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PubMed1991

Inhibitory effects of fibrinogen on phagocytic killing of streptococcal isolates from humans, cattle and horses.

The effects of fibrinogen on phagocytic killing of Streptococcus dysgalactiae from cattle and S. equi from horses were studied in comparison to that of S. pyogenes from humans. Phagocytic killing was determined by a fluorometric microassay using glass adherent polymorphonuclear neutrophils (PMN) from the respective host species, preopsonization with homologous sera led to a dose-dependent increase in phagocytic killing of all streptococcal cultures, preincubation of streptococci with fibrinogen significantly inhibited their phagocytic killing. Fibrinogen had no effect on phagocytic killing of non-fibrinogen binding S. agalactiae cultures. Further characterization studies with S. dysgalactiae and S. pyogenes revealed that a partial inhibition of phagocytic killing could also be achieved by preincubation with monomeric beta-chains of fibrinogen. Digestion of the fibrinogen binding sites on streptococci with proteases resulted in an almost complete loss of the inhibitory effects of fibrinogen on phagocytic killing. It could thus be concluded that by binding fibrinogen animal pathogenic streptococci could evade phagocytic killing in a similar manner as M protein carrying S. pyogenes isolates from human infections.

Animals↗

PubMed2000

Primary phagocytic disorders of childhood.

Primary phagocytic disorders are rare and usually first manifest during childhood. A phagocytic disorder should be considered in patients with unusually severe or recurrent infections by common pathogens or an infection by certain opportunistic pathogens. Common manifestations of primary phagocytic disorders include recurrent soft-tissue infections requiring incision and drainage, severe dental infections leading to premature tooth loss, recurrent pneumonias, and perirectal infections. Primary phagocytic disorders are caused by defects of neutrophil number or function, and the latter, in turn, can be divided into disorders of oxidative and nonoxidative pathways. Certain phagocytic disorders have unique characteristics apart from the immune defect that may facilitate diagnosis. Early diagnosis of phagocytic disorders can be life-saving or lead to a significant reduction in morbidity and relies on a compatible clinical (or family) history and appropriate laboratory diagnostic studies. Key principles of management of such patients involve early recognition and aggressive treatment of infections and appropriate surgical débridement of localized disease. Prophylactic antibiotics, BMT, and the use of exogenous cytokines, such as IFN-gamma and G-CSF, are appropriate for specific phagocytic disorders. Gene therapy is a promising strategy for several of the phagocytic disorders.

Bacterial Infections↗

PubMed2000

Evaluation of phagocytic function of macrophages in rats after partial splenectomy.

BACKGROUND: Understanding the immunologic properties of the spleen has enabled surgeons to practice splenic conservation surgery. If the upper pole of the spleen can be preserved solely on the upper short gastric vessels, will phagocytic function of macrophages in remnant splenic tissue be affected? The aim of this experimental study was to evaluate the phagocytic function of macrophages in partially resected spleens, with hilar excision preserving the short gastric vessels. STUDY DESIGN: Forty-eight female Wistar albino rats were divided into four groups. Groups 1 and 2 underwent sham operations and groups 3 and 4 underwent partial splenectomy. One milliliter of sodium chloride 0.9% was injected into the abdomen of the rats in groups 1 and 3 and 1 mL of Streptococcus pneumoniae type III as an antigenic stimulus was injected into the abdomen of the rats in groups 2 and 4, 6 weeks after the first operation. Forty-eight hours later, relaparotomy was performed in all animals. India ink was used to determine the capacity of uptake in the splenic phagocytes. To evaluate the phagocytic function of the splenic tissues, histologic examinations were performed according to a macrophage grading system. RESULTS: All spleens in all four groups were stained black after injection of India ink. Phagocytic activity of macrophages was reduced in the partially splenectomized groups, compared with intact spleen groups (group 3 versus group 1; p < 0.0001, group 4 versus group 2; p < 0.0001). There was a significant difference between groups 1 and 2 according to phagocytic function of macrophages (p = 0.0121). Also, after Streptococcus pneumoniae type III injection as an antigenic stimulus in group 4, we found that the phagocytic functions of macrophages increased compared with those of the sodium chloride 0.9%-injected group 3 after partial splenectomy (p < 0.0001). CONCLUSIONS: Phagocytic function of macrophages in rats decreased after partial splenectomy. Nevertheless, the remnant spleens in rats could be stimulated when challenged with an antigenic stimulus.

