Синдром хронічної втоми: взаємозв'язок вправ та імунної дисфункції

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Медицина

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Стаття

К-сть сторінок:

22

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English

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of initiating high molecular weight RNase L (83 kDa) proteolysis, generating two major fragments with molecular masses of 37 (a truncated low molecular weight RNase L) and 30 kDa, respectively (5). Experimental data point to an activation of the PKR enzyme, parallel to the 83 kDa RNase L proteolysis, in subsets of CFS (8). PKR activation leads to phosphorylation of the inhibitor of NF (nuclear factor) -kJ3 (IkB) and consequent NF-kB activation, which in turn causes inducible nitric oxide synthetase (iNOS) expression. iNOS generates increased production of NO by monocytes/macrophages. NO mediates important vital physiological functions such as neurotransmission, cell-mediated immune responses (strong antimicrobial and antitumour activities), and vasodilatation. Excessive and/or persistent production of NO, however, is detrimental to the body's functions (21). Elevated NO has been documented in CFS patients (14). Elevated NO levels and consequent vasodilatation might limit CFS patients to increase blood flow during exercise, and might even cause and enhance postexercise hypotension (19). It is hypothesized that PKR activation and consequent elevated NO levels are related to poor exercise performance in CFS patients.

Snell and colleagues (25) showed that CFS patients with evidence of a deregulated 2', 5'-oligoadenylate (2-5A) synthetase/RNase L pathway have a lower peak oxygen uptake than CFS patients without the intracellular immune deregulation, suggesting a link between immunopathology and exercise performance in CFS. As outlined previously (19), the deregulation of the 2-5A synthetase/RNase L pathway may be related to a channelopathy, capable of initiating both intracellular hypomagnesaemia in skeletal muscles and transient hypoglycemia. This might explain muscle weakness and the reduced peak oxygen uptake seen in CFS patients. Thus, it is hypothesized that various components of the 2-5A synthetase/RNase L pathway (i. e., the ratio of 37 kDa RNase L to the 83 kDa native RNase L for the assessment of 83 kDa RNase L proteolysis, RNase L enzymatic activity, and elastase activity) are related to exercise performance in CFS patients. Summarizing the research questions, this study aims at 1) examining whether PKR activation and consequent elevated NO levels predict poor exercise performance in CFS patients, and 2) examining whether exercise performance in CFS is associated with deregulation of the 2-5A synthetase/RNase L pathway (i. e., 83 kDa RNase L proteolysis, RNase L activity, and elastase activity). It is hypothesized that in CFS patients, 1) both PRK activation and consequent elevated NO levels predict poor exercise performance during a graded exercise cycle test, and 2) deregulation of the 2-5A synthetase/RNase L pathway is associated with poor exercise performance during a graded exercise cycle test.

METHODS

Patient recruitment and research design. Sixteen randomly allocated untrained patients with CFS were enrolled. Patients were randomly allocated from consecutive referrals to our chronic fatigue clinic. To be included into the study, patients had to fulfill the U. S. Centers for Disease Control and Prevention criteria for CFS (9). Therefore, all patients underwent an extensive medical evaluation before study participation (see below). All patients had Dutch as their native language, and were within the age range of 18-65 yr. The study sample consisted of eight female and eight male CFS patients. The mean age was 38 ± 10 yr (range 19-59), and the mean illness duration was 31 ± 11 months (range 12-48). An information leaflet was handed out to all patients, and they were instructed to read it carefully and, if applicable, to ask for additional clarification. The study protocol was approved by the local ethics committee (Academical Hospital Vrije Universiteit Brussel; O. G. 016). Patients provided written informed consent and underwent venous blood sampling (arm vein; 40 mL; lying supine). The following immunological variables were assessed: the ratio of 37 kDa RNase L to the 83 kDa native RNase L, RNase L enzymatic activity, protein kinase R activity assay, elastase activity, the percent of monocytes, and nitric oxide determination. Patients were instructed not to take any medication during the 24 h before study participation, and not to smoke, or to drink coffee or tea on the testing day. Afterwards, all patients performed a maximal exercise test on a bicycle ergometer with continuous monitoring of cardiorespiratory variables.

Diagnosis of CFS. All patients were diagnosed as CFS cases by the same physician (the final author). To fulfill the diagnostic criteria for CFS, clinically evaluated, unexplained, persistent, or relapsing chronic fatigue that is of new or definite onset, should result in a substantial reduction in previous levels of occupational, educational, social, or personal activities (9). Furthermore, at least four of the following symptoms must have persisted or recurred during six or more consecutive months and must not have predated the fatigue: impairment in short-term memory or concentration, tender cervical or axillary lymph nodes, muscle pain, multijoint pain, headache, unrefreshing sleep, and pos-texertional malaise for more than 24 h (9). Any active