The irreversible loss of adenine nucleotides and the formation of free radicals have both been suggested as causes of irreversibility following prolonged hemorrhagic shock. This study was performed to assess the effect of xanthine oxidase inhibition (allopurinol 50 mg/kg/day), free radical scavenging (superoxide dismutase 15,000 u/kg, catalase 15,000 u/kg, dimethylsulfoxide 20 mg/kg, and alpha tocopherol 100 mg/kg/day) or both, on the 24-hr survival of dogs subjected to irreversible haemorrhagic shock. Twenty anesthetized dogs were bled to a mean arterial pressure of 30 mm Hg for 4 hr. The dogs were allocated to a control, an allopurinol pretreated, a free radical scavenger, or a combined treatment group. Both groups pretreated with allopurinol had significantly improved survival (P < 0.05) over that seen in the control group, but the free radical scavenger treated group was not significantly different from the control group. This study demonstrates the beneficial effect of xanthine oxidase inhibition on survival, and suggests that it may be due to preservation of adenine nucleotides rather than prevention of free radical formation.
Asymmetric dimethylarginine (ADMA) represents an endogenous inhibitor of nitric oxide (NO) production. The production of ADMA has been shown to increase during cellular stress, e.g., hypoxia. Furthermore, ADMA has recently been reported to accumulate in plasma during terminal renal failure as a consequence of diminished urinary excretion. Since tissue hypoxia and oliguria are both characteristics of severe hemorrhagic shock, this study was performed in order to establish whether plasma concentrations of ADMA increase during hemorrhagic shock. Six pigs were subjected to graded hemorrhage (20% and 40% of the calculated blood volume), resulting in significant (P < 0.05) reductions in blood pressure and cardiac output (from 98 +/- 4 to 36 +/- 5 mm Hg and from 3.0 +/- 0.2 to 1.4 +/- 0.2 L/min, respectively). Plasma ADMA concentrations as determined by high-performance liquid chromatography (HPLC) increased from a pre-hemorrhage value of 3.4 +/- 0.3 microM to 3.9 +/- 0.4 microM (ns) and 5.2 +/- 0.4 microM (P < 0.05), respectively. The present study demonstrates that plasma ADMA concentrations increase significantly during hemorrhagic shock. Thus, inhibition of the arginine-nitric oxide pathway as a result of ADMA accumulation, may represent an additional physiological mechanism to maintain systemic blood pressure in response to acute hypovolemia.
The use of small-volume injections of hypertonic saline solutions (HSS) in resuscitation from hemorrhagic shock is accompanied by well-maintained and pronounced increases in coronary blood flow (CBF) and by increases in myocardial contractility. The present study was performed in open-chest, anesthetized dogs to evaluate the contribution of direct coronary vasodilator and positive inotropic effects of HSS to these therapeutic responses. The left anterior descending coronary artery (LAD) was cannulated and perfused at constant pressure (100 mm Hg) with normal arterial blood. CBF in LAD was measured electromagnetically, and used to calculate myocardial oxygen consumption (MVO(2)) and coronary arterial plasma osmolality. Percent segmental shortening in LAD bed (% SS) was evaluated with ultrasonic crystals. Measurements were obtained during infusion into LAD of 2.5, 5.0, and 7.5% HSS at 2 ml/min. These HSS solutions yielded calculated plasma osmolalities of 329+/-3, 361+/-8, and 378+/-10 mOsm/kg, respectively. The increases in plasma osmolality by 2.5% HSS were in the therapeutic range, whereas those by 5.0 and 7.5% HSS were supertherapeutic. HSS caused initial peak increases in CBF (reflecting decreases in coronary vascular resistance), which waned rapidly to achieve modest steady-state increases within 23 min. The magnitude of the peak and steady-state increases in CBF by HSS correlated to osmolality. The 2.5% HSS had no effect on MVO(2) and % SS, whereas the 5.0% and 7.5% HSS increased these variables in an osmolality-dependent manner. Conclusions: (1) intracoronary infusions of HSS caused modest steady-state coronary vasodilation, (2) Supertherapeutic elevations of plasma osmolality by HSS were required for direct positive inotropic effects, and (3) the present findings suggest that the direct cardiac actions of HSS contribute minimally to the increases in coronary blood flow and myocardial contractility that follow the use of these solutions for resuscitation from hemorrhagic shock. (C) 1994 Wiley-Liss, Inc.
