HMG-1 as a late mediator of endotoxin lethality in mice.

Endotoxin, a constituent of Gram-negative bacteria, stimulates macrophages to release large quantities of tumor necrosis factor (TNF) and interleukin-1 (IL-1), which can precipitate tissue injury and lethal shock (endotoxemia). Antagonists of TNF and IL-1 have shown limited efficacy in clinical trials, possibly because these cytokines are early mediators in pathogenesis. Here a potential late mediator of lethality is identified and characterized in a mouse model. High mobility group-1 (HMG-1) protein was found to be released by cultured macrophages more than 8 hours after stimulation with endotoxin, TNF, or IL-1. Mice showed increased serum levels of HMG-1 from 8 to 32 hours after endotoxin exposure. Delayed administration of antibodies to HMG-1 attenuated endotoxin lethality in mice, and administration of HMG-1 itself was lethal. Septic patients who succumbed to infection had increased serum HMG-1 levels, suggesting that this protein warrants investigation as a therapeutic target.

Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation.

CNI-1493 is a potent anti-inflammatory agent, which deactivates macrophages and inhibits the synthesis of proinflammatory mediators. The objective of the present study was to identify the role of the central nervous system (CNS) and efferent vagus nerve signaling in CNI-1493-mediated modulation of acute inflammation in the periphery. CNI-1493 was administered either intracerebroventricularly (i.c.v., 0.1-1,000 ng/kg) or intravenously (i.v., 5 mg/kg) in anesthetized rats subjected to a standard model of acute inflammation (subcutaneous (s.c.) injection of carrageenan). I.c.v. CNI-1493 significantly suppressed carrageenan-induced paw edema, even in doses at least 6-logs lower than those required for a systemic effect. Bilateral cervical vagotomy or atropine blockade (1 mg/kg/h) abrogated the anti-inflammatory effects of CNI-1493 (1 microg/kg, i.c.v. or 5 mg/kg, i.v.), indicating that the intact vagus nerve is required for CNI-1493 activity. Recording of the efferent vagus nerve activity revealed an increase in discharge rate starting at 3-4 min after CNI-1493 administration (5 mg/kg, i.v.) and lasting for 10-14 min (control activity=87+/-5.4 impulses/s versus CNI-1493-induced activity= 229+/-6.7 impulses/s). Modulation of efferent vagus nerve activity by electrical stimulation (5 V, 2 ms, 1 Hz) of the transected peripheral vagus nerve for 20 min (10 min before carrageenan administration and 10 min after) also prevented the development of acute inflammation. Local administration of the vagus nerve neurotransmitter, acetylcholine (4 microg/kg, s.c.), or cholinergic agonists into the site of carrageenan-injection also inhibited acute inflammation. These results now identify a previously unrecognized role of efferent vagus nerve activity in mediating the central action of an anti-inflammatory agent.

Stimulus-dependent effects in the actions of sodium channel blockers on sensory C-units.

Stimulus-dependent inhibition of discharges from cutaneous C fibers from mechanothermo-sensitive (MTS) units (nociceptive sensors) can explain the paradoxical analgesic effect of local anesthetics at low concentrations, insufficient to block axonal conduction of nerve impulses. Three types of experiments are proposed which could detect the stimulus-dependent inhibition of the terminal section of sensory C units: a method involving repeated series of stimuli, the increasing stimulus method, and the spike encounter method. The applications of these methods to assessing the magnitudes of the neuroleptic effects of local anesthetics and cardiac antiarrhythmics is discussed.

[Stimulus-dependent effects of the sodium channel blockers in the C-fiber sensory units]. / Stimulozavisimye éffekty pri deistvii blokatorov natrievykh kanalov na sensornye C-edinitsy.

The data obtained suggest a use-dependent inhibition in the skin terminals of the C-fibre sensory units. The terminals are discussed in respect to search of efficient local anaesthetising agents as well as cardiac anti-arrhythmic agents with obvious neurotropic effects.

Spermine inhibition of monocyte activation and inflammation.

The innate immune system functions as a defensive front line against pathogenic invasion, but the proinflammatory products of activated monocytes and macrophages (e.g., TNF and NO) can also injure normal cells. Anti-inflammatory mediators restrain the innate immune response and prevent excessive collateral tissue damage. Spermine, a ubiquitous biogenic polyamine, specifically and reversibly suppresses the synthesis of monocyte proinflammatory cytokines. This may provide a counterregulatory mechanism to restrain monocyte activation in injured or infected tissues and in tumors where spermine levels are significantly increased. Here we show that monocyte spermine uptake was significantly increased following lipopolysaccharide stimulation. The polyamine analogue 1, 4-bis(3-aminopropyl)-piperazine (BAP) inhibited LPS-stimulated monocyte spermine uptake via the "nonselective" polyamine transporter. BAP fully restored macrophage TNF synthesis despite the presence of spermine, indicating that the mechanism of monocyte deactivation by spermine is dependent on spermine uptake. Administration of BAP in vivo significantly augmented the development of carrageenan-induced paw edema and nitric oxide release. Thus, endogenous spermine normally inhibits the innate inflammatory response by restraining macrophages.

Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.