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Exhaustive exercise may be a mechanism for upward regulation of integrin adhesive receptors on granulocytes. A study to test the hypothesis that degranulation of granulocytes and regulation upward of the granulocyte integrin MA-1 (CD11b/CD18) are related to duration of exercise and /or its intensity has been carried out. Effects of body temperature/dehydration on MAC-1 expression have been investigated. The hypothesis that changes in leukocyte counts and changes in MAC1 expression with endurance exercise are independently regulated has been tested. Expression of CD11b on granulocytes was found to increase with intense endurance exercise, but not with moderate endurance work. The intense endurance activity can be either incremental maximal treadmill testing or competitive marathon running. The phenomenon might be partially responsible for greater adhesion of granulocytes to endothelial cells and it might help with tissue infiltration after endurance exercise. Eight male amateur runners in Germany were recruited for testing, which involved a treadmill test, a training run and a marathon race.

This randomized, double-blind, placebo-controlled study was designed to determine the influence of carbohydrate supplementation on the granulocyte and monocyte response to 2.5 h of high-intensity running [76.7 [+ or -] 0.4% of maximal oxygen consumption ([VO.sub.2]max)]. Thirty experienced marathon runners ([VO.sub.2]max 53.4 [+ or -] 1.0 mL . [kg.sup.-1] . [min.sup.-1], age 41.5 [+ or -] 1.4 y) were randomly assigned to carbohydrate-supplement (n = 17) and placebo (n = 13) groups. Subjects rested for 10-15 min before a blood sample was taken at 0715, and then ingested 0.75 L carbohydrate beverage or placebo. At 0730 subjects began running at 75-80% of [VO.sub.2]max for 2.5 h, and drank 0.25 L carbohydrate or placebo fluid every 15 min. Immediately after the 2.5-h run (1000), another blood sample was taken, followed by 1.5-h, 3-h, and 6-h recovery samples. Carbohydrate supplementation had a significant effect compared with placebo on the pattern of change in plasma glucose and cortisol, and the blood concentration of neutrophils ([F.sub.[4, 112]]) = 5.13, P = 0.001) and monocytes ([F.sub.[4, 112]] = 4.78, P = 0.001), but not on blood granulocyte and monocyte phagocytosis or oxidative burst activity after 2.5 h of intensive running. Am J Clin Nutr 1997;66:153-9.

Among the different mechanisms involved, polymorphonuclear leukocytes (PMNs) may play a central role in the pathogenesis of adult respiratory distress syndrome (ARDS). PMNs were evaluated in 15 patients with ARDS, in 21 at risk of developing ARDS (AR), and in 36 controls (C). Spontaneous and opsonized zymosan (OZ), phorbol myristate acetate (PMA), and F-Met-Leu-Phe (F-M-L-P)-stimulated oxygen radical production was measured by luminol- and lucigenin-enhanced chemiluminescence (CL). Spontaneous CL activity of PMNs from ARDS patients was significantly greater than that from the PMN control (luminol CL, 2.8 [+ or -] 0.6 vs. 0.8 [+ or -] 0.1 mV, p < 0.001; lucigenin CL, 2.0 [+ or -] 0.6 vs. 0.30 [+ or -] 0.04 mV, p < 0.001), and the CL value from AR patients (luminol CL, 1.3 [+ or -] 0.2 mV, p < 0.001 vs C; lucigenin CL, 0.8 [+ or -] 0.1 mV, p < 0.001 vs. C) was found to be between the ARDS and C patients. The peak of PMA-stimulated CL occurred earlier and it was significantly higher in ARDS patients than in AR patients (p < 0.05) and controls (p < 0.001). When the CL response was elicited with F-M-L-P, no difference among the three groups was found. When stimulated with OZ, the peak CL generated by PMNs from ARDS patients was significantly depressed compared with controls (luminol CL, 26.7 [+ or -] 1.8 vs. 40.9 [+ or -] 2.3 mV, p

