytokines (Granulocyte-Macrophage Colony-Stimulating Factor [GM-CSF] and G-CSF) on the Host Resistance to Streptococcus pneumoniae in Chinchillas Infected With Influenza A Virus

AbstractPatients infected with influenza A virus (IAV) are at increased risk for bacterial superinfections, and this occurs in association with depressed polymorphonuclear leukocyte (PMNL) function. Recently, we reported that in vitro exposure of human PMNL to granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses IAV-induced cell dysfunction. The present study used an established animal model of IAV infection to examine whether G-CSF and/or GM-CSF can overcome IAV-induced PMNL dysfunction and thereby prevent secondary infections. Preliminary studies determined a dosing schedule of these cytokines that caused significant priming of chinchilla PMNL. In subsequent studies, animals were inoculated intranasally with IAV (day 1) followed 3 days later by Streptococcus pneumoniae, and administered daily intraperitoneal injections with a cytokine or placebo on days 3 through 9. Animals had blood obtained on multiple occasions for PMNL studies, and were followed-up for evidence of pneumococcal disease. Both cytokines caused significant priming of the PMNL chemiluminescence response and this was associated with reversal of the IAV-induced PMNL dysfunction. However, neither cytokine decreased the incidence of pneumococcal disease.

Periodontitis in the primary dentition associated with Actinobacillus actinomycetemcomitans infection and leukocyte dysfunction.

Abstract 2 siblings, aged 5 years (girl) and 7 years (boy), with periodontitis in the primary dentition were studied. Actinobacillus actinomycetemcomitans was isolated from the gingival pockets of both children. The liters of IgG antibodies against A. actinomycetemcomitans were elevated, and the polymorphonuclear leukocytes had a decreased capacity to ingest IgG-coated latex particles. Other functions of the polymorphonuclear leukocytes were normal. After antibiotic therapy and for the 7-year-old boy, debridement of the gingival pockets A. actinomycetemcomitans was no longer detectable in the gingival pockets, and the phagocytic capacity of the polymorphonuclear leykocytes was normalized. After 21/2 years, A. actinomycetemcomitans was found again in the gingival pockets of the boy, and once more his polymorphonuclear leukocytes had a decreased capacity to ingest IgG-coated latex particles. The antibiotic therapy was repeated and 6 months later, the number of A. actinomycetemcomitans was very low and the phagocytic capacity of the polymorphonuclear leukocytes was back to normal. This case report suggests that A. actinomycetemcomitans may be involved in the etiology of periodontitis in the primary dentition, possibly by triggering a phagocytic dysfunction of polymorphonuclear leukocytes.

The Ability of Polymorphonuclear Leukocyte Priming Agents to Overcome Influenza A Virus-Induced Cell Dysfunction

The major mortality and morbidity resulting from influenza virus infections are due to secondary bacterial infections which occur in association with virus-induced inhibition of polymorphonuclear leukocyte (PMNL) function. The present study was undertaken to determine if compounds which prime PMNL function to subsequent stimulation with N-formylmethionyl-leucylphenylalanine (FMLP) or phorbol 12-myristate 13-acetate (PMA) can overcome influenza A virus (IAV)-induced inhibition of the PMNL chemiluminescence response to these stimuli. Granulocyte-macrophage colony stimulating factor (GM-CSF), guanosine triphosphate (GTP), and 1-oleoyl-2-acetylglycerol (OAG) were able to prime the PMNL response to FMLP and/or PMA and totally or partially overcome IAV-induced PMNL dysfunction in cells stimulated with FMLP or PMA. A direct correlation was found between the extent of PMNL priming due to GM-CSF, GTP, and OAG and the capacity of these compounds to overcome virus-induced PMNL dysfunction. The implications of these findings in regard to the mechanism by which priming agents overcome IAV-induced cell dysfunction and the potential of these compounds as therapeutic agents to treat secondary bacterial infections are discussed.

Periodontitis in the primary dentition associated with Actinobacillus actinomycetemcomitans infection and leukocyte dysfunction

Abstract 2 siblings, aged 5 years (girl) and 7 years (boy), with periodontitis in the primary dentition were studied. Actinobacillus actinomycetemcomitans was isolated from the gingival pockets of both children. The liters of IgG antibodies against A. actinomycetemcomitans were elevated, and the polymorphonuclear leukocytes had a decreased capacity to ingest IgG‐coated latex particles. Other functions of the polymorphonuclear leukocytes were normal. After antibiotic therapy and for the 7‐year‐old boy, debridement of the gingival pockets A. actinomycetemcomitans was no longer detectable in the gingival pockets, and the phagocytic capacity of the polymorphonuclear leykocytes was normalized. After 21/2 years, A. actinomycetemcomitans was found again in the gingival pockets of the boy, and once more his polymorphonuclear leukocytes had a decreased capacity to ingest IgG‐coated latex particles. The antibiotic therapy was repeated and 6 months later, the number of A. actinomycetemcomitans was very low and the phagocytic capacity of the polymorphonuclear leukocytes was back to normal. This case report suggests that A. actinomycetemcomitans may be involved in the etiology of periodontitis in the primary dentition, possibly by triggering a phagocytic dysfunction of polymorphonuclear leukocytes.

Polymorphonuclear leukocyte dysfunction associated with feline leukaemia virus infection.

