Alterations in Immunocyte Tumor Necrosis Factor Receptor and Apoptosis in Patients With Congestive Heart Failure

Autor: Robert J. Hilkert, Tyrone J. Krause, Alan J. Spotnitz, Stephen F. Lowry, Vishnu Rumalla, Steve E. Calvano, Edward Lin
Rok vydání: 2002
Předmět:
Zdroj: Annals of Surgery. 236:254-260
ISSN: 0003-4932
DOI: 10.1097/00000658-200208000-00015
Popis: Congestive heart failure (CHF) is one of the leading causes of hospitalization of older adults in the United States. At present, this disease accounts for healthcare expenditures of $10 billion per year, and the incidence of CHF continues to rise with an increasing proportion of the elderly in the population. 1 Tumor necrosis factor (TNF) is a proinflammatory cytokine that plays a pivotal role in the host response to infection and injury. Local production of TNF recruits and activates immunocytes and further stimulates the production of other pro- and antiinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-8, and IL-10. 2 Under normal circumstances, TNF exerts some beneficial effects in terms of host containment and eradication of pathogenic microorganisms, whereas it is commonly held that an excessive host TNF response may produce shock and solid organ dysfunction. While TNF is not readily detectable in the normal myocardium, immunoreactive TNF becomes detectable in the failing heart. 3 Furthermore, this cytokine has been detected in the systemic circulation of patients with CHF, and the levels of TNF activity reportedly correlate with the clinical severity of disease. 4,5 These observations suggest that TNF-induced inflammation is a component of the CHF disease process. It is well documented that systemic TNF can reduce vascular smooth muscle tone and myocardial contractility both directly and indirectly via mechanisms that include increased nitric oxide production. 6,7 Because cytokines exert their influences predominantly at the autocrine and paracrine levels, it has been hypothesized that the systemic appearance of TNF may herald the onset of more severe myocardial disease. 4 However, there are limitations to the detection of systemic TNF levels, including the episodic nature of ligand release into the circulation, the short half-life of the molecule, and the diversity of immunologic methods utilized to detect the biologically active ligand. 8 It is also recognized that proinflammatory mediators may act principally at the local level without overt evidence of systemic inflammation. One approach to surmounting these limitations is to assess cellular markers, which might reflect antecedent or very low levels of cytokine activity. 9–11 This laboratory and others have reported decreased polymorphonuclear cell (PMN) and monocyte TNF receptor (TNFR) expression and PMN apoptosis during conditions of systemic inflammation including experimental endotoxemia and severe sepsis. 9,10 Under such circumstances, reduced levels of TNFR activity reflect prior activity of the ligand and, in instances of sepsis, correlate with survival. 11 Similarly, PMN apoptosis, a highly regulated process of cell death and noninflammatory disposal, is delayed during systemic inflammatory responses, 12,13 and several proinflammatory cytokines, including TNF, have been shown to delay immune cell apoptosis in vitro. 14 Furthermore, current research suggests that Fas/CD95 receptor, a member of the TNFR superfamily of proteins, directs the apoptosis seen in the myocardial remodeling during CHF. 15 Because of the consistency of immunocyte TNFR expression regulation and the observed attenuation of PMN apoptosis under differing conditions of systemic inflammation, we hypothesized that such systemic markers of cytokine activity may also be useful indicators of CHF progression. To this end, the present study sought to determine if CHF patients would manifest similar alterations of immune cell phenotype and functional responses as were previously demonstrated in patients with more overt inflammatory process.
Databáze: OpenAIRE
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