Human recombinant tumor necrosis factor alpha infusion mimics endotoxemia in awake sheep

Abstract

The macrophage-derived cytokine tumor necrosis factor alpha (TNF alpha) has been proposed as the major mediator of endotoxin-induced injury. To examine whether a single infusion of human recombinant TNF alpha (rTNF alpha) reproduces the pulmonary effects of endotoxemia, we infused rTNF alpha (0.01 mg/kg) over 30 min into six chronically instrumented awake sheep and assessed the ensuing changes in hemodynamics, lung lymph flow and protein concentration, and number of peripheral blood and lung lymph leukocytes. In addition, levels of thromboxane B2, 6-ketoprostaglandin F1 alpha, prostaglandin E2, and leukotriene B4 were measured in lung lymph. Pulmonary arterial pressure (Ppa) peaked within 15 min of the start of rTNF alpha infusion [base-line Ppa = 22.0 +/- 1.5 (SE) cmH2O; after 15 min of rTNF alpha infusion, Ppa = 54.2 +/- 5.4] and then fell toward base line. The pulmonary hypertension was accompanied by hypoxemia and peripheral blood and lung lymph leukopenia, both of which persisted throughout the 4 h of study. These changes were followed by an increase in protein-rich lung lymph flow (base-line lymph protein clearance = 1.8 +/- 0.4 cmH2O; 3 h after rTNF alpha infusion, clearance = 5.6 +/- 1.2), consistent with an increase in pulmonary microvascular permeability. Cardiac output and left atrial pressure did not change significantly throughout the experiment. Light-microscopic examination of lung tissue at autopsy revealed congestion, neutrophil sequestration, and patchy interstitial edema. We conclude that rTNF alpha induces a response in awake sheep remarkable similar to that of endotoxemia. Because endotoxin is a known stimulant of TNF alpha production, TNF alpha may mediate endotoxin-induced lung injury.

S1P3receptor-induced reorganization of epithelial tight junctions compromises lung barrier integrity and is potentiated by TNF

“…It is significant that TNF synergizes with S1P in the control of epithelial permeability (35)(36)(37)(38) while also regulating pulmonary microvessel endothelium (38,39). TNF at higher concentrations leads to down-regulation of ZO-1 protein expression and disturbance in junctional localization of ZO-1 protein, and functional opening of the tight junction barrier (40).…”

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction

“…More importantly, the increase in endothelial permeability can be induced by a number of sepsisrelated factors. Indeed, the cytokine tumor necrosis factor-α (TNF-α) induces an increase in endothelial cell permeability both in vivo and in vitro (Johnson et al, 1989;Goldblum et al, 1993;Ferro et al, 1997Ferro et al, , 2000. Under in vitro conditions, thrombin also increases endothelial cell permeability, while TNF-α and thrombin act synergistically to induce barrier dysfunction in vitro (Tiruppathi et al, 2001).…”

Left ventricular systolic and diastolic dysfunction after infusion of tumor necrosis factor-alpha in conscious dogs.

“…Administration ofTNFa to humans (8,9), mice ( 10,11 ), rats (12)(13)(14)(15)(16), rabbits ( 17), dogs (18)(19)(20), and sheep (21,22) elicits manifestations of sepsis and septic shock, including fever, hypotension, acidosis, leukopenia, histopathological evidence of organ injury, and death. In experimental animals, survival is improved when monoclonal (23) or polyclonal (24) antibodies against TNFa are administered before challenge with live Escherichia coli or LPS.…”