Strenuous diaphragmatic contractions that are induced by inspiratory resistive breathing initiate an inflammatory response that involves the elevation of both pro-inflammatory and anti-inflammatory cytokines within the diaphragm, which may then spill into the circulation. The production of reactive oxygen species (ROS) within working respiratory muscles increases in response to these strenuous diaphragmatic contractions. At the same time, there is significant decline in diaphragmatic nitric oxide (NO) production, despite a time-dependent increase in nitric oxide synthase (NOS) isoform protein expression. Increased adhesion molecule expression and infiltration of granulocytes and macrophages follows, which may contribute to the contraction-induced diaphragm injury. Enhanced generation of ROS, oxidative stress augmentation, reduced nitric oxide production, and glycogen depletion are potential stimuli for the cytokine induction that is secondary to strenuous diaphragmatic contractions. This production of cytokines within the diaphragm may contribute to the diaphragmatic muscle fiber injury that occurs with strenuous contractions, or to the expected repair process. Tumor necrosis factor-alpha (TNF-), is a cytokine that compromises diaphragmatic contractility and may contribute to muscle wasting. Interleukin-6 (IL-6) is a cytokine that may have beneficial systemic effects by mobilizing glucose from the liver and free fatty acids from the adipose tissue and providing it to the strenuously working respiratory muscles. Thus, cytokine upregulation within the working diaphragm may be both adaptive and maladaptive.