Granulocytes defend the body against invading microbes by producing a complex armamentarium of toxic substances, such as proteolytic enzymes, oxygen radicals and arachidonic acid metabolites. Under certain circumstances, however, such compounds may be released in the absence of phagocytosable particles, resulting in injury to normal cell and connective tissue degradation. Recent experimental studies have emphasized the potential role of granulocytes in the pathogenesis of myocardial ischemia. Clinical investigations have also shown alterations in neutrophil function in stable and unstable clinical manifestations of ischemic heart disease. 'Priming' of granulocytes in stable forms of cornary disease may predispose to the subsequent development of acute coronary events, whereas activation of neutrophils may lead to alterations in vascular permeability and coronary flow regulation, leading to further myocardial and endothelial injury in acute myocardial infarction, unstable angina and coronary agioplasty., Granulocytes are a class of white blood cell charged with specific responsibilities in protecting the body against foreign organisms. To accomplish this task, the granulocytes are equipped with a potent armamentarium, including powerful enzymes and oxygen radicals. However, these cells sometimes harm the body; granulocytes are implicated in the pathogenesis of several diseases, and evidence is accumulating that these cells may play a role in the progression of heart disease as well. Although relatively few data are available, studies of neutrophils, a type of granulocyte, indicate that neutrophil function is altered in patients with unstable angina. The activity of neutrophils may be assessed indirectly by measuring a protein called B-beta. This protein correlates with the release of the enzyme elastase by neutrophils. The elevation of this protein in patients with unstable angina suggests that neutrophils may be entering the heart muscle and contributing to the damage begun by decreased blood flow and oxygen deprivation. However, the participation of granulocytes in the progression of heart disease may not be limited to the exacerbation of damage to the heart muscle. Neutrophils secrete a variety of substances, including several compounds collectively called leukotrienes. Some of these leukotrienes are potent vasoconstrictors, which means they cause blood vessels to constrict. It is possible that the adherence of neutrophils to sites of arterial injury may result in the release of leukotrienes which stimulate vasoconstriction. Since the artery at that point is already damaged by the effects of atherosclerosis, the turbulence resulting from constriction may set the stage for the development of a blood clot. This clot, or thrombus, may then progress to cause either an episode of unstable angina or even sudden death. While much remains to be learned about the role of granulocytes in the progression of heart disease, it is hoped that the function of these cells may provide a point at which drugs might be used to intervene and prevent the development of a heart attack. (Consumer Summary produced by Reliance Medical Information, Inc.)

The author likens the various cytokines to musical instruments; we understand the individual instruments, but do not understand how they are combined to play the symphony. The cytokines are a large and heterogeneous class of proteins which exert a variety of regulatory influences. There are four known colony-stimulating factors, a variety of loosely related proteins called interleukins, the interferons, a handful of macrophage-inflammatory proteins, and a bewildering array of growth factors. In general, each cytokine influences a variety of cells, and each cell type is influenced by a variety of cytokines. The spectrum of action of any two cytokines is different, however. In some cases, two different cytokines with a common target cell can act synergistically, while in other cases one can inhibit the effect of the other. However, until researchers can unravel the complexities of how the various cytokines work together, they will be hampered in their efforts to use these substances for the treatment of immune disorders. For example, one of the potential uses for cytokines is to hasten the recovery of the bone marrow after the marrow cells have been decimated by anti-cancer drugs. Anything which shortens the recovery period will lessen a patient's susceptibility to infection, and may permit the use of a more aggressive and effective chemotherapeutic regimen. Studies have shown that interleukin-1 beta (IL-1) hastens the recovery of neutrophils, an important type of white blood cell in the first line of the body's defense. However, the artificial introduction of IL-1 changes the regulation of cytokine receptors on the surface of many cells. Furthermore, the artificial introduction of IL-1 has many side effects including fever and chills, phlebitis, bone pain, and low blood pressure. Presumably, as more is learned about the interrelationships of the cytokines, it should become possible to increase the desired effects of interleukin-1 while decreasing the unwanted side effects. (Consumer Summary produced by Reliance Medical Information, Inc.)

Leukocyte (white blood cell) adhesion deficiency (LAD) is an inherited disease in which molecules on the surface of leukocytes, known as the leukocyte adhesion molecules, are defective. The leukocyte adhesion molecules include lymphocyte function-associated Ag-1 (CD11a/CD18), CR3 (CD11b/CD18) and p150,95 (CD11c/CD18). The immune system of patients with LAD is impaired and results in varied clinical manifestations, with a predominance of bacterial infections. Defects are seen in the various types of leukocytes including granulocytes, monocytes and lymphocytes. Studies in tissue culture show that cellular uptake or phagocytosis (such as ingestion and digestion of bacteria) is impaired due to defective CR3 molecules, which are normally involved in phagocytosis. Phagocytosis can also be mediated through another molecule, the FcR receptor. There are three classes of FcR receptors found on the various types of leukocytes: FcRI, FcRII, and FcRIII. The expression of the various classes and functions of the receptors on granulocytes and monocytes were examined in patients with LAD. Increased binding and uptake were observed in granulocytes, but not in monocytes. Additional studies revealed that the class of FcR receptors that is expressed to a greater extent in patients with LAD is FcRI, and not FcRII or FcRIII. In normal conditions, FcRI is expressed on monocytes, but has also been shown to be expressed on granulocytes activated by a certain cytokine (cellular factor), interferon-gamma. However, it is thought that interferon-gamma is not involved in the activation of FcRI in patients with LAD. The mechanism for activation of FcRI on granulocytes in patients with LAD is not understood. (Consumer Summary produced by Reliance Medical Information, Inc.)

