Fig. 6.— Integrated view of the origin and functional consequences of resistive breathing-induced cytokines. Resistive breathing results in the generation of oxidative stress and the induction of cytokines within the diaphragm, secondary to the increased muscle activation. Oxidative stress is a major stimulus for this cytokine induction. Tumour necrosis factor (TNF)-α compromises diaphragmatic contractility and contributes to the development of muscle cachexia. Interleukin (IL)-6 attenuates the TNF-α expression, secondary to strenuous diaphragmatic contraction. IL-6 mobilises glucose from the liver and free fatty acid (FFA) from the adipose tissue, which increases the energy available to the strenuously working respiratory muscles. At the same time, cytokines stimulate the hypothalamic-pituitary-adrenal axis either haematogenously or via stimulation of small afferent nerve fibres, leading to production of adrenocorticotropin (ACTH) and β-endorphins. The ACTH response may represent an attempt of the organism to reduce the injury occurring in the respiratory muscles through the production of glucocorticoids by the adrenals and the induction of the acute phase-response proteins. The β-endorphin response would decrease the activation of the respiratory muscles and change the pattern of breathing, which becomes more rapid and shallow, possibly in an attempt to reduce and/or prevent further injury to the respiratory muscles. POMC: pro-opiomelaninocortin; ROS: reactive oxygen species; TG: triglycerides.