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M H Morrison

Publications and source records attributed to M H Morrison.

17 recordsLinked to original sources
PubMed1992

Chloroquine attenuates hemorrhagic shock-induced immunosuppression and decreases susceptibility to sepsis.

Hemorrhagic shock causes a severe suppression of cellular immunity and an increased susceptibility to sepsis that may be due to increased release of prostaglandin E2 by macrophages. Since chloroquine inhibits the secretion of prostaglandin E2 by macrophages in vitro, the effects of chloroquine administration in vivo following hemorrhagic shock on macrophage prostaglandin E2 secretion and on depressed cellular immunity were examined. Inbred C3H/HeN male mice, aged 6 to 8 weeks, were bled to a mean blood pressure of 35 mm Hg, which was maintained for 60 minutes, and adequately, resuscitated. Mice then received intramuscular injections of either saline (vehicle) or chloroquine (10 mg/kg of body weight). Prostaglandin E2 in macrophage supernatants (radioimmunoassay) concanavalin A-dependent splenocyte proliferation, and interleukin 2 in splenocyte supernatants (CTLL 20 interleukin 2-dependent proliferation) were determined 2 or 24 hours later. Hemorrhage caused a significant decrease of splenocyte proliferation (47%) and interleukin 2 release (49%) at 24 hours, while prostaglandin E2 secretion from macrophages was elevated at 2 hours. Chloroquine treatment attenuated depression of splenocyte functions and reduced prostaglandin E2 release. Furthermore, chloroquine treatment decreased the mortality of septic mice after hemorrhage to levels comparable with those of sham-operated mice. Thus, chloroquine may be a useful adjunct in the clinical setting for the treatment of shock-induced immunodepression and increased susceptibility to sepsis following hemorrhage.

Animals↗
PubMed1992

Ibuprofen restores cellular immunity and decreases susceptibility to sepsis following hemorrhage.

Although hemorrhage depresses splenocyte (SPL) functions and increases susceptibility to sepsis, it is not known whether increased tumor necrosis factor (TNF) or prostaglandin (PG) production are responsible for it. To study this, mice (C3H/HeN) were bled to a mean blood pressure of 35 mm Hg, maintained at that pressure for 60 min, resuscitated, and treated with ibuprofen (1.0 mg/kg body weight) or vehicle (saline). Hemorrhage reduced (P less than 0.05) SPL proliferation by 60%, SPL release of interleukin-2 (IL-2) by 47%, interferon-gamma (IFN-gamma) by 67%, TNF by 54%, and interleukin-6 (IL-6) by 46% compared to sham. In addition, splenic macrophage (sM phi) release of interleukin-1 (IL-1) and TNF was decreased by 58 and 67% (P less than 0.05), respectively. However, ibuprofen treatment increased (P less than 0.05) SPL proliferation, lymphokine (IL-2, IFN-gamma, and IL-6) synthesis, and IL-1 release by sM phi compared to hemorrhage alone. Furthermore, ibuprofen enhanced the release of TNF by SPL (+175%, P less than 0.05) and sM phi (+68%) compared to the vehicle group. Ibuprofen also decreased (P = 0.011) the susceptibility to sepsis following hemorrhage. These results indicate that PGs are involved in hemorrhage-induced suppression of cellular immunity and in the increased mortality of such animals following a septic challenge.

Animals↗
PubMed1992

Mechanism of the beneficial effects of ATP-MgCl2 following trauma-hemorrhage and resuscitation: downregulation of inflammatory cytokine (TNF, IL-6) release.

