Advances in the pathophysiology of constitutive and inducible cyclooxygenases: two enzymes in the spotlight

The aim of this commentary is to discuss recent data on the role of prostaglandins generated by both constitutive and inducible cyclooxygenases (COXs). According to a popular hypothesis, COX-1 generates 'good' prostaglandins for physiological 'housekeeping' functions like gastrointestinal (GI) mucosal integrity and regulation of renal blood flow, while COX-2 forms the 'bad' prostaglandins responsible for inflammatory symptoms. However, recent data show that the biological functions of prostanoids formed by the two enzymes are much more complex and interrelated than previously appreciated. Experimental evidence indicates that a full inflammatory response is likely sustained by prostanoids generated by both enzymes, and an effective anti-inflammatory effect requires the inhibition of the two enzymes. Similarly, the selective inhibition of either COX-1 or COX-2 does not elicit GI damage, but inhibition of both enzymes is necessary for GI mucosal damage to develop. Prostaglandins generated by both enzymes contribute to normal renal function by regulating the vascular tone and the normal blood flow. The synthesis of endothelial prostacyclin is mainly driven by COX-2, so that the selective COX-2 inhibition may bias vascular prostaglandin synthesis in favour of COX-1-derived thromboxane A(2) in platelets, leading to a prothrombotic outcome. Moreover, prostaglandins formed by COX-2 appear to have a major role in myocardial protection. We propose that the complexity of the situation in the field of COX-derived mediators should be borne in mind when anti-inflammatory therapy is required.