Animals↗

PubMed1968

The origin and kinetics of mononuclear phagocytes.

The origin and turnover of efferent populations of mouse mononuclear phagocytes has been described. Mononuclear phagocytes were defined as mononuclear cells which are able to adhere to glass and phagocytize. In vitro labeling studies with thymidine-(3)H showed that monocytes in the peripheral blood and peritoneal macrophages do not multiply and can be considered end cells in a normal, steady state situation. However, the mononuclear phagocytes of the bone marrow appear to be rapidly dividing cells. This conclusion was supported by in vivo labeling experiments. A peak of labeled mononuclear phagocytes of the bone marrow was found 24 hr after a pulse of thymidine-(3)H. This was followed, 24 hr later, by a peak of labeled monocytes in the peripheral blood. From these experiments it was concluded that the rapidly dividing mononuclear phagocytes of the bone marrow, called promonocytes, are the progenitor cells of the monocytes. Labeling studies after splenectomy and after X-irradiation excluded other organs as a major source of the monocytes. Peak labeling of both the blood monocyte and peritoneal macrophages occurred at the same time. A rapid entry of monocytes from the blood into the peritoneal cavity was observed, after a sterile inflammation was evoked by an injection of newborn calf serum. These data have led to the conclusion that monocytes give rise to peritoneal macrophages. No indications have been obtained that mononuclear phagocytes originate from lymphocytes. In the normal steady state the monocytes leave the circulation by a random process, with a half-time of 22 hr. The average blood transit time of the monocytes has been calculated to be 32 hr. The turnover rate of peritoneal macrophages was low and estimated at about 0.1% per hour. On the basis of these studies the life history of mouse mononuclear phagocytes was formulated to be: promonocytes in the bone marrow, --> monocytes in the peripheral blood, --> macrophages in the tissue.

Animals↗

PubMed1996

Functional characteristics of enhanced Fc receptor expression of beta 2 integrin-deficient bovine mononuclear phagocytes.

Fc receptor expression, cytoplasmic Ca2+ signaling, chemiluminescent (CL) response, and electron spin resonance (ESR) combined with spin trapping of blood mononuclear phagocytes from control heifers and a heifer with leukocyte adhesion deficiency (LAD) were evaluated to elucidate the relationships between complement receptor type 3 (CR3) and Fc receptor expression and their functional responses. The mean fluorescence intensity of fluorescein isothiocyanate (FITC)-conjugated anti-bovine IgG bound to mononuclear phagocytes from the heifer with LAD was 1.8-fold higher than that of control heifers. The mean increments of cytoplasmic Ca2+ concentrations of mononuclear phagocytes from the heifer with LAD stimulated with OPZ, Agg-IgG, and PMA were 39.4 (P < 0.05), 118, and 71.6% compared with those of control heifers. A 1.27-fold increase in the CL response relative to control heifers was detected when mononuclear phagocytes from the heifer with LAD were stimulated with Agg-IgG. The OPZ-induced CL response of mononuclear phagocytes from the heifer with LAD was significantly (P < 0.05) decreased, whereas the PMA-induced CL response was similar to that of control heifers. The ESR spectrum of mononuclear phagocytes from the heifer with LAD was increased when stimulated with Agg-IgG, and was impaired when stimulated by OPZ compared with that of control heifers. The ESR spectrum of mononuclear phagocytes stimulated with PMA was similar in control heifers and the heifer with LAD. Fc receptors on mononuclear phagocytes from the heifer with LAD were enhanced, and their cytoplasmic Ca2+ signaling, CL response, and ESR-spin trapping when stimulated with Agg-IgG and OPZ appeared to be associated with enhanced Fc receptors.

Animals↗

PubMed2003

Trojan horse effect: phagocyte-mediated Streptococcus iniae infection of fish.

