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Biomedical subjects

J Gauldie

Publications and source records attributed to J Gauldie.

At least 199 records · Page 11Linked to original sources
PubMed1987

Alveolar macrophage/peripheral blood monocyte-derived factors modulate proliferation of primary lines of human lung fibroblasts.

Pulmonary fibrosis is characterized by an alteration in lung collagen synthesis and deposition, as well as by increased fibroblast proliferation. It is also characterized by an intermittent influx of immune and inflammatory cells in the lung. To investigate the nature of the target cell in this disorder, we established a series of primary lines of human adult lung fibroblasts and studied the effect of mediators released from activated normal human alveolar macrophages (AM) and peripheral blood monocytes (PBM) on the proliferation of both normal lung fibroblasts and fibroblasts established from lung tissue of patients with active fibrosis. Our data show that monocyte supernatants containing a 15-18 kD monokine from either AM or PBM inhibits growth of logarithmic phase proliferating lung fibroblasts in a dose-dependent manner. This effect can be entirely abrogated by treating the fibroblasts with indomethacin and is reconstituted by adding exogenous PGE2. A study of the kinetics of this interaction shows that exposure to monocyte supernatant for 30 min to 1 hr is sufficient to cause significant inhibition of fibroblast proliferation and that this effect can be halted, but not reversed, at any stage by incubation with indomethacin. We also show that fibroblasts derived from patients with pulmonary fibrosis are affected more quickly by exposure to the mediators, although the final extent of inhibition seen at each concentration of mediators is similar in normal and "fibrotic" fibroblasts. These studies indicate that activated AM or PBM release cytokines (including IL-1) which inhibit the growth of proliferating normal and fibrotic fibroblasts through activation of the intrinsic arachidonic acid pathway of this cell and also that this effect requires a continuous activation of this pathway to be fully expressed.

Biological Products↗
PubMed1987

Role of epidermal cell thymocyte-activating factor in the proliferation and differentiation of murine B cells.

The role of antigen nonspecific cytokines in T- and B-lymphocyte responses is now well established. Interleukin-1 (IL-1) has been shown to augment B-cell maturation and proliferation. While the major source of IL-1 is from monocytes or macrophages, other cell types have been shown to produce IL-1-like cytokines. Epidermal cells produce a cytokine termed "epidermal cell-derived thymocyte-activating factor" (ETAF) which is similar if not identical with monocyte-derived IL-1. In this report we show that ETAF induces polyclonal stimulation of murine B cells. We show that ETAF augments B cell proliferation and differentiation in the absence of any added antigens or mitogens. This activity can be partially inhibited by anti-IL-1 antibodies. ETAF appears to activate B cells directly, although its activity is increased in the presence of T cells. Thus, ETAF may be involved in local polyclonal antibody responses occurring in the skin.

Animals↗
PubMed1987

Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells.

One of the oldest and most preserved of the homeostatic responses of the body to injury is the acute phase protein response associated with inflammation. The liver responds to hormone-like mediators by the increased synthesis of a series of plasma proteins called acute phase reactants. In these studies, we examined the relationship of hepatocyte-stimulating factor derived from peripheral blood monocytes to interferon beta 2 (IFN-beta 2), which has been cloned. Antibodies raised against fibroblast-derived IFN-beta having neutralizing activity against both IFN-beta 1 and -beta 2 inhibited the major hepatocyte-stimulating activity derived from monocytes. Fibroblast-derived mediator elicited the identical stimulated response in human HepG2 cells and primary rat hepatocytes as the monocyte cytokine. Finally, recombinant-derived human B-cell stimulatory factor type 2 (IFN-beta 2) from Escherichia coli induced the synthesis of all major acute phase proteins studied in human hepatoma HepG2 and primary rat hepatocyte cultures. These data demonstrate that monocyte-derived hepatocyte-stimulating factor and IFN-beta 2 share immunological and functional identity and that IFN-beta 2, also known as B-cell stimulatory factor and hybridoma plasmacytoma growth factor, has the hepatocyte as a major physiologic target and thereby is essential in controlling the hepatic acute phase response.

Acute-Phase Proteins↗
PubMed1987

Mast cell involvement in various inflammatory processes.

