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Dept of Critical Care and Pulmonary Services, University of Athens Medical School, Evangelismos Hospital, Athens, Greece
We would like to thank N.M. Siafakas and I. Mitrouska for their insightful comments about our recent article published in the European Respiratory Journal 1. They suggest that resistive breathing may be a potent stimulus for upregulation of angiogenesis-promoting factors within the diaphragm.
Preliminary data (which have appeared only in abstract form) suggest that resistive breathing might lead to an upregulation of vascular endothelial growth factor (VEGF), but not basic fibroblast growth factor (bFGF) and transforming growth factor-b1 2. Other forms of increased diaphragmatic activation, such as hyperventilation induced by hypercapnia and/or hypoxia, lead to increased expression of the mRNA levels of both VEGF and bFGF 3. This angiogenetic response was not solely caused by the deranged blood gases or by the hyperventilation-induced passive stretching and shortening of the diaphragm, since mechanical ventilation leading to similar blood gases levels did not result in a diaphragmatic angiogenetic response.
The stimuli for the expression of angiogenesis-promoting factors within skeletal muscles (in general) and respiratory muscles (in particular) remain elusive. Interestingly, in an in vitro cell culture system of skeletal myocytes fused into myotubes, reactive oxygen species stimulated the expression of VEGF 4 in a similar fashion to their effect of inducing interleukin-6 production 5. This raises the interesting possibility that oxidative stress generated intramuscularly, secondary to increased muscular activation/contraction 6, might be the stimulus for both upregulation of cytokines and expression of an angiogenesis programme. Despite being sound, such a hypothesis has never been experimentally tested.
Angiogenesis is a prerequisite for the development of hypertrophy and hyperplasia, secondary to chronic exercise training in skeletal muscles. This might be important for the increased ventilation requirements of some elite athletes during athletic performance, although the benefit from additional specific respiratory muscle training is uncertain 7. However, angiogenesis is even more important for the beneficial effects of rehabilitation programmes involving training of the respiratory muscles 8.
Our review focused on the response of the "classical" cytokines (those usually produced by blood mononuclear cells) to resistive breathing. This is why it did not cover other important aspects, such as the response of chemokines or adhesion molecules, as well as angiogenesis-related factors to resistive breathing. More research is needed to study not only the factors driving the expression of an angiogenetic programme within the respiratory muscles, but also the actual process of angiogenesis, as well as its clinical relevance.
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