We investigated the effects of hemorrhagic shock and reinfusion on the cardiac function and contractility, plasma CK and CK-MB activity and lactate concentration, oxyradical-producing activity of polymorphonuclear leukocytes (PMNL-CL), cardiac chemiluminescence (LV-CL), antioxidant enzymatic activity [superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px)], and malondialdehyde (MDA) concentration in anesthetized dogs, to determine the role of oxyradicals in cardiac depression and cellular injury in hemorrhagic shock and reinfusion. The dogs were assigned to four groups: group I (sham), 4 hrs duration; group II, 4 hr of shock; group III, 2 hr of shock, followed by reinfusion for 2 hr; and group IV, as in group III, but pretreated with SOD and catalase. Hemorrhagic shock was produced by withdrawing blood to maintain the mean arterial pressure at 50 +/- 5 mm Hg. Cardiac function and contractility were depressed during hemorrhagic shock. Plasma CK; CK-MB and lactate; and cardiac MDA, Mn-SOD, and CuZn-SOD increased, while catalase activity decreased during shock. Following reinfusion after 2 hr of shock, hemodynamic parameters and plasma lactate tended to return toward control values. Plasma CK and CK-MB, PMNL-CL and cardiac MDA, total SOD, Mn- and CuZn-SOD increased further, while LV-CL and GSH-Px decreased. In spite of the increased antioxidant reserve, oxidative damage was noted. Pretreatment with SOD and catalase attenuated the deleterious effects of shock and reinfusion on the cardiovascular function, plasma CK, CK-MB, and lactate, PMNL-CL, cardiac MDA and SOD, and LV-CL. Protection was incomplete for cardiovascular function and plasma CK and CK-MB. These results suggest that oxyradicals (O2-, H2O2) may be partly involved in the deterioration of cardiovascular function and cellular injury during hemorrhagic shock and reinfusion.
Whole blood from 10 healthy horses was aseptically collected into heparin or citrate anticoagulant and incubated in vitro for 6 hr in the absence (saline control) or presence of 1 ng endotoxin/ml blood. Pentoxifylline (0.1, 1, 10, or 100 micrograms/ml blood) was added 1 hr before, at the same time, or 1 hr after endotoxin. As compared to saline controls, pentoxifylline alone had no effect on mediator production, with the exception of significantly increasing 6-ketoprostaglandin F1 alpha concentration. Pentoxifylline inhibited endotoxin-induced increases in tumor necrosis factor (TNF) and interleukin-6 (IL-6) activity in a dose-related fashion, whether added before, at the same time, or after endotoxin. Pentoxifylline significantly inhibited tissue factor activity, but only when added before endotoxin. Pentoxifylline had no effect on endotoxin-induced 6-keto-prostaglandin F1 alpha production, but significantly inhibited thromboxane B2 (TxB2) production. The results of this study indicate that pentoxifylline, at blood concentrations consistent with those achieved in vivo, has effects that may be beneficial in the treatment of endotoxemia.
To study the clinical significance of the decrease of glucocorticoid receptor (GR) in stress and shock, GR was blocked about 80% by mifepristone (RU38486), and the effects of the blockade on the pathological changes of endotoxemia were studied in rats. The results revealed that GR blockade may exacerbate the pathological and pathophysiological changes of endotoxemia: (1) the more rapid drop in arterial blood pressure, (2) the more severe pathological changes involving multiple organs, especially the lung and small intestine, (3) the increase of leukocyte adherence in venules and more pronounced rheological changes in the mesenteric microcirculation, and (4) the striking elevation of serum acid phosphatase (ACP), phospholipase A2 (PLA2) activity, and lipoperoxide (LPO). The changes of serum ACP, PLA2, and LPO in the rats with 80% GR blockade were more marked than in those with 50% GR blockade. Based on these findings, we propose that the decrease in GR during stress and shock might be a contributing factor in the pathogenesis of shock and multiple organ failure (MOF). The possible mechanisms of the above noted findings are discussed.
