Recombinant Human Tumor Necrosis Factor Produces Hemodynamic Changes Characteristic of Sepsis and Endotoxemia

Schirmer, William J.; Schirmer, James M.; Fry, Donald E.

doi:10.1001/archsurg.1989.01410040055012

Cited by 110 publications

(33 citation statements)

References 21 publications

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“…[40][41][42] As for heat stroke in our previous studies, the plasma levels of TNF-a were greatly elevated during heat stroke in rats. 37) The increased levels of the inflammatory cytokines in the peripheral blood stream were showed to be well related to the severity of heat stroke.…”

Section: Disscusionmentioning

confidence: 73%

Effects of Combination Treatment with Dexamethasone and Mannitol on Neuronal Damage and Survival in Experimental Heat Stroke

Yang

Shih

et al. 2010

Biological & Pharmaceutical Bulletin

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Unless immediately recognized and treated, heat stroke is often lethal, and victims who do survive may sustain permanent neurological damage.1) The clinical diagnosis of heat stroke is demonstrated when hyperthermia is accompanied with circulatory shock (arterial hypotension), intracranial hypertension, and cerebral ischemia and injury. 2,3) Meanwhile, the heat stroke-induced central nervous system dysfunction includes delirium, convulsion, or coma. 4) Hence, prolonging survival time in heat stroke victims may offer more sufficient time for urgent treatment, thereby ameliorating the heat stroke-induced damage.Several lines of evidence indicate that rodents share with humans almost the same heat stroke syndromes, such as arterial hypotension, activated inflammation, and multiorgan dysfunction (in particular, cerebral ischemia, injury, and dysfunction. [5][6][7] In the rodents heat stroke model, significant decrements in both mean arterial pressure (MAP) and cerebral blood flow (CBF), but increments of cerebral monoamines levels and free radical productions are obtained in urethane-anaesthetized rats after heat stroke. 8,9) These pathophysiological changes are known to aggravate the conditions of cerebral ischemia and neuronal damage during heat stroke in rats.10,11) Activated inflammation is evidenced by overproduction of pro-inflammatory cytokines (e.g., tumor necrosis factor-a (TNF-a)) in plasma of heat stroke rats.12,13) High levels of TNF-a in the peripheral blood stream, as well as excessive accumulation of glutamate, hydroxyl radicals, dopamome (DA) and serotonin (5-HT) in the central brain, correlate with the severity of circulatory shock, cerebral ischemia and neuronal damage during heat stroke in rats. 6,9,11,14,15) Various clinical and experimental investigations have shown that single doses of dexamethasone (DXM; exogenous glucocorticoids) or mannitol are extensively used in the treatment of cerebral ischemia and/or cerebral injury. [16][17][18] In the studies of heat stroke, pretreatment with DXM attenuated serum IL-1b levels and improved survival in heat stroke. 19) Additionally, pretreatment with mannitol before the onset of heat stroke caused significant reduction of the heat strokeinduced the increased free radical formation and intracranial hypertension. 20) Although, many therapeutic agent show potential promise in many animal models, the results of most single-agent clinical trials are sobering. Consequently, various authors advocate studies to estimate the efficacy of combined therapeutic approaches. 21,22) Hence, the mannitol that acts to decrease intracranial pressure and radical formation, and a potent inflammatory agent (such as DXM) might be combined to develop an improved fluid therapy for attenuation or amelioration of heat stroke-induced damage. Furthermore, there is less attention to evaluate immediate effects of both DXM and mannitol (the combined agent) on heat stroke-induced pathophysiological changes, let alone their neuroprotective underlying influences, especially in the aspects...