Although ATP-MgCl2 improves hepatocellular function in a nonheparinized model of trauma-hemorrhage and crystalloid resuscitation, it remains unknown whether the beneficial effects of this agent are due to downregulation of the release of the inflammatory cytokines, tumor necrosis factor (TNF), and interleukin-6 (IL-6) under those conditions. To study this, rats underwent a 5-cm laparotomy (i.e., trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximum bleedout volume was returned in the form of Ringer's lactate (RL). The animals were then resuscitated with four times the volume of shed blood with RL over 60 min. ATP-MgCl2 (50 mumoles/kg body weight each) or an equivalent volume of normal saline was infused intravenously for 95 min. This infusion was started during the last 15 min of RL resuscitation. Plasma levels of TNF and IL-6 were measured at 1.5 hr after the completion of resuscitation by cytokine-dependent cellular assays. Hepatic blood flow was determined by in vivo indocyanine green clearance (corrected by hepatic extraction ratio for indocyanine green), radioactive microspheres, and [3H]-galactose clearance techniques. The results indicate that the levels of circulating TNF and IL-6 increased significantly in the hemorrhaged-resuscitated animals. ATP-MgCl2 treatment, however, markedly decreased the synthesis and/or release of these cytokines to levels similar to the sham group. The markedly decreased hepatic blood flow (as determined by three different methods) and hepatic extraction ratio for indocyanine green were also restored by ATP-MgCl2 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1992

Mechanism of the beneficial effects of pentoxifylline on hepatocellular function after trauma hemorrhage and resuscitation.

BACKGROUND: The purpose of this study was to determine whether pentoxifylline administration restores the depressed hepatocellular function after trauma hemorrhage and crystalloid resuscitation and, if so, whether this is the result of the down-regulation of inflammatory cytokines, tumor necrosis factor (TNF) and interleukin-6 (IL-6). METHODS: After laparotomy rats were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximum shed blood volume was returned in the form of Ringer's lactate. They were then resuscitated with Ringer's lactate to four times the shed blood volume. Pentoxifylline (50 mg/kg body weight) or saline solution was infused intravenously for 95 minutes during and after resuscitation. One and a half hours and 4 hours after resuscitation, hepatocellular function (maximal velocity [Vmax] and the efficiency of the active transport [Km] of indocyanine green clearance) and plasma. TNF and IL-6 levels were determined with in vivo hemoreflectometer and cellular assays, respectively. RESULTS: Circulating TNF and IL-6 levels increased significantly after hemorrhage and resuscitation. Pentoxifylline treatment, however, markedly decreased the levels of these cytokines, and the values were similar to those of sham rats. The decreased Vmax and Km values were also restored by pentoxifylline treatment. Moreover, there was a significant correlation between Vmax and TNF or IL-6 levels. CONCLUSIONS: The down-regulation of inflammatory cytokines by pentoxifylline may be the mechanism by which this agent restores the depressed hepatocellular function after trauma hemorrhage and resuscitation.

Animals↗
PubMed1992

Interferon-gamma attenuates hemorrhage-induced suppression of macrophage and splenocyte functions and decreases susceptibility to sepsis.

Although it is known that interferon-gamma synthesis and macrophage functions are depressed after hemorrhage, it remains to be determined whether systemic administration of interferon-gamma has any effect on hemorrhage-induced depression of macrophage and splenocyte functions. To study this, C3H/HEN mice were bled to a mean blood pressure of 35 mm Hg, maintained for 60 minutes, and followed by adequate fluid resuscitation. The mice then received either 1000 units interferon-gamma or saline solution (vehicle). Peritoneal (pM phi) and splenic (sM phi) macrophages and splenocytes were isolated 24 hours later. PM phi antigen presentation was measured by coculturing pM phi with the D10.G4.1 cell clone. Major histocompatibility complex class II (Ia) antigen expression was determined by direct immunofluorescence. Cytokine release by pM phi, sM phi, and splenocytes was assessed with specific bioassays. For survival studies, mice were subjected to sepsis 3 days after hemorrhage. Treatment with interferon-gamma restored (p less than or equal to 0.05) hemorrhage-induced suppression of pM phi antigen presentation capacity and Ia antigen expression and increased (p less than or equal to 0.05) interleukin-1 and tumor necrosis factor release by pM phi and sM phi, as well as splenocyte proliferation (p less than or equal to 0.05). Interferon-gamma also decreased (p less than or equal to 0.007) the susceptibility to sepsis after hemorrhage. Thus interferon-gamma represents a potent agent for treating hemorrhagic shock-induced immunosuppression and for increasing the ability of the host defense system to combat bacterial infections after hemorrhage.