Lymphatic vessels have the ability to contract and transport liquid and protein from tissue spaces to the intravascular space. The purpose of this investigation was to test whether this lymph pump is stimulated following a fixed volume hemorrhage in awake sheep. To quantitate lymphatic pumping in vivo, a mesenteric lymphatic was isolated from all lymph input and provided with Krebs solution at a fixed transmural pressure. A branch of the mesenteric duct was cannulated to provide a measure of lymph flow rate. Each animal was either bled 25% of blood volume over 5 min or was observed. Systemic arterial blood pressure declined in all bled sheep (P < 0.05). Hemorrhage had no effect on lymph flow from mesenteric ducts. However, hemorrhage significantly enhanced lymphatic pumping, approximately 200% of control values 3 hr after hemorrhage (P < 0.01). Increased lymphatic pumping after hemorrhage may play an important role in blood volume and protein restitution.
Major trauma-related immune dysfunction is observed at the time of augmented release of immunopathologic mediators. In the present study, T cell-dependent immunoglobulin (Ig) synthesis in peripheral blood mononuclear cell (PBMC) cultures from blunt trauma patients (N = 12, injury severity score (ISS) 27-50), was reduced by 30- > 90%. This coincided with significantly (P < 0.001-0.01) elevated secretion of the biologically active tumor necrosis factor alpha (TNF alpha). Modulation of the TNF alpha activity by anti-TNF alpha antibody (anti-TNF alpha Ab) led to dose-dependent alterations in IgG synthesis. IgG production increased (up to 300%) in cultures treated with 0.5-2 micrograms/ml of the antibody, where low levels of TNF alpha activity often persisted. However, immunoglobulin synthesis was eradicated in preparations exposed to higher concentrations (10 micrograms/ml) of anti-TNF alpha Ab and devoid of TNF alpha biological activity. The treatment with anti-TNF alpha Ab had no effect on mitogen- or alloantigen-induced PBMC proliferation. Thus, in severely traumatized patients, biological activities of endogenous TNF alpha may include modulation of T cell-dependent B lymphocyte function. Immunoregulatory potential of TNF alpha should, therefore, be considered in therapeutic strategies to abrogate its activity.
The objective of this study was to determine if nitric oxide mediates the effects of exogenously administered adenosine on peripheral blood flow. An intravenous infusion of adenosine (1.0 mumol/kg/min) into male New Zealand white rabbits caused an increase in blood flow, measured using radiolabeled microspheres, throughout the gastrointestinal tract, as well as in the heart and kidneys. Prior administration of nitro-L-arginine methyl ester (L-NAME) 10 mg/kg i.v. completely blocked the hyperemic effect of adenosine on all organs studied. Administration of L-arginine (300 mg/kg bolus and 50 mg/kg/min infusion) together with L-NAME restored the hyperemic effect of adenosine. This phenomenon was specified to the L-arginine/nitric oxide pathway in that a similar pressor response induced by phenylephrine (1.5 micrograms/kg/min) did not block the effects of adenosine. We conclude that the peripheral vasodilator response to intravenously administered adenosine in the rabbit is mediated by nitric oxide.
Gram negative sepsis causes changes in oxygen supply-demand relationships. We have used a primate model of hyperdynamic gram negative sepsis produced by intravenous infusion of Escherichia coli (E. coli) to evaluate sepsis-induced alterations in mitochondrial oxidation-reduction (redox) state in muscle in vivo. The redox state of cytochrome a,a(3), the terminal member of the intramitochondrial respiratory chain, was assessed in the intact forearm by near-infrared (NIR) spectroscopy. The muscle NIR data were compared to routine measures of oxygen delivery (DO2) and oxygen consumption (VO2). After E. coli infusion and fluid resuscitation, DO2 and VO2 showed minimal changes through 24 hr of sepsis. In contrast, changes in cytochrome a,a(3) redox state evaluated by NIR occurred within a few hours and were progressive. Mitochondrial functional responses were correlated with structural changes observed on serial muscle biopsies. Gross morphological changes in muscle mitochondria were present in some animals as early as 12 hr, and, in most animals, by 24 hr. The morphologic changes were consistent with decreases in oxidative capacity as suggested by NIR spectroscopy. The NIR data also suggest that two mechanisms are operating to explain abnormalities in oxygen metabolism and mitochondrial function in lethal sepsis. These mechanisms include an early defect in oxygen provision to mitochondria that is followed by a progressive loss in functional cytochrome a,a(3) in the muscle. (C) 1994 Wiley-Liss, Inc.
