Figure 2.

Illustration of pathomechanisms involving NOX enzymes and reactive oxygen species (ROS) in chronic wounds. Solid black arrows represent promoting interactions, red solid T arrows direct inhibitory interactions and red dashed T arrows indirect inhibitory interactions. Aging, diabetes, and persistent ischemia are associated with excessive ROS production. NOX1 and NOX2 have been reported to be responsible for excessive ROS production during ischemia–reperfusion injury. Through the production of advanced glycation end products (AGE), hyperglycemia triggers an overproduction of ROS. Excessive oxidative stress leads to cell senescence, apoptosis, and chronic inflammation, hampering key processes of wound repair. In addition, persistent ischemia is likely to lead to impaired NOX4 activity, directly interfering with TGFb1 signaling and leading to decreased myofibroblast contractility. Reduced NOX4 activity also seems to reduce HIF1a signaling, making effective angiogenesis impossible and further aggravating the ischemic condition. Diabetes has been shown to lead to a reduced availability of NO, facilitating the destruction of HIF1 and hindering angiogenesis.