Mast cells from different tissue sites may have different histochemical, chemical, and functional properties. Whatever the basis for these differences, they must be important in terms of their biologic significance. Through their mediators, mast cells are involved in many different acute and chronic inflammatory processes. They act in delayed hypersensitivity, immediate hypersensitivity, and in granulomatous reactions. They can influence phagocytosis, chemokinesis, and many aspects of immune activity in several different T and B cell pathways, to mention only a few effects. Mast cells are involved in repair processes including fibroblast function and fibrosis. Their growth may be influenced by T cell-derived factors as well as factors derived from the epithelium. They appear to be intimately involved with nerves and can form apparent communications with neurones, especially those containing Substance P, which causes all types of mast cells to degranulate. Mast cells may therefore act as central switchboards between the central nervous system and migrating and sessile cell types in inflammatory processes.

Animals↗
PubMed1987

Purified interleukin-1 (IL-1) from human monocytes stimulates acute-phase protein synthesis by rodent hepatocytes in vitro.

A universal component of inflammation is the increased synthesis of a series of plasma proteins (acute-phase proteins) by the liver. The postulated messenger of acute-phase protein induction is released by leucocytes at the site of inflammation and has been shown to co-purify with endogenous pyrogen or lymphocyte-activating factor. Interleukin-1, molecular weight 17,000, pI 6 X 8-7 X 2, was purified to homogeneity from adherent human blood monocytes by a combination of affinity chromatography, gel filtration and isoelectric focusing. We examined the direct effect of pure IL-1 on the induction of acute-phase protein synthesis in vitro using rat and mouse hepatocytes. IL-1 caused significant increased synthesis of alpha 1-acid glycoprotein and smaller increases in the synthesis of other acute-phase proteins, and significant decreased synthesis of albumin. The pattern of induction of acute-phase proteins differs from that seen with a separate 30,000 molecular weight hepatocyte-stimulating factor from human monocytes described previously. We conclude that human IL-1 is one of the mediators responsible for the acute-phase protein response of the liver in inflammation and can directly cause stimulation of specific gene expression in normal hepatocytes.

Acute-Phase Proteins↗
PubMed1987

Comparison of the acute phase response of cultured Morris hepatoma 7777 cells and of rat hepatocytes.

Isolated Morris hepatoma cells (line 7777) or adult rat hepatocytes were cultured for 3 days and daily production of four plasma proteins was estimated in the cell media by rocket immunoelectrophoresis with monospecific antisera. Addition of cytokines from rat peritoneal macrophages to cultured hepatocytes or hepatoma cells augmented accumulation in the medium of two positive acute phase proteins: fibrinogen (FIB) and cysteine proteinase inhibitor (CPI). At the same time synthesis of alpha-fetoprotein (AFP) was inhibited in hepatoma cells but remained undetectable in hepatocytes. Rat macrophage cytokines typically depressed synthesis of albumin (ALB) in cultured rat hepatocytes but increased production of this protein by hepatoma cells.

Acute-Phase Proteins↗
PubMed1987

Limited effects of recombinant human and murine interleukin 1 and tumour necrosis factor on production of acute phase proteins by cultured rat hepatocytes.

Albumin, fibrinogen, alpha 1-acid glycoprotein and cysteine proteinase inhibitor were determined by electroimmunoassay in the media of primary cultures of rat hepatocytes exposed to dialysed supernatants of rat, mouse and human macrophages or to recombinant human and murine interleukin 1 and tumour necrosis factor. Recombinant cytokines in the range of 1 to 1000 ng/ml caused only reduction of albumin synthesis and slight stimulation of alpha 1 acid glycoprotein production while crude preparations of macrophage cytokines elicited typical acute phase response. The results suggest that interleukin 1 or tumour necrosis factor are not likely the principal mediators responsible for the direct stimulation of normal rat hepatocytes to acute phase protein synthesis.

Animals↗
PubMed1986

Unique characteristics of local responses in host resistance to mucosal parasitic infections.