The salmonid macrophage-like cell line RTS-11 and purified trout pronephros phagocytes were used to analyze in vitro entry and survival of two Streptococcus iniae serotypes. Efficient invasion by S. iniae occurred in both cells, but only the type II strain persisted in pronephros phagocytes for at least 48 h. Ex vivo models of opsonin-dependent phagocytosis by pronephros phagocytes demonstrated increased phagocytosis efficacy. Analysis of phagocytes collected from diseased fish demonstrated that approximately 70% of the bacteria contained in the blood during the septic phase of the disease were located within phagocytes, suggesting an in vivo intracellular lifestyle. In addition to the augmented levels of bacteremia and enhanced survival within phagocytes, S. iniae type II induces considerable apoptosis of phagocytes. These variabilities in intramacrophage lifestyle might explain differences in the outcomes of infections caused by different serotypes. The generalized septic disease associated with serotype II strains is linked not only to the ability to enter and multiply within macrophages but also to the ability to cause considerable death of macrophages via apoptotic processes, leading to a highly virulent infection. We assume that the phenomenon of survival within phagocytes coupled to their apoptosis plays a crucial role in S. iniae infection. In addition, it may provide the pathogen an efficient mechanism of translocation into the central nervous system.

Animals↗

PubMed2004

Mercury intake by inflammatory phagocytes: in vivo cytology of mouse macrophages and neutrophils by X-ray elemental microanalysis coupled with scanning electron microscopy.

Phagocytes remove and store mercury (Hg) that enters the body. Macrophages and granulocytes respond in opposite ways to Hg: macrophages loose cell viability, and neutrophils become protected from apoptosis. We have investigated the cytology of early intake of Hg by macrophages and neutrophils after a short period (2-4 min) of in vivo exposure to HgCl2. The two types of phagocytes were attracted either to a subcutaneous air pouch or to the peritoneal cavity of BALB/c mice by in situ BSA injection. BSA caused, 72 hours later, inflammatory exudates where neutrophils (air-pouch cavity) or macrophages (peritoneal cavity) were the predominant cell type. A lethal dose of HgCl2 (25 mg) was then injected in the two inflammatory cavities. The mice died 2-4 min later and the cell exudates were harvested and studied by scanning electron microscopy coupled with X-ray elemental microanalysis (SEM-XRM). More than half of the phagocytes showed ingested Hg; a higher percentage of macrophages (around 70%) than neutrophils (around 50%) were positive for the metal. Intracellular particles of Hg were spheroid and presented a small diameter (less than 20 nm). They could be seen in large numbers inside phagocytes (up to 20-30 Hg dots per cell); they were scattered throughout the cytoplasm of the cells. The ability of phagocytes to ingest Hg increased as the BSA-induced inflammation progressed. We conclude that (i) Hg is quickly ingested as small particles by phagocytes; (ii) endocytosis of Hg increases with the degree of activation of phagocytes; and (iii) phagocytes internalize Hg by pinocytosis.

Animals↗

PubMed2006

Localised PtdIns(3,4,5)P3 or PtdIns(3,4)P2 at the phagocytic cup is required for both phagosome closure and Ca2+ signalling in HL60 neutrophils.

Several events accompany integrin-mediated phagocytosis by myeloid cells. These include local pseudopod and phagocytic cup formation followed by Ca(2+) signalling. However, there is also a role for localised phosphatidylinositol (3,4,5) trisphosphate [PtdIns(3,4,5)P(3)] production. Here we report that in neutrophilic HL-60 cells expressing PH-Akt-GFP, binding of iC3b-coated zymosan particles (2 microm in diameter) via beta2 integrin induces an incomplete phagocytic cup to form before either PtdIns(3,4,5)P(3) or phosphatidylinositol (3,4) bisphosphate [PtdIns(3,4)P(2)] production or Ca(2+) signalling. These phosphoinositides then accumulated locally at the site of the phagocytic cup and Ca(2+) signalling and phagosome closure follows immediately. Although photobleaching showed that PH-Akt-GFP was freely diffusible in the cytosol and able to dissociate from the phagocytic cup, it was restricted to the plasma membrane of the formed but open phagosome and failed to diffuse into the surrounding plasma membrane or neighbouring phagocytic cups even if connected. Inhibition of phosphoinositide (PI) 3-kinase or depletion of membrane cholesterol inhibited both Ca(2+) signalling and phagosome closure, but had no effect on particle binding or phagocytic cup formation. We therefore conclude that PtdIns(3,4,5)P(3) or PtdIns(3,4)P(2) generation was not required for the events that initiate the formation of the phagocytic cup, but that anchoring of PtdIns(3,4,5)P(3) at the phagocytic cup is an essential step for phagosome closure and Ca(2+) signalling.

