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Biomedical subjects

J S Warren

Publications and source records attributed to J S Warren.

At least 37 records · Page 2Linked to original sources
PubMed1997

Chemokine expression in experimental tubulointerstitial nephritis.

Chemokines may be important in the pathogenesis of leukocyte infiltration in tubulointerstitial nephritis associated with glomerular disease. We studied the renal cortical expression of the C-C (macrophage inflammatory protein-1alpha (MIP-1alpha)), monocyte chemotactic protein-1 (MCP-1), and RANTES) and C-X-C (interferon-inducible protein-10 (IP-10), MIP-2, and cytokine-induced neutrophil chemoattractant (CINC)) chemokines 4, 6, 8, 10, 14, and 21 days after the induction of puromycin aminonucleoside (PAN) nephrosis. There was a 7- to 10-fold increase in the steady state mRNA expression of IP-10 and MCP-1 in the renal cortex of rats 6 to 8 days after the administration of PAN that declines thereafter reaching control values by day 21. The site of IP-10 and MCP-1 mRNA production was localized to intrinsic tubulointerstitial cells and not to infiltrating monocytes or macrophages. By comparison, there was a low basal expression of RANTES mRNA in the renal cortex of nephrotic rats that did not differ from those of control rats. In contrast, CINC, MIP-2, and MIP-1alpha mRNAs were not detected. Translation of MCP-1 mRNA into protein was confirmed with an ELISA. These changes in chemokine gene expression were associated with a tubulointerstitial T lymphocyte and macrophage infiltration beginning on day 6 that peaked on day 10. Administration of a neutralizing Ab to rat MCP-1 (n = 5) beginning on day 4 resulted in a 45% decline in tubulointerstitial macrophage infiltration from 8.4 +/- 1.3% to 4.6 +/- 0.4% (p < 0.001) on day 6. These data provide evidence that MCP-1, and possibly IP-10, are important in the pathogenesis of monocyte/macrophage infiltration in the tubulointerstitial nephritis associated with PAN nephrosis.

Animals↗
PubMed1997

Comparison of the ultrasonic scalpel to CO2 laser and electrosurgery in terms of tissue injury and adhesion formation in a rabbit model.

OBJECTIVE: To determine the relative effect of an ultrasonic scalpel on reproductive tissue compared with CO2 laser and electrosurgery. DESIGN: Prospective, randomized animal study. SETTING: University laboratory setting. ANIMALS: Sixteen New Zealand White rabbits. INTERVENTION(S): A steel scalpel, an ultrasonic scalpel, a CO2 laser, or electrosurgery were used to perform an ovarian wedge resection and to remove the distal uterine horn. A 3-cm longitudinal incision also was made in the uterine horn. MAIN OUTCOME MEASURE(S): The number of 1-second bursts of needle-tip electrosurgery required for hemostasis, the depth and degree of coagulation necrosis, degree of fibrin deposition, and postoperative adhesion formation. RESULT(S): The amount of electrosurgery needed to achieve hemostasis was less for any of the four power techniques than for the steel scalpel, with the exception of the ultrasonic scalpel at level 5 when used on the ovary. The depth (range: 0.30 to 0.38 mm) and the degree of coagulation necrosis was not different for any of the power techniques. The fibrin score was greatest for the ultrasonic scalpel at level 5 in both the ovarian tissue and the uterine tissue. There was no difference in adhesion scores for the power techniques and the steel scalpel. CONCLUSION(S): The ultrasonic scalpel at level 3 is not different from either CO2 laser or electrosurgery in terms of hemostatic properties, coagulation necrosis, or adhesion formation in the rabbit model.

Animals↗
PubMed1997

Hypoxic-ischemic injury induces monocyte chemoattractant protein-1 expression in neonatal rat brain.

