Mechanisms of Systemic Effects - Chronic Obstructive Pulmonary Disease - page 432

this cytokine than healthy controls (16); (c) several authors have now shown
increased plasma; and, finally, (d) TNF a can affect muscle cells in several
ways (61). In differentiated myocites studied in vitro, TNF a induces proteo-
lysis through the ubiquitin-proteasome complex (U = P) by an NF- k B-depen-
dent mechanism (61). In fact, NF- k B plays an important role in activating
specific transcriptional mechanisms of atrophy (62). Several studies have
now shown that a disregulation of the U = P system contributes to the loss
of muscular mass caused by sepsis or tumors in rats (63). In this context,
recently a number of genes, whose expression is characteristic of the muscle
wasting process, have been identified, including ubiquitin ligases as atrogin-
1 and MURF (64) and myostatin (65). Whether this occurs also in COPD
patients has not yet been investigated. Alternatively, TNF a can induce the
expression of a variety of genes, such as the inducible form of the nitric oxide
synthase (iNOS), the TNF a gene itself or those of many other proinflamma-
tory cytokines, that would create a closed loop and contribute to the persis-
tence and amplification of the inflammatory cascade (61). Finally, TNF a
can induce apoptosis in several cell systems (66). We have recently detected
the presence of apoptosis markers as positivity for nuclear transferase-
mediated dUTP nick end labeling (TUNEL) staining and the presence of
poly-(ADP-ribose) -polymerase (PARP) proteolytic fragments in skeletal
muscle of patients with COPD and low body weight indicating that apoptosis
may play a role in the process of unintentional weight loss in this disease (67).
Increased levels of circulating TNF a and increased apoptosis of skeletal mus-
cle cells have also been described recently in patients with chronic heart failure
(68,69), suggesting that this mechanismmay be operating in other chronic dis-
eases and may not be unique to COPD (30). Given that cytochrome c release
from the mitochondria is an early event in apoptosis (70,71) and that the
activity of cytochrome oxidase is increased in these patients (47), it is possible
that mitochondrial abnormalities can play a mechanistic role in this context.
This will have to be examined carefully in the future, because a better under-
standing of the molecular pathways controlling this phenomenon may lead to
the development of new therapeutic alternatives for these patients (72).
E. Oxidative Stress
As discussed above, patients with COPD present oxidative stress in their
systemic circulation, particularly during exacerbations of the disease (7) that
could also be relevant for the pathogenesis of an SMD (38). Oxidative stress
causes muscle fatigue (73) and facilitates proteolysis (63,74). This would be
particularly relevant since the regulation of glutathione (GSH), the most
important intracellular antioxidant (38), is abnormal in skeletal muscle of
patients with COPD (75). Finally, oxidative stress is an important contribu-
tor to the normal process of aging characterized by, among other things, loss
of muscle mass (76,77). Whether or not a premature and = or accelerated