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Section: Disscusionmentioning

confidence: 73%

Effects of Combination Treatment with Dexamethasone and Mannitol on Neuronal Damage and Survival in Experimental Heat Stroke

Yang

Shih

et al. 2010

Biological & Pharmaceutical Bulletin

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“…This function can be important for the clearance of certain microorganisms, such as Listeria monocytogenes (3,4), but can also contribute to a number of disease processes, such as endotoxemia and septic shock (5)(6)(7). Although some of its pathological effects are due to a series of cytokine reactions, TNF␣ can also exert direct cytotoxic effects on the cell (8 -11).…”

Section: Tnf␣mentioning

confidence: 99%

Activation of Pro-death Bcl-2 Family Proteins and Mitochondria Apoptosis Pathway in Tumor Necrosis Factor-α-induced Liver Injury

Zhao

Childs

et al. 2001

Journal of Biological Chemistry

119

105

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Tumor necrosis factor-␣ (TNF␣)-induced cytotoxicity contributes to the pathogenesis in inflammatory and immune responses. Here, we studied the role of prodeath Bcl-2 family proteins and the mitochondria apoptosis pathway in the development of TNF␣-induced hepatic injury during endotoxemia. After treating mice with lipopolysaccharide or TNF␣ in the presence of Dgalactosamine, Bid was cleaved and translocated to mitochondria in hepatocytes. Independently, Bax was also activated by the death receptor engagement and translocated to mitochondria. However, its subsequent insertion into the mitochondrial membrane depends on Bid. Nevertheless, Bid was required, but Bax could be dispensed for the mitochondrial release of cytochrome c from mitochondria, suggesting that Bid could activate additional downstream molecules other than Bax. The lack of this Bid-dependent mitochondria activation and cytochrome c release in the bid-deficient mice was responsible for the significantly delayed effector caspase activation and hepatocyte injury upon endotoxin treatment, culminating in a prolonged survival of the biddeficient mice. Additional genetic factor(s) could further modify the dependence of TNF␣ toxicity on the mitochondria pathway as the bid-deficient 129/SvJ mice manifested an even higher resistance than the same type of mice in C57BL/6 background. The functional significance of the mitochondria apoptosis pathway was thus elucidated in the TNF␣-mediated pathogenesis in vivo.

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“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Pagani

Baker²,

Hsi³

et al. 1992

J. Clin. Invest.

258

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We used a load-insensitive index of systolic left ventricular (LV) function and an analysis of diastolic pressure-dimension relationships to test the hypothesis that recombinant human (rh) tumor necrosis factor-a (TNFa) impairs LV function in dogs. Animals were studied 7-10 d after aseptic implantation of instrumentation to monitor cardiac output, external anteriorposterior LV diameter, and LV and pleural pressures. Data were analyzed from seven dogs that received active rhTNFa (100 Mg/kg over 60 min) and from five dogs that received heatinactivated rhTNFa. At 24 h after infusion of active rhTNFa, the slope of the LV end-diastolic dimension-stroke work relationship decreased significantly, indicating a decrement in LV systolic contractility. Simultaneously, LV unstressed dimension increased significantly, suggesting diastolic myocardial creep. The end-diastolic relationship between LV transmural pressure and normalized LV dimension (strain) was markedly displaced to the left, suggesting increased diastolic elastic stiffness. Despite these changes in LV performance, cardiac index was maintained by tachycardia. The abnormalities in LV function were resolved by 72 h. We conclude that rhTNFa reversibly impairs LV systolic and diastolic function in unanesthetized dogs. Because dysfunction occurs > 6 h after the infusion of rhTNFa and persists for 24-48 h, the mechanism underlying this phenomenon may involve secondary mediators or a change in myocardial gene expression. (J. Clin. Invest. 1992. 90:389-398.)

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Recombinant Human Tumor Necrosis Factor Produces Hemodynamic Changes Characteristic of Sepsis and Endotoxemia

Cited by 110 publications

References 21 publications

Effects of Combination Treatment with Dexamethasone and Mannitol on Neuronal Damage and Survival in Experimental Heat Stroke

Effects of Combination Treatment with Dexamethasone and Mannitol on Neuronal Damage and Survival in Experimental Heat Stroke

Activation of Pro-death Bcl-2 Family Proteins and Mitochondria Apoptosis Pathway in Tumor Necrosis Factor-α-induced Liver Injury

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

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