Calcium Signaling↗

PubMed1988

Changes of phagocytic biological rhythm by reduction of circadian times and by influences upon hypothalamus.

The circadian oscillations of central temperature and phagocytic activity of blood polymorphonuclears were studied in guinea pigs after circadian times have been reduced, under the effect of chlorpromazine or in animals with bilaterally lesioned hypothalamus in preoptic or in tuberomammillary area. The phagocytic activity was assayed against staphylococcus epidermidis in heparinized blood. In the animals exposed to artificial light in conditions of space restriction (stressed) the phagocytic activity is depressed in the lighting period, the differences light-dark being higher (300%) as in controls (25%). Chlorpromazine lowers both central temperature and phagocytic activity, without changes of their circadian rhythms. Bilateral symmetrical injuries of the preoptic hypothalamic area determined a rise of the central body temperature in the beginning of the dark period. The phagocytic activity of these animals decreases especially at the end of the dark period. Lesions of the tuberomammillary area reduces the phagocytic activity to very low levels and attenuates to a marked extent its circadian oscillations. Body temperature remain unaffected. The circadian biorhythm of the body temperature and of the phagocytic activity, usually concurrently, are controlled by separate hypothalamic mechanisms. After tuberomammillary lesions the phagocytic response of animals to an endovenous injection of a bacterial suspension is very low. The results are discussed on the basis of present data and of prior researches of this laboratory.

Animals↗

PubMed1999

The effects of HIV viral load on the phagocytic activity of monocytes activated with lipopolysaccharide from oral microorganisms.

A study was undertaken to determine whether viral load status in HIV+ patients has any potential effect on monocyte phagocytic function both before and after challenge of the monocytes with lipopolysaccharide (LPS) isolated from oral microorganisms. LPS of two putative periodontal pathogens Porphyromonas gingivalis (P. gingivalis) and Fusobacterium nucleatum (F. nucleatum) was prepared. Whole blood samples in EDTA were collected from 30 HIV+ patients presenting for dental care at the University of Maryland. Control samples were prepared from appropriate uninfected individuals. Viral load was determined using quantitative RT-PCR (Amplicor, Roche Diagnostics). Phagocytic function was determined using FITC labeled Saccharomyces species in resting isolated monocytes and in cells after 24 h stimulation with 1 microgram/ml of LPS of P. gingivalis or F. nucleatum. Immunohistochemical staining was performed for complement receptor CR-1 (CD-35) on phagocyte cells. In HIV+ patients with high viral load (> 10,000 copies/ml), 13.5% of isolated resting monocytes demonstrated phagocytic activity, while 23% of the resting control monocytes from non-infected individuals showed phagocytic function. When the monocytes were stimulated with 1 microgram/ml of LPS of F. nucleatum, phagocytic activity was observed in 18.5% of monocytes in patients with high viral load, 33.5% with moderate viral load (400-10,00 copies/ml) and 51% with low viral load (<400 copies/ml), while 62% of the control monocytes demonstrated phagocytic activity. Stimulation of monocytes with LPS of P. gingivalis showed similar results. Complement receptor CD-35 showed a 50% decrease in expression in HIV+ patients with high viral load. A progressive decrease in monocyte/macrophage phagocytic function and CD-35 expression with and without oral LPS activation occurs after HIV infection and this trend appears to be accentuated in patients with high viral load. This relationship may contribute to increased susceptibility to oral opportunistic infections in advanced HIV+ patients.

Adult↗

PubMed1977

Leukocyte phagocytic function and dysfunction.