Evidence of a role for oxygen-derived free radicals in the pathophysiology of endotoxic shock has been found in animal models. However, the importance of free radicals in chronic models of bacterial infection has not been examined. In this study a novel nitrone radical spin trap is described and its activity in animal models of endotoxic shock and chronic bacteremia were explored. MDL 101,002 is a cyclized variant of alpha-phenyl N-tert-butyl nitrone (PBN), an established spin trap. MDL 101,002 can react with free radicals to form persistent adducts as demonstrated by electron paramagnetic resonance (EPR) spectroscopy. This agent is about 10 times more potent than PBN as an in vitro antioxidant and scavenger of hydroxyl radicals. In a rat endotoxic shock model MDL 101,002 (3-30 mg/kg, i.p.) administered 30 min prior to endotoxin (30 mg/kg, i.p.) treatment reduced mortality in a dose-dependent manner. Peroxide-enhanced chemiluminescence in hepatic homogenates from endotoxin treated rats was elevated indicating that oxidative stress and antioxidant depletion was increased. Importantly, treatment with MDL 101,002 (30 mg/kg, i.p.) 30 min prior to, and 120 min following endotoxin, minimized the increase in chemiluminescence. MDL 101,002 also reduced mortality in a model of chronic bacteremia employing implantation of infected fibrin clots into the peritoneal cavity of gentamicin-treated leukopenic rats. MDL 101,002 (2.5 mg/kg/hr) increased survival from 24% to 52% in these rats. These data are consistent with a role for free radicals in the pathophysiology of endotoxic shock and suggest free radicals are also important mediators in chronic models of sepsis.
Gram-negative bacterial sepsis is associated with endotoxemia and a high mortality rate. In previous studies, we demonstrated the therapeutic benefit of an anti-lipopolysaccharide factor isolated from amebocytes of Limulus polyphemus, and of a recombinant version of this protein, termed endotoxin neutralizing protein (ENP), in rabbits challenged with purified lipopolysaccharides. To assess the benefit of ENP in treating a live bacterial infection, we established a rabbit model of Escherichia coli (E. coli) peritonitis and bacteremia with high mortality despite gentamicin treatment. Twenty-four pairs of New Zealand white rabbits were challenged intraperitoneally (IP) with E. coli O18ac K1 in 5% porcine mucin (mean bacteria per dose = 2.5 x 10(8)). The animals were treated with intravenous (i.v.) gentamicin (2.5 mg/kg), and with either ENP (5 mg/kg) or saline i.v. at 1 hr after E. coli challenge. All rabbits were bacteremic 1 hr after challenge (geometric mean 4.1 +/- 1.2 x 10(4) cfu/mL). Peak geometric mean serum endotoxin (2.62 v 10.54 EU/mL, P = .013) and tumor necrosis factor (TNF) (2540 v 6438 TNF units/mL, P = .046) concentrations were lower in ENP-treated animals as compared to control animals. Seven of 24 animals treated with ENP survived 24 hr compared with 4 of 24 controls (Kaplan-Meier analysis, P = .19). However, in the subgroup of 13 paired animals in whom bacteremia was eliminated by gentamicin treatment, 5 of 13 ENP-treated animals survived 24 hr, compared with 1 of 13 controls (Kaplan-Meier analysis, P = .032).(ABSTRACT TRUNCATED AT 250 WORDS)
The major objective of the present study was to determine the effects of a partial structure of the lipid A moiety of gram-negative lipopolysaccharide, monophosphoryl lipid A (MLA), on endotoxin-induced mortality and disseminated intravascular coagulation (DIC) in rats. A second objective was to examine the role of polymorphonuclear neutrophil invasion to visceral organs, including lung, liver, heart, and kidney in the pathogenesis of the compromised multiorgan function which occurs in endotoxic shock. Finally, a third aim was to determine if the potential protective effects of MLA might be mediated via inhibiting neutrophil invasion to various visceral organs. Male Sprague-Dawley rats (220-260 g) were fasted over night and used the following day. In control rats, endotoxin (S. abortus equi LPS, 15 mg/kg, i.v.) produced a 89% mortality at 48 hr following its administration, and gross pathological and laboratory signs of DIC at 3 hr after injection. The latter included increased serum fibrin(ogen) degradation products (FDP, 24.00 +/- 7.81 vs. 0 micrograms/ml, P < .05), prothrombin time (PT, 16.20 +/- 1.12 vs. 13.03 +/- 0.20 sec, P < .05), and activated partial thromboplastin time (APTT, 32.70 +/- 3.83 vs. 20.11 +/- 0.60 sec, P < .05), and decreased plasma fibrinogen (233.2 +/- 41.6 vs. 406.3 +/- 23.2 mg/dl, P < .05) as well as evidence of gross visceral hemorrhage. Pretreatment with MLA (5 mg/kg) for 24 hr produced a marked reduction in endotoxin-induced mortality at 48 hr (0% versus 89% in controls) and inhibited all of the manifestations of DIC produced by endotoxin.(ABSTRACT TRUNCATED AT 250 WORDS)
