Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation.

Abstract

Severe weight loss and debilitative wasting of lean body mass frequently complicate the treatment of patients suffering from malignancy or chronic infection. Termed cachexia, this syndrome of anorexia, anemia, and weakness further increases cancer mortality; some data indicate that as many as 30% of cancer patients die from cachexia, rather than tumor burden (1-3). The severity of cachexia may be unrelated to tumor size or parasite load, and profound wasting has been observed in patients with tumor burdens of only 0.01-5.0% body mass (4). If not reversed, cachexia-associated derangements of homeostasis lead to immunological deficiencies, organ failure, and multiple metabolic abnormalities . While it is clear that a variety of mechanisms participate in the pathogenesis of cachexia, and that cachexia adversely affects prognosis, the etiology of this syndrome is not known.For a number of years we have been searching for endogenous, humoral mediators of cachexia, beginning with the characterization of metabolic changes in trypanosome-infected rabbits that develop profound cachexia and lose up to 50% of lean body mass within weeks. In later stages of disease a paradoxical increase in circulating triglycerides occurs, attributable to systemic suppression of lipoprotein lipase (LPL)t (5). A bacterial LPS-inducible serum factor which suppresses LPL in mice, and several other key lipogenic enzymes in the adipocyte cell line 3T3-L1, was isolated and named cachectin (6, 7). Cachectin evokes a state of cellular cachexia by suppressing the expression of several mRNAs encoding essential lipogenic enzymes (8, 9). Myocytes also show changes in cellular metabolism after exposure to cachectin in vitro, including a prompt decrease in resting transmembrane potential difference and depletion of intracellular glycogen stores with increased lactate efflux, and a later increase in hexose transporters (10,11). It has been suggested that cachectin may play a

Plasma levels of tumour necrosis factor and its soluble receptors correlate with clinical features and outcome of Hodgkin's disease patients

“…Several studies have revealed possible ways in which excessive TNF production could contribute to this phenomenon (Tracey et al, 1988;Lindemann et al, 1989;Denz et al, 1993;. Importantly, all these adverse conditions may result in a poor performance status of the host and may influence the patient's ability to tolerate therapy and, as a consequence, result in a worse prognosis.…”

Tumour necrosis factor enhances the asbestos-induced production of reactive oxygen metabolites by human polymorphonuclear leucocytes (PMN)

“…TNF. on the other hand, has been shown to induce diffuse alveolar damage with neerosis of alveolar epithelial and endothelial cells [37]. Thus, in the response to respirable mineral fibres, TNF will add a synergistic factor to the generation of reactive oxygen species by PMN.…”

Systemic manifestations and comorbidities of COPD

“…Increased systemic TNF-a has been implicated as a mechanism of cachexia, skeletal muscle atrophy and weakness in COPD patients. Chronic administration of TNF-a in animals results in cachexia, anaemia, leukocytosis and infiltration of neutrophils into organs such as the heart, liver and spleen [17].…”