Although some species of bacteria are killed in vitro by humoral factors in cell-free serum, the in vivo experience with leukopenic patients illustrates the critical role played by phagocytic leukocytes in host resistance to infection. Effective ingestion and killing of micro-organisms requires the sequential and integrated function of the elements of the phagocytic system. Each step in the phagocytic process is also a potential crack in the armor of host defense, and an increasing number of clinically significant disorders of phagocytic function are being recognized and described (5). The phagocytic leukocytes are equipped with a variety of intracellular microbicidal mechanisms which provide a degree of overkill capacity and allow these cells to meet the challenges posed by the many and varied microbial transfressors. Undoubtedly, other phagocytic disorders will be discovered and other important aspects of the intraleukocyte killing mechanisms will be elucidated. For instance, little is known about the function of leukocytes within the relatively hypoxic environment of injured tissue where so many bacterial infections begin. As our understanding of phagocytic function develops, new ways may be found to augment host resistance by preservation or stimulation of the phagocytes.

Animals↗

PubMed1988

Function of phagocytes obtained from lacteal secretions of lactating and nonlactating cows.

Phagocytes, macrophages and neutrophils, were obtained from lacteal secretions of lactating (n = 13) and nonlactating cows (n = 14). Secretions from nonlactating cows were collected at 7 and 14 days after cessation of lactation. Phagocytes were incubated in vitro with Staphylococcus aureus or Escherichia coli, and function was assessed by fluorescent microscopy of cell suspensions stained with acridine orange and crystal violet. A greater percentage of macrophages from nonlactating cow secretions collected on day 14 phagocytized bacteria than did those collected on day 7. A greater percentage of macrophages from nonlactating cow secretions collected on days 7 and 14 phagocytized bacteria than did neutrophils obtained from the same secretions. A similar percentage of phagocytes from nonlactating cow secretions phagocytized bacteria, compared with phagocytes from lactating cow secretions. Results indicated that the intramammary macrophage may be most important in defense of the mammary gland during the early nonlactating period, because it was more phagocytic than the neutrophil and was more active at 14 days than at 7 days into the nonlactating period.

Animals↗

PubMed1993

Assay of phagocytic cell functions.

The fundamental role of the immune system is recognition of the self from the non-self; in this way the principal functions of the immune system can be summarized as: resistance against the cells and foreign substances which are potentially damaging the tissues; identification of neoplastic cells to be destroyed. The cells which have this role are essentially lymphocyte, neutrophils and macrophages: extracellular and cellular humoral factors also play their role into the inflammatory process. In fact, we define the normal responses of phagocyte as the capacity of the specific phagocytic cell to respond to various stimuli and to migrate to the location of the damage. This complex cellular defense mechanism comprises several steps that can be summarized as following: opsonization of particles to be ingested, adhesion and aggregation of phagocytes to vascular endothelium, migration of phagocytes through the vessel walls, chemotaxis of phagocytes towards pathogenic agents, recognition of the particles/antigens by the phagocytes which subsequently adhere to their surface, ingestion of the particles with formation of a phagosome. This process is completed with the fusion of the phagosome with cellular granules (lysosomes) and formation of phagolysosomes, degranulation and release of the enzyme laden granules into the phagolysosome, lysis and killing of ingested particles and bacteria. It is clear from this schematic summary, that the response to pathogens can be very complex and each of the processes involved in the above described steps could be deranged leading to various pathological changes. We analyze the most classical and new methods to study the physiopathology of granulocytes, which are important for clinical diagnosis of phagocyte diseases or for phagocytic dysfunction in various syndromes and in neoplastic patients.

Cell Adhesion↗

PubMed1975

The role of superoxide anion generation in phagocytic bactericidal activity. Studies with normal and chronic granulomatous disease leukocytes.