Intravital video microscopy was used to monitor and quantify leukocyte-endothelial cell adherence, leukocyte emigration, venular shear rate, and leukocyte rolling velocity in cat mesenteric venules exposed to E. coli endotoxin lipopolysaccharides (LPS). LPS induced a steady decrease in venular shear rate and leukocyte rolling velocity while increasing leukocyte adherence and emigration. The molecular determinants and chemical mediators of LPS-induced leukocyte-endothelial cell adhesion were investigated using monoclonal antibodies (MAbs) against the adhesion glycoproteins CD11/CD18 on leukocytes (MAb IB4) and ICAM-1 (MAb RR1/1) on endothelial cells as well as superoxide dismutase (SOD) and a platelet-activating factor receptor antagonist (WEB 2086). Leukocyte adherence was significantly (P < .05) reduced by administration of either the CD11/CD18 MAb or SOD, while the PAF receptor antagonist and ICAM-1 MAb had no effect. None of the four agents studied significantly altered LPS-induced leukocyte emigration, venular shear rate, or leukocyte rolling velocity. These results indicate that the leukocyte adherence induced by LPS is dependent on the adhesion glycoprotein CD11/CD18 and superoxide, and that an endothelial cell ligand other than ICAM-1 participates in this adhesion process.
The effect of methylprednisolone on superoxide production by pulmonary and circulating blood neutrophils was investigated in rats after the intravenous injection of lipopolysaccharide. Superoxide production by both types of neutrophils was increased by lipopolysaccharide injection, and pretreatment with methylprednisolone inhibited this increase. The inhibitory effect of methylprednisolone on pulmonary neutrophils was greater than that on circulating blood neutrophils. Methylprednisolone also prevented the increase in pulmonary vascular permeability induced by lipopolysaccharide, but failed to inhibit intrapulmonary neutrophil accumulation. These results suggest that the suppression of superoxide production may be one mechanism by which methylprednisolone prevents endotoxin-induced lung damage.
We have reported that an intravenous anesthetic, ketamine, has a potent suppressive effect on lipopolysaccharide (LPS)-induced TNF-alpha production in vitro [Takenaka et al., Anesthesiology 80:402-408, 1994]. The purpose of the present study was to investigate the overall effects of ketamine on hemodynamics, serum TNF-alpha level, arterial blood gases (ABGs), blood glucose level, liver function, and lethality in carrageenan (CAR)-sensitized endotoxemic models. All animals were pretreated intraperitoneally with CAR (150 mg/kg) 16 hr before LPS stimulation. The control rats were injected LPS with 0.5 mg/kg intravenously (i.v.). The ketamine-treated rats were injected with 100 mg/kg of ketamine intramuscularly 30 min before LPS (0.5 mg/kg) i.v. injection, followed by an i.v. infusion at 0, 5, or 10 mg/kg/hr. Serum TNF-alpha, ABGs, blood glucose, and hematological studies were determined at 0, 2, and 6 hr after the LPS challenge. Serum hepatocellular enzyme levels were measured at 6 hr after the injection. In CAR-sensitized rats, serum TNF-alpha activity remarkably increased in accordance with the mild decrease of mean arterial pressure (MAP) at 2 hr after LPS stimulation. In addition, severe metabolic acidosis, hypoglycemia as well as severe hepatic injury were induced at 6 hr after the LPS challenge. By contrast, ketamine treatment significantly attenuated the decrease in MAP and LPS-induced TNF-alpha activity. Ketamine also significantly improved arterial oxygen tension (PaO2), metabolic acidosis and hypoglycemia, and attenuated endotoxin-induced hepatic injury in a dose-dependent fashion. In addition, ketamine treatment significantly improved LPS-induced lethality in CAR-sensitized mice.(ABSTRACT TRUNCATED AT 250 WORDS)
To determine the efficacy of low-volume resuscitation in dehydrated subjects, 7.5% hypertonic saline/6% dextran 70 (HSD) and lactated Ringer's (LR) treatments were compared in conscious pigs dehydrated for 48 hr prior to a 37% blood volume hemorrhage. Pigs randomized to treatment were resuscitated with equivalent sodium loads of either HSD (4 ml/kg) or LR (33.3 ml/kg) following the 60-min hemorrhage. Dehydration resulted in a 7-8% body weight loss. Mortality through 180 min of recovery was 1/13 (7.7%) for HSD, 1/11 (9.1%) for LR, and 4/8 (50%) for a group of dehydrated and untreated controls (DC). HSD and LR solutions elicited similar heart rate, cardiac output, arterial pressure, and oxygen transport responses in the recovery period following hemorrhage and resuscitation. HSD was as effective as LR in expanding plasma volume in dehydrated hemorrhaged pigs. Serum chemistries provided no evidence for a sustained systemic toxicity from HSD treatment. These findings support low-volume HSD resuscitation of hemorrhagic shock in moderately dehydrated subjects.
