Cachectin (tumor necrosis factor), a protein produced in large quantities by endotoxin-activated macrophages, has been implicated as an important mediator of the lethal effect of endotoxin. Recombinant human cachectin was infused into rats in an effort to determine whether cachectin, by itself, can elicit the derangements of host physiology caused by administration of endotoxin. When administered in quantities similar to those produced endogenously in response to endotoxin, cachectin causes hypotension, metabolic acidosis, hemoconcentration, and death within minutes to hours, as a result of respiratory arrest. Hyperglycemia and hyperkalemia were also observed after infusion. At necropsy, diffuse pulmonary inflammation and hemorrhage were apparent on gross and histopathologic examination, along with ischemic and hemorrhagic lesions of the gastrointestinal tract, and acute renal tubular necrosis. Thus, it appears that a single protein mediator (cachectin) is capable of inducing many of the deleterious effects of endotoxin.

https://science.sciencemag.org/content/sci/234/4775/470.full.pdf

Shock and tissue injury induced by recombinant human cachectin.

THE metabolic impact of infectious and neoplastic disease states has long been known to clinicians.1 2 3 4 Invasive diseases may disrupt normal homeo-static mechanisms, both locally and systemically. For example, acute gram-negative infections frequently lead to profound metabolic acidosis and to biphasic changes in plasma glucose concentration, both seen in the context of hypotension, disseminated intravascular coagulation, and widespread tissue injury.5 6 7 8 9 10 11 12 Chronic infectious diseases, as well as neoplastic diseases, may provoke a severe wasting diathesis, in which negative calorie and nitrogen balance lead to death despite the absence of a large parasite or tumor burden. It was once widely believed that invasive . . .

Cachectin: more than a tumor necrosis factor.

Methods in Lignin Chemistry

In this chapter, current concepts about the mechanisms of action of endotoxin are reviewed. Particular attention is focused upon endotoxin-induced production of soluble mediators from macrophages and mononuclear cells and on the potential contribution of these mediators to endotoxin shock. In many cases, the interrelationships between these mediators as primary and/or secondary consequences of endotoxin stimulation of mononuclear phagocytes are discussed. Final comments address the relevance of these mediators to the therapy of endotoxin shock.

Endotoxins and disease mechanisms

https://chemistry.mdma.ch/hiveboard/rhodium/pdf/piper.phytochemistry.pdf

Phytochemistry of the genus Piper

Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone.

Platelet-activating factor (PAF) is a potent lipid mediator of inflammation and asthma. Using a receptor preparation of rabbit platelet membranes, we identified a novel antagonist of PAF in the methylene chloride extract of a Chinese herbal plant, haifenteng (Piper futokadsura). The active antagonist, kadsurenone, was isolated and characterized in several in vitro and in vivo assays. It is a specific and competitive inhibitor of PAF binding to its receptor with a Ki of 5.8 X 10(-8) M vs. a Ki of 6.3 X 10(-9) M for PAF itself. It inhibits PAF-induced aggregation of rabbit platelets and human neutrophils at 2.4-24 microM, without showing any PAF agonistic activity. It potently inhibits PAF-induced degranulation of human neutrophils at 2.5-50 microM, also without any agonist activity. Kadsurenone is active orally at 25-50 mg/kg of body weight in blocking PAF-induced cutaneous permeability in the guinea pig. It also inhibits PAF-induced increases of hematocrit and circulating N-acetylglucosaminidase in the rat at greater than 10 mg/kg i.p. in a dose-dependent manner. Kadsurenone does not interfere with the function of several pharmacological mediators and receptors tested. Its structural specificity is evidenced by the poor PAF-antagonistic activities of three related structures isolated from the same haifenteng extract.

https://www.pnas.org/content/pnas/82/3/672.full.pdf

Characterization of a platelet-activating factor receptor antagonist isolated from haifenteng (Piper futokadsura): specific inhibition of in vitro and in vivo platelet-activating factor-induced effects.

Specific binding sites for platelet activating factor in human lung tissues.

Characterization of cutaneous vascular permeability induced by platelet-activating factor in guinea pigs and rats and its inhibition by a platelet-activating factor receptor antagonist.

5-(2,4-Difluorophenyl)salicylic acid, diflunisal (25), is the best compound, in terms of both efficacy and safety, from over 500 salicylates investigated in our laboratories. It is a chemically distinct, nonacetylating salicylic acid, more active than aspirin as an analgesic and antiinflammatory agent and superior in duration of action and therapeutic index. Some recent clinical and biochemical observations are briefly discussed.

T. Y. Shen

Papers

Platelet activating factor (PAF) involvement in endotoxin-induced hypotension in rats. Studies with PAF-receptor antagonist kadsurenone.

Characterization of a platelet-activating factor receptor antagonist isolated from haifenteng (Piper futokadsura): specific inhibition of in vitro and in vivo platelet-activating factor-induced effects.

Specific binding sites for platelet activating factor in human lung tissues.

Characterization of cutaneous vascular permeability induced by platelet-activating factor in guinea pigs and rats and its inhibition by a platelet-activating factor receptor antagonist.

Novel analgesic-antiinflammatory salicylates.