The capacity of human phagocytes to generate superoxide anion (O2-), a free radical of oxygen, and a possible role for this radical or its derivatives in the killing of phagocytized bacteria were explored using leukocytes from normal individuals and patients with chronic granulomatous disease (CGD). Superoxide dismutase, which removes O2-, consistently inhibited phagocytosis-associated nitroblue tetrazolium (NBT) reduction indicating the involvement of O2- in this process. Similarly, superoxide dismutase inhibited the luminescence that occurs with phagocytosis, implicating O2- in this phenomenon, perhaps through its spontaneous dismutation into singlet oxygen. Subcellular fractions from homogenates of both normal and CGD leukocytes generated O2- effectively in the presence of NADH as substrate. However, O2- generation by intact cells during phagocytosis was markedly diminished in nine patients with CGD. Leukocytes from mothers determined to be carriers of X-linked recessive CGD by intermediate phagocytic reduction of NBT elaborated O2- to an intermediate extent, further demonstrating the interrelationship between NBT reduction and O2- generation in phagocytizing cells. Activity of superoxide dismutase, the enzyme responsible for protecting the cell from the damaging effects of O2-, was approximately equal in homogenates of normal and CGD granulocytes. Polyacrylamide electrophoresis separated this activity into a minor band that appeared to be the manganese-containing superoxide dismutase associated with mitochondria and a more concentrated, cyanide-sensitive, cytosol form of the enzyme with electrophoretic mobility that corresponded to that of erythrocyte cuprozinc superoxide dismutase. Superoxide dismutase inhibited the phagocytic killing of Escherichia coli, Staphylococcus aureus, and Streptococcus viridans. A similar inhibitory effect was noted with catalase which removes hydrogen peroxide. Neither enzyme inhibited the ingestion of bacteria. Peroxide and O2- are believed to interact to generate the potent oxidant, hydroxyl radical (.OH). A requirement for .OH in the phagocytic bactericidal event might explain the apparent requirement for both O2- and H2O2 for such activity. In agreement with this possibility, benzoate and mannitol, scavengers of .OH, inhibited phagocytic bactericidal activity. Generation of singlet oxygen from O2- and .OH also might explain these findings. It would seem clear from these and other studies that the granulo cyte elaborates O2- as a concomitant of the respiratory burst that occurs with phagocytosis. To what extent the energy inherent in O2- is translated into microbialdeath through O2- itself, hydrogen peroxide, .OH, singlet oxygen, or some other agent remains to be clearly defined.

Catalase↗

PubMed1979

Inhibition by glucocorticoids and choleragen of the conditional growth of poorly adherent mononuclear phagocytes of newborn hamster liver and lung (hormonal control of macrophage growth).

Conditions for in vitro growth of mononuclear phagocytes from newborn hamster liver and lung were studied. In the primary cultures of liver and lung, round cells outgrew and frequently floated off into the culture medium. They were separated from fibroblast-like cells adherent to plastic by collecting the medium. The round cells were identified as mononuclear phagocytes on the criteria of phagocytic capacity of heat-killed bacteria and IgG-coated erythrocytes, fine cell structure and cytochemistry. The phagocytes that had not been activated previously proliferated for about ten generations in F12 medium supplemented with 10% fetal calf serum depending on a growth factor produced by hamster brain, liver or lung cells. Without the factor, the cells quickly cytolysed. Mononuclear phagocytes from blood had the same characteristics of growth and cytochemistry, but had fewer IgG receptors at the cell surface than similar cells from the liver and lung. The effects of a variety of chemical compounds on the growth of the liver and lung cells were studied. Insulin stimulated their growth by 20-30%, but was not replaceable for the growth factor. Glucocorticoids, dexamethasone and hydrocortisone, inhibited the growth of the phagocytes at the physiological concentrations: 3 x 10(-9) M and 2 x 10(-8) M for 50% inhibition, respectively. Indomethacin, non-steroid anti-inflammatory reagent, at 10(-8) M to 10(-6) M gave no effect. Choleragen that increases the intracellular cyclic AMP level, inhibited the growth at a concentration as low as 5 pg/ml. These data suggest that the growth of mononuclear phagocytes is controlled not only by a growth factor produced by other cells but also by glucocorticoids.

Animals↗

PubMed2002

Oxidative stress in phagocytes--"the enemy within".

Phagocytes represent a powerful defense system against invading microorganisms that threaten the life or functional integrity of the host. The capacity to generate and release substantial amounts of reactive oxygen species is a unique property of activated polymorphonuclear and mononuclear phagocytes. The crucial role of these molecules in killing microorganisms and their consecutive contribution to tissue damage during injury and inflammation is widely known. Although much research has been done to explore the molecular events involved in the interaction of oxygen intermediates with microbes or host tissue, surprisingly little attention has been paid to the effect of reactive metabolites on the phagocyte itself. This fact is especially surprising, since it is apparent that the activated phagocyte is directly exposed to its own toxic metabolites. The potential damage occurring during excessive radical formation might notably alter the vital functions of these primarily immunocompetent cells. Moreover, the critical role of oxygen radicals in apoptosis of leukocytes has been recently revealed. Apoptosis is now supposed to represent a key mechanism in neutrophil deactivation and resolution of inflammation. Therefore, this review will focus on the delicate balance between released oxidants and antioxidative protection within the phagocytes themselves. General and phagocyte-specific antioxidative mechanisms, which have co-evolved with the radical generating machinery of phagocytes, are discussed, since the outcome of local inflammation can directly depend on this antioxidative capacity and might range from adequate elimination of the pathogen with minimal acute tissue damage to progression towards a systemic inflammatory response syndrome.