Because of the tremendous impact that parasitic infections have on the health and productivity of humans and domestic animals, considerable research effort has been focused upon understanding the mechanisms of host-parasite coexistence, host resistance and immunopathology. Studies have employed a range of approaches including: kinetic analysis of parasite establishment, development, fecundity and survival in naive and previously-infected hosts; correlation between parasite survival and histopathologic responses at the site of infection; vaccination with attenuated parasites or their products; cellular and serum transfer of immunity to naive or immunocompromised hosts; pharmacologic manipulation of potential mediators of host defense using agonistic and antagonistic drugs. However, it is becoming increasingly clear that to understand the mechanisms associated with host resistance and parasite survival, one must define the characteristics of the local microenvironment at the host-parasite interface. One of the approaches by which such studies can be made involves the isolation and characterization of cells derived from the local infection site. This manuscript reviews some of these studies on local aspects of mucosal immune responses in parasitic infections. Examples that will be discussed include IgA antibody, intraepithelial leukocytes from the intestine, intestinal mast cell populations, macrophages derived from bronchoalveolar lavage, and local immunoregulatory responses during respiratory and intestinal parasitic infection. These studies have established unequivocally that local responses to mucosal parasitic infection can only be appropriately investigated using cells derived from the specific microenvironment. This conclusion should encourage others to further study these local responses and to be innovative in investigating unexplored aspects of the host-parasite interface.

Animals↗
PubMed1986

Bleeding time in hemophilia A: potential mechanisms for prolongation.

Prolongation of bleeding time has been previously observed in hemophilia, although no cause has been elucidated. We measured bleeding time, platelet aggregation, nucleotide release, and thromboxane B2 (TXB2), plasma 6-keto-PGF 1 alpha, platelet-associated IgG (PAIgG), and circulating immune complexes in 31 unselected patients with severe hemophilia A and in 17 controls. In 85% of patients with hemophilia A, the bleeding time was greater than 2 SD above the control level (greater than 8 minutes). Sixty-six percent of patients with hemophilia A had circulating immune complexes, and there was a striking relationship between the presence of these complexes and prolonged bleeding time. Plasma 6-keto-PGF 1 alpha levels were significantly elevated in the patient group, and correlated with bleeding time changes. Platelet aggregation and nucleotide release were normal in the patients with hemophilia, although reduced platelet TXB2 biosynthesis was noted in 26%. No correlation was demonstrated between bleeding time and impairment of platelet TXB2 formation. Seventy-two percent of the patients with hemophilia A had elevated levels of PAIgG, and an inverse relationship between PAIgG and platelet count was observed. No relationship was noted between platelet count and bleeding time. This study indicates that the majority of patients with hemophilia A have prolonged bleeding times. The close correlation between bleeding time, plasma 6-keto-PGF 1 alpha levels, and the presence of circulating immune complexes suggests a role for immune complex-mediated defects in vascular function as the basis for bleeding time prolongation.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Interleukin-1 and interleukin-2 production in resistant and susceptible inbred mice infected with Trypanosoma congolense.

In vitro production of interleukin-1 (IL-1) by LPS-stimulated adherent peritoneal exudate and spleen cells and alveolar macrophages, and interleukin-2 (IL-2) by concanavalin A-stimulated splenocytes were measured in resistant (C57BL/6J) and susceptible (A/J) inbred mice during the early stages of subacute infections with the African trypanosome, Trypanosoma congolense. Production of IL-1 was severely depressed in both mouse strains as early as 24 hr after intraperitoneal injection of bloodstream trypanosomes. Similarly, in both mouse strains, an early decline in IL-2 activity was observed, followed by partial recovery then depression to subnormal levels. These changes in measurable IL-1 and IL-2 activity in infected mice concurred with progressive depression in the spleen cell proliferative response to the mitogen concanavalin A.

Animals↗
PubMed1985

A simple bioassay for monocyte-derived hepatocyte stimulating factor: increased synthesis of alpha 2-macroglobulin and reduced synthesis of albumin by cultured rat hepatocytes.