Monocyte chemoattractant protein-1 (MCP-1) regulates monocyte accumulation in several macrophage-dependent experimental disease models. In the neonatal brain, activated microglia accumulate rapidly after hypoxic-ischemic injury. These cells produce potentially neurotoxic factors that may contribute to the progression of injury. To determine whether MCP-1 could be one of the molecular signals that influences the microglial response to hypoxic-ischemic injury in the neonatal brain, we examined the impact of acute hypoxic-ischemic injury on MCP-1 mRNA and protein expression. Seven-day-old rats underwent right carotid artery ligation, followed by 3 hours of 8% oxygen exposure, to elicit ipsilateral forebrain hypoxic-ischemic injury. To detect MCP-1 mRNA in situ hybridization assays were performed using 35S-labeled antisense riboprobes generated from rat MCP-1 cDNA. Animals were evaluated 0, 1, 2, 4, 8, 16, 24, 48, and 120 hours after hypoxic exposure (N > or = 3/group). Immunocytochemistry (with a polyclonal rabbit antirat MCP-1 antibody) was used to determine the anatomic and temporal distribution of MCP-1, in samples obtained 10 minutes to 5 days after hypoxic exposure (N > or = 3/group). Monocyte chemoattractant protein-1 mRNA was first detected in periventricular regions of the lesioned hemisphere 1 hour after hypoxia-ischemia; periependymal and intraparenchymal MCP-1 mRNA expression were detected at 4 hours; hybridization signal peaked at 8 to 24 hours; and no MCP-1 mRNA was detected at 48 and 120 hours. In lesioned forebrain, MCP-1 protein expression were consistently detected at 2.5 to 48 hours after hypoxia-ischemia. Many immunoreactive cells appeared to be neurons. These results suggest that in the developing brain, MCP-1 could represent a functionally important molecular signal for the microglial response to hypoxic-ischemic injury.

Animals↗
PubMed1997

Neutrophils and reactive oxygen intermediates mediate glucan-induced pulmonary granuloma formation through the local induction of monocyte chemoattractant protein-1.

Monocyte chemoattractant protein-1 (MCP-1), which is required for full development of glucan-induced granulomas, in the rat, is expressed in the walls of blood vessels at sites of glucan embolization. Early (1 hour) vessel wall expression of MCP-1 is temporally and anatomically linked to the transient accumulation of neutrophils, even though these cells are not present within definitive lesions. To ascertain the potential pathophysiologic role of neutrophils in glucan-induced granuloma formation, rats were neutrophil-depleted using specific antiserum. There was a marked reduction in mean granuloma size and number in neutrophil-depleted animals when compared with neutrophil-sufficient controls. To determine potential mechanisms through which neutrophils may participate in granuloma formation, the antioxidant enzymes superoxide dismutase and catalase were administered to neutrophil-sufficient animals that had received glucan. Superoxide dismutase treatment did not reduce granuloma formation, whereas catalase treatment resulted in decreased granuloma size, suggesting that H2O2 plays an important role in this process. The local expression of MCP-1 mRNA and protein, as determined by in situ hybridization and immunohistochemical analysis, respectively, was decreased in both neutrophil-depleted and catalase-treated animals but not in superoxide dismutase-treated rats. Quiescent human umbilical vein endothelial cells incubated with either H2O2 or activated neutrophils secreted MCP-1. These data indicate that neutrophils and H2O2 are required for both full granuloma development and early blood vessel wall-associated MCP-1 expression after glucan infusion. These in vivo data, coupled with in vitro data that indicate that both catalase-sensitive reagent H2O2 and neutrophil-derived reactive oxygen intermediates (ie, H2O2) can induce MCP-1 secretion by human umbilical vein endothelial cells, support the hypothesis that neutrophils and neutrophil-derived products (H2O2) influence granuloma formation through induction of local MCP-1 expression.

Animals↗
PubMed1997

Sublytic concentrations of the membrane attack complex of complement induce endothelial interleukin-8 and monocyte chemoattractant protein-1 through nuclear factor-kappa B activation.