The chemiluminescent characteristics of enriched (greater than 95%) peripheral blood polymorphonuclear leukocyte populations (PMN) from normal and feline leukaemia virus (FeLV)-infected cats were investigated. FeLV-infected cats demonstrated a significantly lower (P less than 0.001) PMN chemiluminescent response when compared to the response of normal age-matched controls. Normal PMN treated with FeLV-infected cat serum exhibited a depressed response in comparison to control cells. A titration of serum from infected cats supplemented with normal serum revealed a titratable suppression of chemiluminescence with increasing concentration of serum from the infected cats. However, PMN from FeLV-infected cats treated with normal serum displayed a slight increase in chemiluminescence over the same cells in autologous serum. The addition of inactivated FeLV to normal PMN caused a titratable decrease in chemiluminescence.

Diminished production of thromboxane B2 and prostaglandin E by stimulated polymorphonuclear leukocytes from insulin-treated diabetic subjects.

As an initial step to investigate the possibility that abnormal polymorphonuclear leukocyte (PMNL) function in diabetes might be related to abnormalities of arachidonic acid metabolism, product of the cyclooxygenase pathway were assayed in PMNL from 27 insulin-treated diabetic subjects and 27 age- and sex-matched nondiabetic subjects. It was found that the major prostanoid products formed were thromboxane B2 (TxB2) and prostaglandin E (PGE). Production of both these substances was greatly enhanced in PMNL from control and diabetic subjects by exposure to a killed preparation of Staphylococcus aureus (S. aureus) or to zymosan. There was a marked reduction in the production of TXB2 by PMNL from diabetic subjects in response to stimulation by both S. aureus [670 +/- 98 (SE) versus 1010 +/- 76 pg/10(6) PMNL/90 min, P less than 0.01] and zymosan (583 +/- 53 versus 1034 +/- 46 pg/10(6) PMNL/90 min, P less than 0.001). Similarly, production of PGE was significantly reduced in diabetics in response to both S. aureus (145 +/- 29 versus 232 +/- 16 pg/10(6) PMNL/90 min, P less than 0.05) and zymosan (181 +/- 21 versus 271 +/- 27 pg/10(6) PMNL/90 min, P less than 0.01). There was no relation between the plasma glucose at the time of the test and the production of either prostanoid. Diminished production of cyclooxygenase products of arachidonic acid metabolism should be added to the known abnormalities of PMNL in diabetes. In view of the demonstrated or inferred effects of cyclooxygenase products on aspects of PMNL function, this observation may be important in understanding the pathogenesis of PMNL dysfunction in diabetes.

Influenza A virus-induced polymorphonuclear leukocyte dysfunction.

Previous studies have shown that influenza A virus can activate the polymorphonuclear leukocyte (PMN) respiratory burst and that upon subsequent stimulation of the cell there is depressed metabolic function. We examined the mechanism by which influenza virus causes PMN dysfunction by measuring the effect upon the chemiluminescent activity of cells of varying the type of influenza virus used, the period of time that cells were exposed to virus, and the secondary stimulus that was used. The various types of intact influenza virus elicited different amounts of chemiluminescent activity, but when cells were subsequently stimulated with phorbol myristate acetate, each virus caused equivalent depression of the PMN response. Purified glycoproteins incorporated into a liposome structure similarly stimulated the PMN chemiluminescence, yet did not induce PMN dysfunction. Depressed PMN function was noted after as little as 5 min of incubation of cells with virus and occurred to both receptor-dependent (zymosan, N-formylmethionyl-leucyl-phenylalanine, and phorbol myristate acetate) and -independent (calcium ionophore A23187) stimuli.

Influenza A virus-induced polymorphonuclear leukocyte dysfunction in the pathogenesis of experimental pneumococcal otitis media.

The role of influenza A virus-induced polymorphonuclear leukocyte and eustachian tube dysfunction in the pathogenesis of acute purulent otitis media was studied in chinchillas. Polymorphonuclear leukocyte function, middle ear pressure, and the incidence of pneumococcal otitis media were observed after intranasal inoculation with influenza A virus, Streptococcus pneumoniae, or both. Results showed that depressed negative middle ear pressure and polymorphonuclear leukocyte chemiluminescence and chemotactic activity occurred after influenza inoculation, but not after inoculation with pneumococcus alone. The greatest incidence of pneumococcal otitis media occurred when the pneumococcus was inoculated just before the time of influenza-induced polymorphonuclear leukocyte dysfunction and negative middle ear pressure. Animals that had unilateral tympanostomy tubes placed before inoculation of influenza with pneumococcus showed no difference in the occurrence of pneumococcal otitis media in ventilated and nonventilated ears, suggesting that polymorphonuclear leukocyte dysfunction contributes more to the pathogenesis of pneumococcal otitis media than does negative middle ear pressure in this animal model.

Polymorphonuclear leukocyte dysfunction in children with recurrent otitis media

Depressed PMN chemotactic responsiveness was observed in 17.5% of 97 patients studied, depressed PMN bactericidal activity in 23.3% of 30 patients, and depressed PMN chemiluminescence activity in 15.8% of 19 patients. Depressed chemotactic

Juvenile periodontitis (periodontosis): current concepts

The clinical signs and symptoms of periodontosis have been described. Although initially described as a degenerative, noninflammatory disease, recent evidence suggests that periodontosis is inflammatory, with virulent gram-negative microorganisms, selective immune deficiencies, dysfunction of polymorphonuclear leukocytes, genetic predisposition, or any combination of these as possible etiologic factors. Several authors have, therefore, advocated replacing the term periodontosis, which implies a degenerative disease, with destructive or idiopathic juvenile periodontitis. Although various treatments have been proposed, a definitive therapy for the disease depends on the future elucidation of the specific causative factors.