Clinical biology of nitric oxide

Sir In the review by Mr Davies and colleagues' (Br J Surg 1995; 82: 1598-610) it was concluded that 'nitric oxide (NO) appears to play a significant role in the physiology and homoeostasis of many of the body's systems. Its role in pathophysiology of disease remains to be fully elucidated. It is unclear whether alterations in NO production or release and degradation are primary events in a pathological process or sequel of an as yet undefined primary insult'. The multiple properties of nitric oxide are a major challenge when an attempt is made to integrate its diverse functions into the mechanisms that produce the greater part of the physiological and pathological conditions in the human organism. Regarding the acute inflammatory response to injury by mechanical energy, we have recently proposed that, whether local or systemic, this is based on the successive functional predominance of the nervous, immune and endocrine systems. This hypothesis implies that the final and prevalent functions of these systems may represent the consecutive phases of the response to stress developed by a single system: the psychoneuro-immune-endocrine systemzs3. If we consider that these functions are expressed by the endothelium and, by extension, the vascular wall, the posttraumatic local inflammatory response would include a nervous or immediate phase, with vasoconstriction and vasodilatation with ischaemia-reperfusion injury. There would then be an immune or intermediate phase, with exudation secondary to an increase in endothelial permeability, which is the cause of swelling and diapedesis or cell migration, especially of neutrophils, which is associated with phagocytosis and necrosis. This would be followed by an endocrine or late phase, characterized by proliferation with endothelial and vascular wall modelling in which, if the evolution has been favourable, anabolism and tissue regeneration or wound repair*. In addition, in the systemic response to injury by mechanical energy, as in the polytraumatized patient, the nervous or immediate phase would be represented by shock and ischaemia-reperfusion; the immune or intermediate phase would be characterized by the systemic inflammatory response syndrome; and the endocrine or late phase would be represented by anabolism in the convalescence period2. The hypothetical similarity of the local and systemic responses could be attributed to the existence in the organism of a general response mechanism to injury, which is based on the successive and predominant expression of the nervous, immune and endocrine functions. In this scheme, the functions that characterize each phase of response make it possible to integrate current biochemical knowledge about conditions considered as diverse, such as traumatic injury', heart failure4, pulmonary and arterial hypertension5, and rejection in organ transplantation6. In this proposal, nitric oxide would be closely regulated at every step of the acute inflammatory response according to the predominant function in the different phases which make up this response. SO, in a first immediate or nervous phase, nitric oxide is a mediator of analgesia', contraction or relaxation of the vascular smooth muscle, myocardial contractility, bronchodilatation, relaxation of gastrointestinal smooth muscle and neurotransmission'. In the intermediate or immune response to injury, this molecule would be involved in capillary permeability, platelet adhesion and aggregation, leucocyte adhesion and cytotoxicity of macrophages'. And finally, in the late or endocrine phase, nitric oxide would be involved in endothelial regeneration and smooth muscle cell proliferation',x. If nitric oxide successively expresses functions considered as nervous, immune and endocrine, in a similar way to the endothelium and, by extension, the vascular wall during the inflammatory response, it may be necessary to enlarge our current concept of the nervous, immune and endocrine systems. This notion is not limited to these systems; the whole organism is involved. These systems, however, make up a systemic response integrated by the characteristics of the nervous, immune and endocrine system^'*^,^. This functional concept implies that the cells and biochemical components of the organism, for example nitric oxide, have the property of modifying functional expression in the successive phases of response to injury. For this reason the characteristics of each phase of this response might make it possible to integrate current biochemical knowledge into the evolution of many diseases and thereby into the clinical evolution of a patients.h. Finally, it is tempting to suggest that the succession in expression of the nervous, immune and endocrine systems might represent an ancestral response. The efficiency of this response may have made it possible for the organism to exist on the level of cells, tissues, organs and individuals, in both normal physiological situations and pathological one^^^^^^.