Animals↗
PubMed1991

Chloroquine attenuates hemorrhagic shock-induced suppression of Kupffer cell antigen presentation and major histocompatibility complex class II antigen expression through blockade of tumor necrosis factor and prostaglandin release.

Hemorrhagic shock suppresses the ability of Kupffer cells (KC) to present antigen and express the major histocompatibility complex class II (Ia) antigen. These alterations are concomitant with an enhanced release of cytokines (tumor necrosis factor [TNF], interleukin-1 [IL-1], IL-6) and prostaglandin E2 (PGE2) by KC after hemorrhagic shock. The aim of this study was to determine whether chloroquine (CQ) administration in vivo before or after hemorrhage affects the altered cytokine and PGE2 release by KC as well as the capacity of KC to present antigen and express Ia. To study this, C3H/HeN mice were bled to and maintained at a mean arterial blood pressure of 35 mm Hg for 60 minutes, followed by fluid resuscitation. Chloroquine (10 mg/kg body weight) was injected intramuscularly 2 hours before or during resuscitation following shock. The administration of CQ led to a significant reduction in the hemorrhage-induced elevation of TNF, IL-6, and PGE2 release by KC; however, IL-1 secretion was not affected by CQ. In addition, CQ treatment abolished the hemorrhage-induced increase in circulating TNF and IL-6. These changes in cytokine and PGE2 release following CQ administration correlated with a significant enhancement of the antigen-presenting capacity of KC. No differences were observed between pretreatment and posttreatment with CQ. Our data indicate that CQ selectively inhibits the release of TNF, IL-6, and PGE2 by KC, while IL-1 secretion was unaffected. Because the reduction of these inflammatory mediators was concomitant with a significant improvement of KC capacity to present antigen and express Ia, we propose that TNF, IL-6, and PGE2 play a pivotal role in the induction of posthemorrhage immunosuppression. Furthermore, the data suggest that the suppression of KC functions occurs during or after resuscitation, because posttreatment with CQ was as effective as pretreatment. Additional studies indicated that the survival of animals after hemorrhage and sepsis was significantly increased by posttreatment of hemorrhaged mice with CQ. Thus, CQ, because of its unique ability to selectively inhibit the release of inflammatory cytokines and prostaglandins, represents a potent immunomodulating agent in the treatment of conditions associated with increased cytokine release and for decreasing the mortality from sepsis after hemorrhage.

Animals↗
PubMed1991

Blockade of prostaglandin production increases cachectin synthesis and prevents depression of macrophage functions after hemorrhagic shock.

Although hemorrhage severely depresses macrophage functions, it is not known whether the increased TNF-alpha or PGE2 production is responsible for it. To study this C3H/HeN mice were bled to mean blood pressure of 35 mmHg for 60 minutes, resuscitated, and treated with either ibuprofen (1.0 mg/kg body weight) or vehicle (saline). Hemorrhage increased plasma prostaglandin E2 (PGE2) levels by 151.7% +/- 40.0% (p less than 0.05) and significantly decreased peritoneal macrophage (pM phi) antigen presentation (AP) by 60.5% +/- 7.3%, Ia expression by 52.3% +/- 7.6%, and interleukin-1 (IL-1) synthesis by 60.5% +/- 12.3% compared to shams. However ibuprofen treatment reduced PGE2 plasma levels by 61.3% +/- 12.1% and significantly increased AP (+237.0% +/- 95.3%), Ia expression (+72.8% +/- 27.5%), IL-1 synthesis (+235.7% +/- 134.7%), and cachectin synthesis (+485.8% +/- 209.0%) compared to vehicle-treated animals. These results indicate that prostaglandins but not cachectin are involved in the suppression of pM phi functions following hemorrhage because blockade of prostaglandin synthesis improved depressed macrophage functions despite enhanced cachectin synthesis.