One of the most common side effects of anticancer drugs is the suppression of the immune system, which may lead to infection as a serious complication of treatment. A great deal of research has explored the effect of chemotherapeutic agents on polymorphonuclear leukocytes (PMNLs), phagocytic white blood cells which can eat and destroy bacteria. Much of the research has been contradictory, however, and few conclusions have been drawn. Since the ability of PMNLs to kill bacteria in an experimental assay may be affected by many laboratory conditions, an attempt was made to examine a fundamental characteristic of the cells that is critical to their ability to destroy bacteria. Polymorphonuclear cells generate quantities of the superoxide anion, which is an oxygen molecule with an added negative charge. This ion is highly reactive chemically and can literally ''burn'' the proteins and other constituents of a target organism. Eleven chemotherapeutic drugs were incubated with PMNLs prior to the assay of the ability to produce superoxide. Only predonine did not suppress superoxide production. The remainder, which included commonly used anticancer agents cisplatin, doxorubicin, 5-fluorouracil, and etoposide, suppressed superoxide production, and may thus exert a similar effect when administered to patients. Curiously, the suppressive effects of cisplatin were reduced when the cells were incubated in the drug for a longer time; there is no obvious explanation for this phenomenon. While it is not known in what way chemotherapeutic drugs might influence the production of superoxide anions, the phenomenon must be considered as a possible mechanism for the increased susceptibility to infection observed among patients undergoing chemotherapy. (Consumer Summary produced by Reliance Medical Information, Inc.)

Pulmonary edema often results from abnormal function of the cardiovascular system. But when pulmonary edema is not due to this cause, and results in inadequate oxygenation of the patient's blood, the syndrome is called adult respiratory distress syndrome (ARDS). Some current concepts suggest that neutrophils in the lung may promote the pulmonary edema that occurs in patients with ARDS. It is clear that neutrophils, a type of white blood cell, are present in greater numbers in patients with ARDS, and that patients with more severe disease tend to have more neutrophils. Neutrophils are normally lured into tissues where they are needed by substances called chemotactic factors. One particular chemotactic factor is C5a, which is a fragment of C5, a part of the complement system. The molecule serves particularly well as a chemotactic factor. As the complement system attacks a foreign organism, C5 is likely to be cleaved to form C5a; neutrophils are called into the fight virtually automatically. However, in ARDS there is no infection to be fought, and the lung tissue might be calling in neutrophils erroneously. Under normal conditions, C5a can be inactivated to prevent the chemotaxis of the neutrophils. This so-called chemotactic factor inactivator might be what is missing in ARDS, in which a build-up of neutrophils is clearly taking place. The levels of chemotactic factor inactivator were measured in 29 patients with ARDS and in 14 control subjects. Measuring bronchoalveolar lavage fluid, or fluid obtained by literally rinsing the lungs with a small amount of saline, investigators showed that the total quantity of chemotactic factor inactivator was actually increased in the patients with ARDS. However, when the activity of the factor was assayed, it was significantly less than that of the normal controls. The results indicate that, although greater than normal quantities of chemotactic factor inactivator are present in patients with ARDS, the substance is in some way being prevented from accomplishing its normal task. This functional deficit may promote the chemotaxis of neutrophils and contribute to the development of life-threatening pulmonary edema in patients with ARDS. (Consumer Summary produced by Reliance Medical Information, Inc.)

To directly measure some of the chemical events that occur during an allergic skin reaction, researchers have devised a clever method in which a chamber is placed over a small area of denuded dermis. Previous studies using this method have shown that a large number of neutrophils, a type of white blood cell, accumulate during an allergic reaction. To determine if these neutrophils are contributing pathogenic chemicals to the reaction site, the accumulation of several different substances was measured. Lactoferrin, elastase, and myeloperoxidase, all present in granules, were measured, as was lactic dehydrogenase, which is present in cell cytoplasm. The amount of histamine was also evaluated; this substance is present in mast cells and basophils, and other cells involved in the allergic reaction. (Histamine is not present in neutrophils.) Results obtained from 13 volunteers with allergies to pollen revealed that lactoferrin and elastase accumulated slowly over a period of four hours after the allergic stimulus. It was found that the levels of elastase and lactoferrin did not reflect the accumulation of neutrophils during this period. However, lactoferrin levels correlated with the amount of histamine released during the first hour of the reaction. This finding indicates that, during an allergic reaction, neutrophil components are released in living tissue. The relation of lactoferrin to the release of histamine, which is mediated by cells other than neutrophils, suggests that the release of lactoferrin may be related to the earlier activation of the mast cells. Since lactoferrin plays a role in reactive oxidants effects, and elastase is a nonspecific enzyme which degrades proteins, it seems likely that these substances may play a role in the tissue damage which occurs in the later phases of allergic responses. (Consumer Summary produced by Reliance Medical Information, Inc.)

