Bench-to-bedside review: nitric oxide in critical illness--update 2008.

Nitric oxide (NO) is a unique and nearly ubiquitous molecule that is widely utilized as a signaling molecule in cells throughout the body. NO is highly diffusible, labile, and multiply reactive, suiting it well for its role as an important regulator of a number of diverse biologic processes, including vascular tone and permeability, platelet adhesion, neurotransmission, and mitochondrial respiration. NO can protect cells against antioxidant injury, can inhibit leukocyte adhesion, and can participate in antimicrobial defense, but can also have deleterious effects, including inhibition of enzyme function, promotion of DNA damage, and activation of inflammatory processes. This molecule's chemistry dictates its biologic activity, which can be both direct and indirect. In addition, NO has bimodal effects in a number of cells, maintaining homeostasis at low doses, and participating in pathophysiology in others. Perturbation of NO regulation is involved in the most important and prevalent disease processes in critical care units, including sepsis, acute lung injury, and multiple organ failure. Given that NO is ubiquitous, highly diffusible, and promiscuously reactive, its regulation is complex. The NO concentration, kinetics, and localization, both inside and outside the cell, are clearly crucial factors. In the present update we review a selection of studies that have yielded important information on these complex but important issues. Interpretation of these and other studies aimed at elucidating physiologic and pathophysiologic roles of NO must take this complexity into account. A full review of the role of NO in these diseases is beyond the scope of the current manuscript; the present article will focus on recent advances in understanding the complex role of NO in health and disease.