Animals↗
PubMed1991

The complex pattern of cytokines in sepsis. Association between prostaglandins, cachectin, and interleukins.

Although the cytokines tumor necrosis factor (TNF), interleukin-1 (IL-1), and interleukin-6 (IL-6) are important mediators of hemodynamic, metabolic, and immunologic alterations in the host during sepsis, it is not known whether there is any association between the release of these cytokines and prostanoids during sepsis. Sepsis induced by cecal ligation and puncture in rats led to a persistent elevation (p less than 0.05) of plasma TNF until 10 hours, steadily increasing (p less than 0.05) IL-1 plasma levels, and enhanced (p less than 0.05) IL-6 plasma levels at all time points compared to the sham group. Prostaglandin E2 plasma levels were elevated (p less than 0.05) at 5 hours (153 +/- 29 pg/mL; control: 47 +/- 11 pg/mL) and 10 hours (96 +/- 16 pg/mL; control: 21 +/- 5 pg/mL). Prostaglandin E2 production by splenic macrophages (sM phi) from septic animals was increased (p less than 0.05) at 5 hours (9.1 +/- 2.2 ng/mL) and 10 hours (5.6 +/- 1.5 ng/mL) compared to controls (3.3 +/- 0.3 ng/mL at 5 hours; 1.3 +/- 1.3 ng/mL at 10 hours). Incubation of sM phi from septic animals with ibuprofen enhanced (p less than 0.05) IL-1 and TNF synthesis, while IL-6 production was reduced (p less than 0.05). These results indicate that the alterations in prostanoid release and elevated plasma prostanoids may regulate the release and consequently the circulating levels of cytokines during sepsis.

Animals↗
PubMed1991

Eicosanoids regulate tumor necrosis factor synthesis after hemorrhage in vitro and in vivo.

The aim of this investigation was to determine whether PGE2 regulates TNF release in vitro and in vivo following hemorrhage. To study this, C3H/HeN mice were bled to a mean blood pressure (BP) of 35 mm Hg, maintained for 60 minutes, and then resuscitated. For in vitro studies, peritoneal (pM phi) and splenic (sM phi) macrophages obtained at 2 hours and 24 hours after hemorrhage were stimulated with LPS for 24 or 48 hours with or without ibuprofen (IBU). For in vivo studies, M phi were harvested 24 hours following hemorrhage with and without IBU treatment and stimulated with LPS for 48 hours. The decreased TNF release by pM phi but not sM phi from hemorrhaged mice was restored by IBU in vitro. IBU treatment in vivo significantly enhanced TNF release by pM phi compared with untreated hemorrhaged animals, while TNF release by sM phi was only slightly increased. These data indicate a major role of PGE2 in the regulation of TNF release by pM phi following hemorrhage.

Animals↗
PubMed1991

Anti-TNF monoclonal antibodies prevent haemorrhage-induced suppression of Kupffer cell antigen presentation and MHC class II antigen expression.

Kupffer cells (KC), by virtue of their ability to present antigen (AP) and express major histocompatibility complex (MHC) class II antigen (Ia), play a pivotal role in the host defence system against invading micro-organisms. Although haemorrhagic shock depresses the above KC functions, it is not known whether increased KC tumour necrosis factor (TNF) production and elevated TNF plasma levels following haemorrhage are responsible for it. To study this, C3H/HeN mice were pretreated intraperitoneally with either anti-murine TNF antibody (anti-TNF Ab) or saline. Twenty hours later mice were bled and maintained at a mean blood pressure of 35 mmHg for 60 min followed by adequate fluid resuscitation. Two and 24 hr later, plasma was collected and KC were isolated. AP was measured by co-culturing KC with the D10.G4.1 Th cell clone. Ia expression was determined by direct immunofluorescence. Interleukin (IL)-1, IL-6 and TNF levels in KC supernatants and plasma were measured with bioassays or ELISA. Haemorrhage increased circulating TNF levels by 215% at 2 hr and by 76% at 24 hr (P less than 0.05), which was prevented by pretreatment with anti-TNF Ab. Haemorrhage-induced increase of circulating IL-6 was abolished (P less than 0.05) at 2 hr but not at 24 hr in the anti-TNF Ab group. The suppression of KC AP (P less than 0.05) and Ia expression (P less than 0.05) due to haemorrhage was attenuated (P less than 0.05) in anti-TNF Ab-treated mice at 2 and 24 hr and KC IL-1 and TNF synthesis was further (P less than 0.01) increased. These results indicate that TNF plays a critical role in the initiation and regulation of KC AP, Ia expression, and cytokine production following haemorrhage.