Activation of the complement cascade and subsequent assembly of the membrane attack complex (MAC) occur in a number of pathophysiological settings. When formed on the surface of endothelial cells in sublytic concentrations, the MAC can induce a number of proinflammatory activities, including the secretion of soluble mediators (eg, interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1) and the up-regulation of cell surface adhesion molecules. Available data indicate that MAC-induced cell activation may occur through several complex signal transduction pathways, but little is known about the intranuclear mechanisms by which complement-derived products promote the up-regulation of inflammatory mediators. Using purified distal complement proteins (C5-9) to assemble functional MAC on early-passage human umbilical vein endothelial cells (HUVECs), we examined mechanisms of MCP-1 and IL-8 induction. Formation of sublytic concentrations of MAC promoted an increase in nuclear factor (NF)-kappa B DNA binding activity within 60 minutes as determined by serial electrophoretic mobility shift assay. Cytosolic to nuclear translocation of NF-kappa B was confirmed by Western immunoblot and immunocytochemical analyses. Formation of the C5b-8 complex also promoted NF-kappa B translocation but to a lesser degree than observed in HUVECs containing complete MAC. No cytosolic to nuclear translocation of the p65 NF-kappa B subunit was observed in unstimulated HUVECs or in cells incubated with the MAC components devoid of C7. Preincubation of HUVECs with pyrrolidine dithiocarbamate prevented MAC-induced increases in IL-8 and MCP-1 mRNA concentrations and protein secretion. A direct cause and effect linkage between MAC assembly and NF-kappa B activation was established through examination of the pharmacological effect of the peptide SN50 on IL-8 and MCP-1 expression. SN50 is a recently engineered 26-amino-acid peptide that contains a lipophilic cell-membrane-permeable motif and a nuclear localization sequence that specifically competes with the nuclear localization sequence of the NF-kappa B p50 subunit. This study provides direct in vitro evidence that the distal complement system (MAC) can promote proinflammatory endothelial cell activation, specifically, increases in IL-8 and MCP-1 mRNA concentrations and protein secretion, and that cytosolic to nuclear translocation of NF-kappa B is necessary for this response.

Blotting, Northern↗
PubMed1997

Cytokines in autoimmune disease.

Cytokines are peptide hormones that regulate a wide variety of immune and inflammatory processes. Individual cytokines are produced by many different cell types and exhibit pronounced pleiotropism. Cytokines such as tumor necrosis factor alpha interleukins -5, -10, and -12 play important roles in immunity. Interleukins -2 and -4, and transforming growth factor gamma mediate lymphocyte activation and differentiation.

Autoimmune Diseases↗
PubMed1996

Expression and function of monocyte chemoattractant protein-1 in experimental nephrotic syndrome.

This study investigates the expression and function of monocyte chemoattractant protein-1 (MCP-1) in rats with aminonucleoside nephrosis induced by a single intraperitoneal injection of puromycin aminonucleoside (PAN). On Day 7, PAN-treated rats had a sixfold increase in renal MCP-1 messenger (m)RNA levels and a twofold increase in interleukin-1 beta mRNA levels. During the course of PAN nephrosis, most of the de novo MCP-1 protein resembled protein droplets that were prominent in glomeruli between Days 3 and 14 and weaker but visible in tubules between Days 5 and 10. In addition, occasional tubules showed a cytoplasmic staining pattern for MCP-1. Two studies evaluated the effect of MCP-1 neutralization on renal monocyte recruitment. In the first study, PAN-treated rats were treated with affinity-purified MCP-1-neutralizing rabbit IgG on Days 0, 1, 3, and 5; kidneys were harvested on Day 7. There was no difference in the mean number of interstitial macrophages [119 +/- 28 vs 88 +/- 9 ED-1+ cells/1000 tubulointerstitial (TI) cells; 106 +/- 28 vs 119 +/- 33 Ia+ cells/1000 TI cells] or intraglomerular macrophages [2.0 +/- 0.9 vs 1.7 +/- 0.5 ED-1+ cells/glomerular cross section (gcs); 1.2 +/- 0.3 vs 1.1 +/- 0.4 Ia+ cells/gcs] compared with nephrotic rats treated with nonimmune rabbit IgG. In the second study, a group of PAN-treated rats was treated with MCP-1-neutralizing IgG administered continuously by an intraperitoneal miniosmotic pump for 7 days and was compared with a control group treated in an identical fashion with PAN and nonimmune IgG. On Day 7 there was no difference in the mean number of interstitial macrophages (55 +/- 45 vs 67 +/- 16 ED-1+ and 70 +/- 63 vs 61 +/- 13 Ia+ cells/1000 TI cells) and intraglomerular macrophages (1.0 +/- 0.4 vs 1.6 +/- 0.9 ED-1+ and 0.6 +/- 0.1 vs 1.1 +/- 0.7 Ia+ cells/gcs). The results of this study suggest that although MCP-1 gene and protein expression are increased in the kidneys of rats with aminonucleoside nephrosis, MCP-1 does not appear to play an essential role in early renal monocyte recruitment in this model.

