Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock.

Abstract

Endotoxin, an LPS found in the outer membrane of Gram-negative bacteria, has been considered by many to be the principal toxin involved in the pathogenesis of Gram-negative septic shock (1). However, it is now clear that endotoxin may cause most (ifnot all) of its biological effects via the release of host factors (2-5) . Several studies have suggested that TNF, a cytokine produced by macrophages during septic shock, is one ofthe endogenous mediators that causes cardiovascular injury and death (2-5).Previous studies examining the effects of endotoxin and TNF in animal models have used a number of techniques to study cardiovascular function during the first 1-12 h after challenge. Most of these investigations have shown evidence of myocardial depression (2-11) . However, recent studies of human and animal septic shock have demonstrated that cardiovascular function continues to change over a period of several days. Typically, the left ventricular ejection fraction (LVEF)' falls to a nadir 2-3 d after the onset of hypotension. This progressive decrease in LVEF is associated with IV dilatation and maintenance of normal or increased cardiac output. In survivors, these cardiovascular changes return to normal in 7-10 d (12-20).The present study shows that dogs given a single intravenous bolus of TNF produce all the same complex cardiovascular changes over 7-10 d as those seen in septic shock over the same period . Furthermore, endotoxin without any other bacterial products can also produce the same serial changes in cardiovascular function seen in human septic shock.

Acute Reversible Myocardial Depression Associated with Sepsis.

“…As mentioned earlier, endotoxin might have caused a transient LV systolic dysfunction (8,9), but both endotoxin itself and endotoxin-producing bacteria were not detected from the sera of this patient. As a consequence, it was suggested that this patient's heart failure might have been due to functional depression of myocardial contractility resulting from a direct effect of the cytokines towards the cardiomyocytes, a pathophysiologic state compatible with the so-called "septic myocardial depression".…”

“…This condition has been termed "septic myocardial depression (6)" or "acute septic cardiomyopathy (7)". Endotoxin (8,9), TNF-a (9) and ILip (10) have been reported to induce the same hemodynamic changes as seen in the clinical settings; hypotension and decrease in cardiac output, systemic vascular resistance and LVEF (8,9). Experimental studies (6, 7, 10, ll) have shown that proinflammatory cytokines such as TNF-a (6, 7, 10, 1 1) and IL-ip (6, 7, 10) induce a negative inotropic effect through nitric oxide (NO)-dependent (6, 10) or NO-independent (6, 7, 10, ll) mechanisms; TNF-a is reported to exert its myocardial depressant effects by activation of myocardial constitutive NOsynthase (CNOS)and gene expression of inducible NOS (iNOS) leading to increased NO production.…”

TNF-Induced Shedding of TNF Receptors in Human Polymorphonuclear Leukocytes: Role of the 55-kDa TNF Receptor and Involvement of a Membrane-Bound and Non-Matrix Metalloproteinase

“…However, excessive TNF production may turn TNF activities from beneficial to extremely injurious. In fact, acute release of large amounts of TNF in the circulation is followed by the characteristic manifestations of septic shock, i.e., decrease in capillary resistance, capillary leakage, falling in cardiac output, diffuse coagulation with necrosis of vital organs, and cardiopulmonary collapse (47)(48)(49). PMN are crucial targets of TNF activity, and if exposed to high TNF doses they may become key effectors of its toxic effects.…”

Herz in der Sepsis

“…1; [84]). Dieselbe Arbeitsgruppe konnte 4 Jahre später zeigen, dass ihre Ergebnisse auf dem Vorhandensein von Tumor-Nekrose-Faktor-α (TNF-α) beruhten [76]. In folgenden Untersuchungen wurde belegt, dass hierbei auch Interleukin-1β (IL-1β) eine Rolle spielt [53], und mehrere jüngere Studien postulieren eine Schlüsselrolle für diverse proinflammatorische Zytokine (.…”