Animals↗
PubMed1991

Insights into the mechanisms of defective antigen presentation after hemorrhage.

Although hemorrhage depresses macrophage antigen presentation (AP), a critical component in eliciting an antigen-specific immune response, it is not known which particular step in macrophage AP (i.e., uptake, ingestion, catabolism, or presentation of degraded antigens to T cells) is defective. To study this, C3H/HeN mice were bled to an arterial mean blood pressure of 35 mm Hg, maintained for 60 minutes, and then adequately resuscitated. Peritoneal and splenic macrophage cultures were prepared 2 and 24 hours after hemorrhage. Macrophage AP capacity was measured by coculturing macrophages with the T-helper cell clone D10.G4.1. To gain information about macrophage ability to digest the specific antigen conalbumin, lysosomal activity was bypassed by use of chemically denatured conalbumin peptides. To study macrophage ability to present conalbumin peptides, macrophages were fixed and D10.G4.1 proliferation in response to fragmented conalbumin was determined. AP of native conalbumin by peritoneal macrophages and splenic macrophages was depressed (p less than 0.05) by 50% (peritoneal macrophages) and 55% (splenic macrophages) 2 hours and 57% (peritoneal macrophages) and 35% (splenic macrophages) 24 hours after hemorrhage. In contrast, presentation of conalbumin peptides was only slightly decreased. In addition, the ability of fixed peritoneal macrophages and splenic macrophages to present conalbumin peptides was similar in hemorrhaged and sham mice. Because bypassing of macrophage lysosomal activity with degraded native antigens prevented the suppression of AP, the results suggest that hemorrhage-induced suppression of AP is not caused by a reduced macrophage capacity to present antigenic peptides but by decreased antigen catabolism by macrophages.

Animals↗
PubMed1990

Immunoprotective effect of a calcium channel blocker on macrophage antigen presentation function, major histocompatability class II antigen expression, and interleukin-1 synthesis after hemorrhage.

Hemorrhage induces a severe suppression of the immune system resulting in increased susceptibility to sepsis. Although studies indicate beneficial effects of calcium channel blockers on cell and organ functions after low-flow conditions, it remains unknown whether such agents have any effects on different immune responses after hemorrhage. To study this, C3H/HeN mice were bled to a mean blood pressure of 35 mm Hg and were maintained for 60 minutes, followed by resuscitation with their own shed blood and adequate fluid. The mice received either the water-soluble calcium channel blocker diltiazem (400 or 2400 micrograms/kg body weight) or saline solution (vehicle). Peritoneal macrophages were obtained by lavage 24 hours later. Antigen presentation was measured by coculturing peritoneal macrophages with the D10.G4.1 helper T-lymphocyte clone. Immune associated antigen (Ia) expression was determined by direct immunofluorescence. Interleukin (IL)-1, 6, and tumor necrosis factor-alpha (TNF) levels in peritoneal macrophage supernatants were measured by use of cytokine-specific cellular assays. Hemorrhage caused a significant decrease in peritoneal macrophage antigen presentation function, Ia expression, and IL-1 and IL-6 synthesis in the vehicle-treated group, whereas TNF levels were increased. However, both doses of diltiazem significantly improved peritoneal macrophage antigen presentation, Ia expression, and IL-1 synthesis. IL-6 synthesis was only increased with high doses of diltiazem, whereas both diltiazem doses decreased TNF production. These results indicate that the calcium channel blocker diltiazem can markedly improve macrophage functions after hemorrhage. The use of diltiazem might offer a new therapeutic modality in the treatment of immunosuppression and in decreasing the susceptibility to sepsis after hemorrhagic shock.