Bacterial lipopolysaccharide (LPS) stimulates the production and release of endogenous mediators [e.g., tumor necrosis factor (TNF), interleukins-1 and -6 (IL-1 and IL-6), and Platelet Activating Factor [PAF] responsible for the pathophysiologic changes and the mortality associated with sepsis. We recently demonstrated that lysozyme (LZM) bound to LPS (LZM-LPS complex) suppresses LPS-induced tumor necrosis factor-alpha (TNF-alpha) production in vivo. In the present study, we investigated the effect of LZM-LPS complex formation on LPS-induced IL-6 production, both in vitro and in vivo. With the addition of LZM-LPS complex, TNF-alpha and IL-6 release was significantly reduced compared with that by LPS in a dose-dependent manner in mouse macrophage-like cells, RAW264.7. IL-6 production in serum by LPS in carrageenan (CAR)-primed mice peaked at 2 hr following injection. LZM-LPS and LZM-Escherichia coli cell complex (as 1 microgram of LPS per mouse) released significantly reduced concentrations of IL-6 in serum (P < 0.01 and P < 0.001 versus CAR-pretreated LPS- or cell-injected mice). These results emphasize the important role of LZM in vivo in the neutralization of endotoxin. However, in the case of IL-6, by administration of a lethal dose of LPS (as 100 micrograms of LPS per mouse), the IL-6 level was reduced by LZM, but a significant concentration of IL-6 was still released; although the TNF- alpha concentration was negligible in this experimental condition. Thus, it is suggested that LZM might regulate the systemic inflammation induced during Gram-negative bacterial infections by inhibiting the release of cytokines in serum.
The interactions of two anti-lipid A monoclonal antibodies (mAb)--HA-1A and SdJ5-1.17.15--with their antigenic sites on lipid A, were compared using a dot-blot assay and lipid A structural analogues, as well as lipid A-high-density lipoprotein (HDL) complexes. The reactivities of both mAb were affected by the type of fatty acid side chains and by the phosphate group on the glucosamine residue II; however, the interaction of SdJ5-1.17.15 appeared to be more markedly affected by the fatty acid side chains. A determination of the biological significance of these antigenic differences was made. Human peripheral blood mononuclear cells (hPBMC) challenged with Escherichia coli 055:B5 lipopolysaccharide (LPS) pre-incubated with SdJ5-1.17.15 released significantly less tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), compared to hPBMC exposed to vehicle preincubated LPS. HA-1A did not attenuate the in vitro release of either cytokine. The ability of both mAb to neutralize the in vivo toxicity of LPS was also evaluated. Rats administered E. coli 055:B5 pre-incubated with SdJ5-1.17.15 had a significantly reduced 24-hr mortality rate compared to vehicle controls. HA-1A did not attenuate the in vivo mortality rate. Therefore, the reactivity of anti-lipid A mAb with the antigen is preferentially affected by different residues on the lipid A moiety. Thus, the differences in biological activity seen with SdJ5-1.17.15 and HA-1A may be due in part to differences in their recognition sites on lipid A.