Animals↗
PubMed1996

Role of intercellular adhesion molecule-1 in glucan-induced pulmonary granulomatosis in the rat.

Glucan-induced pulmonary granulomatous vasculitis in the rat mimics several human lung diseases (e.g., Wegener's granulomatosis, intravenous talcosis). We sought to clarify the role of intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of glucan-induced granulomatous vasculitis. Immunohistochemical analysis of lung sections from rats with florid vasculitis (48 hours) revealed marked alveolar septal and lesional expression of ICAM-1. An ex vivo binding analysis with isotope-labeled antibodies and lung sections taken at various times up to 48 hours after glucan infusion revealed a progressive increase in whole-lung ICAM-1 expression. In vivo measurements of vascular wall-associated ICAM-1 expression revealed an earlier rise that began less than 6 hours after glucan infusion, peaked at 24 to 48 hours, and then declined to near baseline during the ensuing 24 to 96 hours. To assess whether ICAM-1 expression both within blood vessel walls and within lesions per se is important in granuloma development, we carried out in vivo neutralization experiments with several different routes of administration of antibody to ICAM-1. Monoclonal antibody to rat ICAM-1 was either infused intravenously at time 0 (when glucan was infused), infused intravenously at time 0 and after 24 hours, instilled only intratracheally 24 hours after glucan infusion, or given both intravenously (time = 0 and 24 hours) and intratracheally (time = 24 hours). Infusions of monoclonal antibody to rat ICAM-1 resulted in dose-dependent reductions in mean granuloma number and cross-sectional area. Intrapulmonary instillation of antibody to rat ICAM-1 (via tracheostomy 24 hours after glucan infusion) resulted in a modest reduction in mean granuloma number and cross-sectional area. When antibody to ICAM-1 was both infused and instilled via the trachea, we found an additive reduction in mean granuloma size and number. There was a 12-fold increase in adhesion of ED-1-positive peripheral blood mononuclear cells (monocytes) to granuloma-bearing frozen lung sections prepared 48 hours after glucan infusion. Moreover, 73% of the additional adherent monocytes were bound specifically to granulomas per se. The increase in ex vivo monocyte binding to lung sections prepared at 48 hours was reduced 62% when sections were incubated with monoclonal antibody to ICAM-1. Taken together, these data indicate that ICAM-1 expression in evolving glucan-induced granulomatous vasculitis occurs first within blood vessel walls and then within lesional cells per se. The in vivo blocking studies suggest that ICAM-1 expression in both anatomic sites is important in granuloma development.

Animals↗
PubMed1996

Monocyte chemoattractant protein 1 mediates glomerular macrophage infiltration in anti-GBM Ab GN.

Monocyte chemoattractant protein 1 (MCP-1) is a C-C chemokine with potent monocyte chemotactic and activating properties that may contribute to glomerular macrophage infiltration in anti-GBM Ab GN. We have previously reported increased glomerular steady state expression of MCP-1 mRNA relative to GAPDH mRNA in the heterologous phase of experimental anti-GBM Ab GN. In this report, we expand upon these data by demonstrating that the increase in MCP-1 mRNA correlated with MCP-1 protein expression at 24 hours that was determined with an ELISA (2069 +/- 147 pg/mg glom lysate). This increase in MCP-1 expression was associated with glomerular monocyte/ macrophage infiltration which peaked at 24 hours (8.2 +/- 1.0 ED-1 cells/glom). The site of MCP-1 mRNA production was localized by combining immunohistochemistry with in situ hybridization. The majority of cells which expressed MCP-1 mRNA at three hours were intrinsic glomerular cells, while 55% of the cells that expressed MCP-1 mRNA at 15 hours were monocytes/macrophages. To determine if MCP-1 affected glomerular macrophage infiltration, rats with alpha-GBM Ab GN were administered a polyclonal neutralizing Ab to rat MCP-1. This resulted in a 38% decline in glomerular macrophage infiltration (3.3 +/- 0.3 vs. 1.8 +/- 0.2 ED-1 cells/glom, P = 0.0001) that was associated with a 45% reduction in urinary protein excretion (260 +/- 53 vs. 162 +/- 46 mg/d, P = 0.0001). These data demonstrate an important role for MCP-1 in the pathogenesis of glomerular macrophage infiltration in anti-GBM Ab GN.

