Variation in endotoxin-induced kinin production and effect between the rabbit and rhesus monkey

Nies, Alan S.; Kl, Melmon

doi:10.1152/ajplegacy.1973.225.1.230

Cited by 10 publications

(3 citation statements)

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“…Endotoxin neither directly affects vascular smooth muscle function (27) nor depresses cardiac function (28,29). However, endotoxin can interact with both cellular systems and noncellular plasma enzymes to release a variety of active substances such as leukocyte pyrogen (23,30), bradykinin (5,(9)(10)(11)(12)(13)31), and lysosomal enzymes (11)(12) and to activate both the clotting (31) and immune mechanisms (32).…”

Section: Discussionmentioning

confidence: 99%

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Cardiovascular and Metabolic Effects of Whole or Fractionated Gram-Negative Bacterial Endotoxin in the Unanesthetized Rhesus Monkey

Reichgott

Melmon

Forsyth

et al. 1973

Circulation Research

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Rhesus monkeys were infused with endotoxin lipopolysaccharide (LPS) (10 mg/kg [LPS 10 ] or 2.5 mg/kg {LPS 28 ]) or with fractions of LPS containing 6.3% lipid (PSJ or 0.5% lipid (PS 2 ) (2.5 mg/kg). Systemic and regional hemodynamics, leukocyte counts, blood gases, pH, and plasma bradykinin concentration were measured. Monkeys receiving LPS 10 , LPS 2 5 , or PS t became hypotensive (mean blood pressure -37 ± 10 mm Hg) and had decreased peripheral vascular resistance (-10% to -24% of the base line), compensated metabolic acidosis, and elevated plasma bradykinin concentrations (14 ± 6 ng/ml) 2 hours after infusion. Vasodilation occurred in coronary, hepatic, and splanchnic vasculature; vasoconstriction occurred in the spleen. Cardiac output was diverted from muscle to viscera. Monkeys receiving PS 2 were normotensive with elevated peripheral vascular resistance (+46%) and no measurable plasma bradykinin concentration. By 6 hours, marked elevation of peripheral vascular resistance developed in monkeys given LPS 10 ( + 113%) and LPS 2S (+57%). Monkeys receiving PS X returned to base-line values, but monkeys receiving PS 2 remained unchanged. Leukopenia (-50% to -65%) was persistent only in monkeys receiving LPS or PS V Toxicity of LPS apparently depends on the lipid portions of the molecule. Vasodilation and bradykinin generation are correlated with persistent granuloeytopenia. Late toxicity may be independent of early cardiovascular events. KEY WORDS lipopolysaccharidebradykinin microspheres cardiac output polysaccharides granuloeytopenia regional blood flow• Gram-negative bacterial endotoxin, a complex lipopolysaccharide, causes species-specific effects (1). Primates, both human and subhuman, develop vasodilation, granuloeytopenia, and elevated plasma concentrations of bradykinin as the initial response to endotoxemia (2-4). Although granuloeytopenia is common, vasodilation does not occur in other species exposed to endotoxin (1), and bradykinin does not participate in the endotoxinshock syndrome in these animals (5-6).Leukocyte kinin-generating capabilities differ between primates and other species (7-9), but plasma kinin-generating systems are similar (9-10). Leukocyte interactions with endotoxin depend on lipid portions of the bacterial preparation (11-12), although endotoxin-plasma interactions require only bacterial polysaccharide antigens (12).Therefore, the interaction of leukocytes with lipid portions of endotoxin may result in the generation of vasoactive substances which mediate the cardiovascular events of endotoxemia. Bradykinin may be an important mediator in the primate (3, 13). To test this hypothesis, lipid-containing and lipid-free preparations of bacterial endotoxin were infused into unanesthetized Rhesus monkeys. The results confirmed the importance of Iipids for both the generation of bradykinin and the development of hemodynamic effects. The results also supported the hypothesis that interaction of endotoxin with leukocytes is the primary pathogenetic mechanism. 346

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Section: Discussionmentioning

confidence: 99%

“…Leukocyte kinin-generating capabilities differ between primates and other species (7)(8)(9), but plasma kinin-generating systems are similar (9)(10). Leukocyte interactions with endotoxin depend on lipid portions of the bacterial preparation (11)(12), although endotoxin-plasma interactions require only bacterial polysaccharide antigens (12).…”

mentioning

confidence: 99%

Cardiovascular and Metabolic Effects of Whole or Fractionated Gram-Negative Bacterial Endotoxin in the Unanesthetized Rhesus Monkey