Animals↗

PubMed2000

Neither Fas ligand nor endotoxin is responsible for inducible peritoneal phagocyte apoptosis during sepsis/peritonitis.

Regulation of the phagocyte apoptotic response appears to play a significant role in the pathophysiology of sepsis. In this regard, prior studies have shown that the onset of phagocyte apoptosis, as well as those agents that regulate it at the nidus of infection, differ significantly from those seen in circulation. The aim of this study therefore was to determine if the increase in inducible phagocyte apoptosis and caspase activities seen in the peritoneum during sepsis is due to endotoxin or Fas ligand. To study this, male C3H/HeN (endotoxin-sensitive), C3H/HeJ (endotoxin-tolerant), and C3H/HeJ-FasL(gld) (endotoxin-tolerant/FasL-deficient) mice were subjected to cecal ligation and puncture or sham operation. Twenty-four hours later, phagocytes were collected and cultured with lipopolysaccharide (LPS), then harvested for apoptosis (propidium iodide cell cycle or cell death ELISA analysis), cytokine release (ELISA), and caspase activity (fluorogenic assay) determination. The data indicate that there was a marked increase in apoptosis in LPS-stimulated phagocytes which was associated with a significant increase in caspase 3, 8, and 9 activities but a decrease in caspase 1 activity from C3H/HeN and C3H/HeJ-FasL(gld) septic mice and an increase in caspase 3 and 8 activities in phagocytes from C3H/HeJ septic mice. Furthermore, cells from septic mice, including all three strains, lost their ability to produce IL-1beta and IL-6 in response to LPS stimulation. The inability to completely suppress these changes suggests that neither endotoxin (via signaling through TLR-4 pathway) nor Fas ligand regulates the peritoneal phagocyte apoptotic responses seen during the late phase of polymicrobial sepsis/peritonitis.

Animals↗

PubMed1992

Effect of Aeromonas hydrophila enterotoxins on function of mouse phagocytes.

Two enterotoxins produced by Aeromonas hydrophila isolate SSU have been characterized in this laboratory. One is a cholera toxin cross-reactive cytolytic enterotoxin (CTC toxin) and the other is a non-cholera toxin cross-reactive cytotonic enterotoxin (non-CTC toxin). The two enterotoxins are capable of causing fluid accumulation in animal models; however, only the CTC toxin is lethal to mice and expresses hemolytic as well as cytotoxic activities. In this study, we have investigated the effects of these two toxins on mouse phagocytes. Four hours after intraperitoneal injection of a sublethal dose (460 micrograms/kg of body weight) of CTC toxin, the chemiluminescence (CL) response of phagocytes in mouse blood was depressed significantly when compared with that observed for controls (intraperitoneal injection of only Hanks' balance salt solution, non-CTC toxin or before treatment with CTC toxin). When fresh whole blood was incubated with various concentrations (2.3, 11.5, 23, 230, 2300 ng/ml) of CTC toxin for 1.5 hr at 37 degrees C, the CL response of blood phagocytes was reduced strikingly in a dose-dependent fashion; however, non-CTC toxin did not inhibit the CL response. The inhibitory effect induced by CTC toxin of the phagocytic function not only was abolished completely, but phagocytosis was enhanced in the presence of interferon-gamma (IFN-gamma). In addition, IFN-gamma alone induced the largest enhancement of the CL response in mouse phagocytes. These results demonstrated that CTC toxin inhibits the phagocytic ability of phagocytes either in vivo or in vitro and that IFN-gamma pretreatment can overcome this toxic effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Aeromonas hydrophila↗