Animals↗
PubMed1996

Expression of monocyte chemoattractant protein-1 in the corpus luteum of the rat.

The known accumulation of macrophages in corpora lutea (CL) at the time of luteal regression prompted us to investigate whether the chemoattractant protein monocyte chemoattractant protein-1 (MCP-1) is expressed in the rat CL. On the day of confirmed mating (Day 0 of pregnancy), regressing CL from the previous (nonfertile) estrous cycle contained immunodetectable MCP-1 and numerous monocytes/macrophages, whereas the newly formed CL of pregnancy, within the same ovary, contained little MCP-1 and few monocytes/macrophages. MCP-1 diminished in the regressing CL on Days 3 and 9 of pregnancy, although numerous monocytes/macrophages remained. The CL of pregnancy on Days 3 and 9 of pregnancy contained minimal MCP-1 and relatively few monocytes/macrophages. By Days 17 and 21 of pregnancy, however, prior to parturition and prior to an accumulation of monocytes/macrophages, expression of MCP-1 increased in the CL of pregnancy. Northern blots revealed a resurgence of luteal MCP-1 mRNA on Day 21 of pregnancy: 3805 +/- 1077 on Day 21 vs. 1059 +/- 177 on Day 9 (p < 0.05; expressed as densitometric units relative to beta-actin). In conclusion, the expression of MCP-1 in the rat CL in association with, or preceding, the appearance of monocytes/macrophages at the time of luteal regression is consistent with the known role of MCP-1 as a potent chemoattractant for monocytes/macrophages. This suggests that MCP-1 might have a prominent role in the immunological process of luteal regression.

Animals↗
PubMed1996

Prolactin-induced regression of the rat corpus luteum: expression of monocyte chemoattractant protein-1 and invasion of macrophages.

Monocyte chemoattractant protein-1 (MCP-1) is a potential mediator of the recruitment of monocytes/macrophages into the regressing corpus luteum (CL). We investigated whether the luteolytic effect of prolactin in the rat is associated with the expression of MCP-1 and an invasion of monocytes/macrophages. Ovulation was induced in immature female rats by injection of eCG (5 IU, s.c.) at 30 days of age. All rats were hypophysectomized 3 days later. Rats received injections of ovine prolactin (250 micrograms, s.c.) at 12-h intervals on Day 9, 10, and 11 posthypophysectomy; controls received injection of vehicle. Rats were killed by decapitation 24, 48, or 72 h after the first injection of prolactin or vehicle. In rats treated with prolactin, immunoreactive MCP-1 was detected in the CL at 24 h after the first injection, and a consistent level of staining was reached by 72 h with immunodetectable MCP-1 diffused throughout individual CL. The number of monocytes/macrophages in the CL (mean +/- SEM) increased significantly after prolactin treatment, from 3.1 +/- 1.8 at 24 h to 49.3 +/- 8.2 at 72 h (p < 0.05), and the number of monocytes/macrophages was different from that in control, vehicle-treated rats at 72 h (10.3 +/- 4.1; p < 24 and 72 h in prolactin-treated rats (p < 0.05). It is concluded that a potentially important component of the luteolytic effect of prolactin in the rat is the expression of MCP-1 and invasion of monocytes/macrophages into the CL.

20-alpha-Dihydroprogesterone↗
PubMed1996

Inhibition of T cell recruitment and cutaneous delayed-type hypersensitivity-induced inflammation with antibodies to monocyte chemoattractant protein-1.

Leukocytes express chemokine receptors that, upon ligand recognition, are believed to activate and induce the directed migration of these cells from the vasculature to sites of tissue injury. Previous investigations of human and animal inflammatory tissue have revealed that expression of chemokines can be increased in association with leukocyte infiltration. Monocyte chemotactic protein-1 (MCP-1) mediates monocyte chemotaxis in vitro and migration of monocytes to inflammatory sites in vivo. More recently T cell chemotaxis to MCP-1 has been observed in vitro, but the contribution of this protein to T cell migration in vivo and to lymphocyte-mediated inflammation has not been determined. In this report, we show that using a rat model of cutaneous delayed hypersensitivity, MCP-1 expression correlates spatially and kinetically with T cell and monocyte recruitment and that antibodies directed to MCP-1 when administered therapeutically to animals undergoing delayed hypersensitivity can almost completely abolish T cell migration and inflammatory sequelae. Moreover the concentration of antibody needed to inhibit T cell trafficking to inflammatory sites is almost on order of magnitude lower than that needed to impede monocyte recruitment. Therefore, MCP-1 is functionally relevant in the genesis of delayed hypersensitivity and may be a useful therapeutic target for diseases mediated in part by T lymphocytes.