Reichgott

Melmon

Forsyth

et al. 1973

Circulation Research

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“…Since non-human primates (NHP) share physiological and anatomical features similar to humans and have shown to respond similar to humans when exposed to live Gram-negative bacteria (19), they represent a more relevant pre-clinical model than rodents-model to study the inflammatory responses during the acute phase of sepsis. With these advantages in mind, in a previous study we developed a rhesus macaque model of septic shock induced by intravenous (i.v.)…”

Section: Introductionmentioning

confidence: 99%

Recombinant Fasciola hepatica fatty acid binding protein (Fh15) as a novel anti-inflammatory biotherapeutic in an acute gram-negative non-human primate sepsis model

Rosado‐Franco

Armina-Rodríguez

Marzan-Rivera

et al. 2021

Preprint

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Due to their phylogenetic proximity to human, non-human primates (NHP) are considered and adequate choice for basic and pre-clinical model of sepsis. Gram-negative bacteria are the primary causative of sepsis. During infection bacteria continuously release the potent toxin lipopolysaccharide (LPS) into the bloodstream, which triggers an uncontrolled systemic inflammatory response leading to death. Our previous research has demonstrated in vitro and in vivo using a mouse model of septic shock that Fh15, a recombinant variant of Fasciola hepatica fatty acid binding protein, acts as an antagonist of TLR4 suppressing the LPS-induced pro-inflammatory storm. The present study aimed to demonstrate that Fh15 suppress the cytokine storm and other inflammatory markers during the early phase of endotoxemia induced in rhesus macaques by i.v. infusion with lethal doses of live E. coli. Fh15 was administered as isotonic infusion 30 min prior to the bacterial infusion. Among the novel findings reported in this communication, I) Fh15 significantly prevents bacteremia, suppressed LPS levels in plasma and the production of C-reactive protein and procalcitonin, which are key signature of inflammation and bacterial infection, respectively, II) notably reduced the production of pro-inflammatory cytokines, and III) increased innate immune cell populations in blood, which suggest a role in promoting a prolonged steady state in rhesus macaques even in the presence of inflammatory stimuli. THis is the first report demonstrating that a F. hepatica-derived molecule possesses potential as anti-inflammatory drug against endotoxemia in an NHP model.

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Outlining key inflammation‐associated parameters during early phase of an experimental gram‐negative sepsis model in rhesus macaques (Macaca mulatta)

Rosado‐Franco

Ramos‐Benitez

Parodi

et al. 2019

Anim Models and Exp Med

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The aim of this study was to identify inflammation‐associated markers during the early phase of sepsis in rhesus macaque. Four rhesus macaques were given an intravenous dose of 1010 CFU/kg of E. coli. Blood samples were collected before, or 30 minutes, 2, 4, 6 and 8 hours after E. coli infusion. Physiological parameters, bacteremia, endotoxemia, C‐reactive protein (CRP), procalcitonin (PCT), and plasma cytokines/chemokines were determined for each animal. Bacteremia was present in all animals from 30 minutes to 3 hours after E. coli infusion whereas endotoxin was detected during the full‐time course. CRP and PCT levels remained at detectable levels during the whole experimental window suggesting an ongoing inflammatory process. Signature cytokines and chemokines such as TNF‐α, MIP‐1α, and MIP‐1β peaked about 2 hours after E. coli infusion and decreased thereafter. Plasma IL‐6, IL‐12p40, IFN‐γ, and IL‐1Ra, as well as I‐TAC, MIG, IP‐10 and MCP‐1, remained at detectable levels after 4 hours of E. coli infusion. This nonhuman primate model could be useful for the assessment of new therapeutics aiming to suppress key inflammatory markers throughout sepsis early phases.

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Variation in endotoxin-induced kinin production and effect between the rabbit and rhesus monkey

Cited by 10 publications

References 0 publications

Cardiovascular and Metabolic Effects of Whole or Fractionated Gram-Negative Bacterial Endotoxin in the Unanesthetized Rhesus Monkey

Cardiovascular and Metabolic Effects of Whole or Fractionated Gram-Negative Bacterial Endotoxin in the Unanesthetized Rhesus Monkey

Recombinant Fasciola hepatica fatty acid binding protein (Fh15) as a novel anti-inflammatory biotherapeutic in an acute gram-negative non-human primate sepsis model

Outlining key inflammation‐associated parameters during early phase of an experimental gram‐negative sepsis model in rhesus macaques (Macaca mulatta)

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