Cytokines released from monocytes upon stimulation by lipopolysaccharide cause a number of cells to undergo proliferative and synthetic changes. At least one of these cytokines affects hepatocytes in vivo causing increased synthesis of a series of acute-phase proteins. We have established an in vitro micro-assay for hepatocyte stimulating factor (HSF) using primary cultures of normal rat hepatocytes. Measurement of increased synthesis of alpha 2-macroglobulin and decreased synthesis of albumin caused by exogenously added factor constitute a sensitive parameter for quantifying HSF. For comparing various cytokines preparations, we have defined a unit of HSF activity in terms of a stimulation index. We have used this assay to follow some preliminary attempts to isolate the factors responsible for stimulation of synthesis of acute-phase reactant by the liver.

Acute-Phase Proteins↗
PubMed1985

Multinucleate giant cells in murine and rat lungs during Nippostrongylus brasiliensis infections. A study of the kinetics of the response in vivo, cytochemistry, IgG- and C3-mediated functions.

The cytochemical and functional characteristics of broncho-alveolar multinucleate giant cells and the kinetics of the giant cell response in the lungs of mice and rats during Nippostrongylus brasiliensis infection were studied. Primary infections resulted in significantly increased numbers of recoverable giant cells for up to 30 and 50 days in rats and mice, respectively. During secondary infections in the rat the giant cell response was more rapid and greater in magnitude than in a primary infection, suggesting that it was immunologically mediated. The giant cells displayed decreased C3- and IgG-dependent binding or phagocytic potential compared with mononucleate alveolar macrophages. Fusion of mononucleate alveolar macrophages into giant cells may therefore compromise complement and antibody dependent helminthocidal activity of these cells.

Animals↗
PubMed1985

Acute phase response in infectious disease.

In considering the pathology associated with infectious diseases, the most common host response to such infection is inflammation. The mechanism(s) whereby inflammation is initiated and the cell types involved will dictate the kinds of acute phase plasma changes that can be seen associated with the infection. Bacteria seem to initiate the classical type of inflammatory response and plasma protein changes similar to those seen in experimental inflammation induced by chemical means. Viruses, on the other hand, in the absence of cytopathology do not appear to induce the same kind of inflammatory changes and avoid the induction of the acute phase protein response since they may not initiate activation of monocytes and/or macrophages. Those viruses that do cause macrophage activation would be expected to have acute phase protein changes associated with that activation. Parasites, however, appear to initiate the acute phase plasma response only when their migration leads to tissue destruction and local inflammation such as caused by parasitemia with Trypanosoma cruzi in the mouse or with migration of Nippostrongylus brasiliensis in the rodent. Human parasitic diseases require much more investigation in order to clarify the role played by acute phase proteins in the subsequent establishment of the host-parasite relationship. We postulate that the macrophage or monocyte on interaction with the infectious pathogen becomes activated and secretes a number of factors, including interleukin 1 and hepatocyte-stimulating factor, which have a marked effect on the total acute phase reaction. In addition to an effect on phagocytic and immune systems, the mediators cause hepatocytes to markedly increase the secretion of plasma acute phase proteins. Some of these proteins return to the site of inflammation and interact with the infectious pathogen and/or cells and proteins of the host, thereby affecting the final outcome of inflammation. We also propose that the initial interaction of an organism such as a parasite and the mammalian host involves early recognition by the macrophage, thereby initiating both the humoral and cellular acute phase reactions and subsequently affects the immune response against the parasite. Variations in the acute phase reaction may help to explain differences in susceptibility to infectious organisms and the presence or lack of host killing mechanisms for the parasite.

Acute-Phase Proteins↗
PubMed1985

Synthesis of alpha 1-protease inhibitor by resident and activated mouse alveolar macrophages.

Alpha 1-protease inhibitor (alpha 1Pi), an acute-phase reactant, is the major inhibitor of neutral proteases causing lung tissue injury, such as elastase. While examining the acute-phase reaction to the nematode parasite Nippostrongylus brasiliensis, we noticed that the alveolar macrophage was closely associated with alpha 1Pi when the larvae were present in the lung. Histologic examination revealed marked edema and hemorrhage with numerous alveolar macrophages that stain intensely for intracellular alpha 1Pi. Isolation of these cells by bronchoalveolar lavage showed the macrophage to be activated. Cultured alveolar macrophages from normal and infected animals synthesized and secreted alpha 1Pi, as revealed by [35S]-methionine incorporation, but the amounts were insignificant compared with that synthesized by hepatocytes. There was, however, no apparent difference in alpha 1Pi synthetic activity between normal and activated macrophages. The presence of demonstrable intracellular alpha 1Pi in the parasite-activated alveolar macrophage likely represents endocytosis as host protease- and/or parasite protease-antiprotease complexes. Although alpha 1Pi is synthesized primarily by hepatocytes, synthesis by alveolar macrophages may provide immediate local protection in the microenvironment of the lung during an acute inflammatory response.