Animals↗
PubMed1989

Adherent lymphokine-activated natural killer cells in normal and severe combined immunodeficiency mice: large granular lymphocytes with natural killer cell phenotype and high cytolytic activity.

Plastic-adherent lymphokine-activated natural killer (LANK) cells were generated from nylon wool-nonadherent murine splenocytes cultured in recombinant interleukin-2 (IL-2). Under such conditions, adherent lymphokine-activated killer cells capable of killing natural killer (NK)-resistant targets were not generated. Adherent LANK cells proliferated rapidly and closely resembled NK cells in their morphology, cytotoxic reactivity, and surface marker expression. Mice with severe combined immunodeficiency (scid) were used to generate adherent LANK cells to define the role of T cells in LANK cell development. Scid lymphocytes responded to IL-2 by becoming adherent LANK cells with potent NK-like activity, suggesting that soluble lymphokines other than IL-2 that may have been produced by T cells were not required for the generation of LANK cell activity in mice.

Animals↗
PubMed1986

Poly-N-acetyllactosamine alterations of Thy-1 glycoprotein in lymphocyte differentiation.

Developmental changes in murine lymphocyte Thy-1 include both quantitative and qualitative alterations involving N-linked oligosaccharides. Comparison of immature with mature T-cells has shown that the oligosaccharides of Thy-1 are characterized by an increase in the number of sialic acid residues responsible for the acidic pI of peripheral T-cell Thy-1, and a decrease in those oligosaccharides responsible for Mr heterogeneity of thymocyte Thy-1. The research reported here suggests that the basis of the large Mr heterogeneity in Thy-1 of immature T-cells is the presence of repeating N-acetyllactosamine (R'Gal beta 1,4GlcNAc beta 1,3R") units in the oligosaccharide portion of the molecule. Lymphocytes were surface iodinated and 125I-thy-1 was purified by immunoprecipitation and preparative nonequilibrium pH gradient electrophoresis. The minimal Mr of unglycosylated Thy-1 after endoglycosidase F digestion was 15,000-16,000. Digestion of Thy-1 with endo-beta-galactosidase suggested that the complex type N-linked glycans in thymocytes, but not in lymph node T-cells, contained increased levels of polylactosamine. The presence of polylactosamine was confirmed by binding to a Datura stramonium lectin column which retarded and bound approx. 50% of thymocyte Thy-1 and only about 18% of lymph node T-cell Thy-1. Affinity chromatography using anti-i antibody immobilized on agarose beads indicated that the polylactosamine is probably present in a predominantly linear form. Since alterations of polylactosamine structures have been implicated in development and transformation in several systems, the present results suggest an important role for these glycans in immune-cell differentiation.

Animals↗
PubMed1986

The kinetics of 4-nitrophenol conjugation by perfused livers and hepatic microsomes from streptozocin-induced diabetic rats.

The formation of both glucuronide and sulphate conjugates of 4-nitrophenol is deficient in perfused livers from male diabetic rats. Experiments with 'native' hepatic microsomes demonstrated that the defect in glucuronidation is due to a decrease in the maximal velocity of the reaction. There is no alteration in the affinity of the glucuronyltransferase for 4-nitrophenol. Non-linear regression analysis of the 4-nitrophenol liver perfusate concentrations showed that the elimination follows saturable Michaelis-Menten kinetics. Clearance values in 'native' microsomal preparations and in perfused livers were calculated and found to be similar in both systems. This provides evidence that glucuronyltransferase is 'native' in the intact liver.

Animals↗