While allergic reactions are generally associated with allergen-specific immunoglobulin E (IgE), there is some evidence that a subset of immunoglobulin subclass 4 (IgG4) molecules may be involved in allergic processes. (Basophils are a type of white blood cell that plays an important role in the allergic response.) Although the presence of IgG4 molecules on basophils has not been established, the stimulation of basophils with antibodies against IgG4 results in the release of enzyme-containing granules and histamine. Since the release of these granules is both easily visible and readily quantifiable, degranulation was used as the basis of a more detailed examination of the role of IgG4 in the allergic response. Although the net result was the same, it was found that basophils can be affected by antibodies to IgG4 in two distinct ways. At higher antibody concentrations, ranging from 10 to 100 micrograms per milliliter, anti-IgG4 could affect the basophils directly and induce the release of the granules without the presence of any other cell. However, at over a thousand-fold lower concentrations, ranging from 1 to 100 picograms per milliliter, anti-IgG4 could induce degranulation of the basophils when eosinophils were present. Eosinophils, a subclass of white blood cells referred to as polymorphonuclear cells, apparently respond to anti-IgG4 and release substances which then induce the granulation of the basophil. Experiments with the tissue culture supernatant of IgG4-treated eosinophils revealed the presence of a positively charged protein, capable of inducing the release of granules by the basophils. There are, therefore, at least two distinct mechanisms by which the degranulation of basophils results from a pathway involving IgG4. (Consumer Summary produced by Reliance Medical Information, Inc.)

Neutrophils, a type of white blood cell, can become activated during sepsis, widespread infection in the bloodstream. Neutrophils are also activated by C5a, a fragment released as part of activation of complement, a step in the immune response. C5a and related complement complexes are noted after regular hemodialysis treatment (RDT). RDT is a treatment for kidney failure in which the blood is removed from the body, filtered through a machine, and returned. C5a is found after RDT when the dialyzers are made of cuprophane (a kind of cellulose), but not when they are made of noncellulosic materials. It is therefore possible that neutrophils in dialysis patients with acute renal failure (ARF) and sepsis would become excessively activated, resulting in detrimental changes in white blood cell function. To study this, investigators took blood samples from 21 patients in ARF, 11 of whom had also developed sepsis, who underwent dialysis with dialyzers of both cuprophane and polysulfone (a noncellulosic material). Control values were obtained from patients with uremia (high blood levels of urea) who underwent RDT. Results showed that white blood cell counts fell in all three groups (ARF with sepsis, ARF without sepsis, and controls) during dialysis with cuprophane dialyzers, with much smaller drops after polysulfone dialysis. This indicated that granulocytes had moved into the small blood vessels in the lungs, a sign that their adherent properties had been altered. Patients undergoing RDT showed increased levels of most granulocyte-associated enzymes during dialysis with cuprophane, and patients with ARF without sepsis showed an even greater increase. Those with ARF and sepsis showed the greatest increase, however. All groups showed only mild elevations after dialysis with polysulfone dialyzers. Since excessive neutrophilic degranulation (activation) can lead to increased susceptibility to infection, the development of dialysis membranes that are more biocompatible may be indicated. (Consumer Summary produced by Reliance Medical Information, Inc.)

Granulocyte macrophage colony stimulating factor (GM-CSF) causes the proliferation and maturation of granulocyte and macrophage blood cells. Human GM-CSF can be produced by biotechnological methods in large quantities. Recombinant GM-CSF caused the activation of neutrophils when it was given to human neutrophils in culture. There was an increase in protein synthesis in general and an increase of at least 10 identifiable proteins, including two proteins that are cationic (have a basic pH). Neutrophils can kill microorganisms, such as bacteria, fungi, and parasites, by two major pathways: one, with oxygen metabolites and the other without oxygen. The latter includes cationic proteins. The cationic proteins produced by GM-CSF-stimulated neutrophils were cultured with the bacteria Salmonella typhimurium, which can cause food poisoning, and caused death of the bacteria. Therefore, GM-CSF can enhance the ability of neutrophils to kill bacteria by cationic proteins. (Consumer Summary produced by Reliance Medical Information, Inc.)