Animals↗
PubMed1985

In vivo initiation of unstimulated in vitro interleukin-1 release by alveolar macrophages.

Alveolar macrophages (AM) can be stimulated in vitro with material such as lipopolysaccharide, and this activation releases cytokines, collectively called interleukin-1, that can stimulate local cells such as fibroblasts, systemic cells such as lymphocytes, and/or distant parenchymal cells such as hepatocytes. During murine infection with the nematode Nippostrongylus brasiliensis, AM are activated as the parasite larvae migrate through the lung. We examined AM for unstimulated release of lymphocyte-activating factor (LAF) and hepatocyte-stimulating factor (HSF) as evidence of in vivo activation. Two days after infection, marked unstimulated release of LAF was demonstrated along with a smaller increase in unstimulated release of HSF activity. Release of both activities could be further augmented by in vitro stimulation with lipopolysaccharide. Eight days after infection unstimulated HSF activity was even higher than on Day 2, whereas unstimulated LAF release returned to normal. These findings suggest that a natural infective process causes activation of the resident AM population, resulting in release of potent immune and inflammatory-modulating cytokines in situ and that AM play a crucial role in the initiation of host defense and repair responses to infection.

Animals↗
PubMed1985

IgA-mediated phagocytosis by mouse alveolar macrophages.

Ingestion of antibody-opsonized sheep red blood cells by murine alveolar and peritoneal exudate macrophages was studied. Alveolar macrophages or peritoneal macrophages were isolated by lavage and incubated with TNP-SRBC, which had been preincubated with anti-DNP IgG, IgA, and IgE. Significant enhancement of phagocytosis by alveolar macrophages of TNP-SRBC was mediated by all classes of antibody examined, most markedly with IgG and less so with IgA and IgE. Enhancement of phagocytosis by peritoneal macrophages was mediated by IgG and IgE, but not by IgA. These results suggest that the interaction of IgA and Fc receptors for IgA on alveolar macrophages may increase the level of this cell's function in the mammalian lung to clear pathogens and immune complexes from the alveolar spaces.

Animals↗
PubMed1985

The concentration of IgG in the serum is a major determinant of Fc-dependent reticuloendothelial function.

Defective Fc receptor-specific reticuloendothelial (RE) function has been reported in certain patients with a variety of immunologic and nonimmunologic diseases. The mechanism responsible for the impaired RE function is uncertain, but it could be caused by immune complexes that are present in many of these disorders. Alternatively, the impaired RE function could be a secondary effect of the high concentrations of monomeric IgG in the serum of these patients, since monomeric IgG can compete with complexed IgG for macrophage receptors in vitro. We studied the Fc-dependent RE function in 30 healthy control subjects and 27 patients using IgG-coated radiolabeled autologous red cells. There was a significant relationship between the concentration of IgG in the serum and the rate of clearance of antibody-sensitized cells (r = 0.51, P less than .01). Patients with hypergammaglobulinemia had the slowest Fc-dependent clearance, whereas those with hypogammaglobulinemia had the most rapid clearance. Immune complexes (Raji or polyethylene glycol) could not be shown to contribute to Fc-dependent RE clearance above the effect of the IgG in the serum. The unusually rapid clearance in a patient with hypogammaglobulinemia could be returned to normal by raising the concentration of IgG in the serum. This study supports the concept that serum (monomeric) IgG competes with immune complexed IgG for macrophage Fc receptors in vivo. The competition for Fc receptors determines the level of competence of Fc-dependent RE function. Based on the results of this study, one can predict that a number of disorders characterized by hypergammaglobulinemia also will have impaired Fc-dependent RE function.

Agammaglobulinemia↗