Animals↗
PubMed1996

The membrane attack complex of complement induces interleukin-8 and monocyte chemoattractant protein-1 secretion from human umbilical vein endothelial cells.

Cell surface assembly of the membrane attack complex (MAC) of complement occurs in a variety of pathophysiological settings. Depending upon the density and size distribution of pores formed by the MAC and the functional integrity of membrane regulators of complement activation, the MAC can either cause direct cell lysis or transduce cell activation. We have examined the functional capacity of sublytic concentrations of MAC to induce the secretion of specific alpha- and beta-chemokines from human umbilical vein endothelial cells (HUVECs). Endothelial cell activation by the MAC has particular relevance to complement-dependent inflammatory processes including ischemia-reperfusion injury and acute lung injury. Assembly of sublytic concentrations of the MAC on HUVECs resulted in the sequential secretion of both neutrophil and monocyte chemotactic activities. Analysis of conditioned medium from MAC-bearing HUVECs revealed that the neutrophil chemotactic activity was largely attributable to interleukin (IL)-8, whereas the monocyte chemotactic activity, which was detected later (peak at 8 hours versus 4 hours), was largely attributable to MCP-1. This temporal pattern of MAC-induced secretion of IL-8 and MCP-1 was confirmed using IL-8- and MCP-1-specific enzyme-linked immunosorbent assays. Northern hybridization analysis of HUVECs revealed that MAC deposition was accompanied by an increase in IL-8 and MCP-1 mRNA levels. These data indicate that assembly of sublytic concentrations of the MAC on HUVECs can induce the sequential secretion of both neutrophil and monocyte chemotactic activities and that the former is largely attributable to IL-8 whereas the latter is largely attributable to MCP-1.

Cell Membrane↗
PubMed1995

Enhancement by the complement membrane attack complex of tumor necrosis factor-alpha-induced endothelial cell expression of E-selectin and ICAM-1.

Although TNF-alpha and several products of the activated complement system (e.g., C3b, iC3b, and C5a) are known to modulate endothelial cell function in vitro, relatively little is known about the potential modulatory role of the membrane attack complex (MAC) in endothelial cell activation. Using an in vitro neutrophil-endothelial adhesion assay and a quantitative whole cell ELISA to measure endothelial E-selectin and intracellular adhesion molecule-1 (ICAM-1) expression, we examined the modulatory role of the MAC in TNF-alpha-induced neutrophil-endothelial cell adhesive interactions. Activation of quiescent human umbilical vein endothelial cells (HUVECs) with TNF-alpha results in a concentration-dependent increase in neutrophil adhesion measured at 4 h. Assembly of sublytic concentrations of the MAC on endothelial cells did not result in changes in neutrophil-HUVEC adhesion measured at 4 h. Activation of HUVECs with TNF-alpha followed by assembly of the MAC resulted in a marked increase in neutrophil binding as compared with that observed in cells treated with TNF-alpha alone. Blocking studies of mAb revealed that in either TNF-alpha-stimulated or TNF-alpha and MAC-activated endothelial cells enhanced neutrophil binding was nearly entirely attributable to E-selectin and ICAM-1. This conclusion was further supported by a whole-cell ELISA, which provided evidence that the MAC augments TNF-alpha-induced up-regulation of both E-selectin and ICAM-1. This study provides data that support the conclusion that the distal complement system (MAC) can enhance TNF-alpha-induced proinflammatory endothelial cell functions.

Cell Adhesion↗
PubMed1995

Up-regulation of lung vascular ICAM-1 in rats is complement dependent.

Intrapulmonary deposition of IgG immune complexes in rats causes acute inflammatory lung injury that is neutrophil, complement, cytokines (IL-1, TNF-alpha), and intercellular adhesion molecule (ICAM-1) dependent. In the current studies involving the same model of lung injury, complement depletion or complement blockade resulted in substantial reductions in up-regulation of pulmonary vascular ICAM-1, accompanied by reduced lung injury and neutrophil accumulation. Complement depletion neither reduced the amount of immune complex deposited in lung nor the TNF-alpha content in bronchoalveolar lavage fluids. In the same model of inflammatory lung injury, neutrophil depletion (which is highly protective) did not affect up-regulation of lung vascular ICAM-1. Up-regulation of lung vascular ICAM-1 by intratracheally administered TNF-alpha was also prevented by complement depletion. These studies indicate an unexpected in vivo relationship between complement and up-regulation of lung vascular ICAM-1.

Animals↗
PubMed1995

Regulation of monocyte chemoattractant protein-1 gene expression and secretion in rat pulmonary alveolar macrophages by lipopolysaccharide, tumor necrosis factor-alpha, and interleukin-1 beta.

Chemotactic cytokines coordinate the recruitment of leukocytes into the lung during pulmonary inflammation. In a previous study, we determined that rat pulmonary alveolar macrophages (PAMs) facilitate monocyte recruitment and activation in the lung during acute inflammatory lung injury, in part, through the inducible expression of monocyte chemoattractant protein-1 (MCP-1). MCP-1 is an 11 to 15 kD basic peptide that specifically mediates monocyte chemotaxis and activation. Inflammatory mediators that regulate the expression and secretion of MCP-1 by rat PAMs have not been identified. We determined that stimulation of resident rat PAMs with bacterial lipopolysaccharide (LPS), murine tumor necrosis factor-alpha, or human interleukin-1 beta resulted in the inducible expression of MCP-1 mRNA and the secretion of biologically active MCP-1. In contrast, phorbol myristate acetate, a nonphysiologic leukocyte activator, was significantly less effective in stimulating either enhanced MCP-1 mRNA expression or secretion of MCP-1. These results indicate that the expression of MCP-1 mRNA and the secretion of MCP-1 by rat PAMs are regulated by bacterial products (LPS) and inflammatory cytokines. Further, these results suggest PAMs are regulated by bacterial products (LPS) and inflammatory cytokines. Further, these results suggest that resident PAMs, through elaboration of MCP-1, may play a pivotal role in regulating recruitment and activation of monocytes in the lung during acute inflammatory lung injury.

Alkaloids↗
PubMed1995

Antibodies to neutrophil cytoplasmic antigens induce monocyte chemoattractant protein-1 secretion from human monocytes.

Antibodies to neutrophil cytoplasmic antigens (ANCA) have been found in the serum samples of patients with a number of vasculitides (e.g., Wegener's granulomatosis, small vessel vasculitis, and idiopathic necrotizing and cresentic glomerulonephritis). Although detection of ANCA in serum samples has proven to be useful diagnostically and in selected activity of disease monitoring situations, the pathogenetic role of ANCA in vasculitis remains ill-defined. We sought to determine whether purified ANCA promotes the secretion of monocyte chemoattractant protein-1 (MCP-1) from isolated human peripheral blood monocytes. P (perinuclear)- and C (cytoplasmic)- ANCA were purified from the serum samples of patients with either Wegener's granulomatosis, small vessel vasculitis, or idiopathic necrotizing and cresentic glomerulonephritis. Human peripheral blood monocytes from healthy subjects were incubated with either C-ANCA immunoglobulin G (IgG), P-ANCA IgG, or nonspecific IgG, and the conditioned media were analyzed for MCP-1 activity. A monocyte chemotaxis assay was utilized to functionally quantify secreted chemotactic activity. Secretion of monocyte chemotactic activity was found to be antibody concentration-dependent and time-dependent, with maximal chemotaxis measured in media collected 24 hours after the addition of either C- or P-ANCA IgG. A specific antibody directed against human MCP-1 largely inhibited monocyte chemotaxis, indicating that MCP-1 is the predominant monocyte chemotactic mediator present in the conditioned medium. An MCP-1 enzyme-linked immunosorbent assay further supported the conclusion that P- and C-ANCA IgG can trigger MCP-1 secretion by monocytes. These data indicate that incubation of monocytes with ANCA promotes the dose-dependent release of the chemotactic beta-chemokine MCP-1.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Antineutrophil Cytoplasmic↗