Exhaled Nitric Oxide (NO), NO Synthase Activity, and Regulation of Nuclear Factor (NF)-κ B

Nitric oxide (NO) and related molecules are produced in the lung by virtually all cellular constituents, including the epithelium, the endothelium, neurons, neuroendocrine cells, resident inflammatory cells, and alveolar macrophages (1). An increase in respiratory NO production, as measured by exhaled NO levels, has been touted as a marker of lung inflammation: exhaled NO is increased in patients with asthmatic flares, bronchiectasis, and active tuberculosis (2‐4). In contrast, it is lowered in primary pulmonary hypertension (PPH) (5). The precise role of NO in lung inflammation is still under debate. It may contribute to injury in some instances. Increasing evidence, however, points to salutary functions in general, and in particular to significant immunomodulatory roles. One of the mechanisms by which NO might modulate lung inflammation is through its interaction with the transcription factor NFk B, which is activated by diverse inflammatory stimuli and has been causally linked to respiratory cell inflammation and pulmonary disease (6‐8). In this issue, Raychaudhuri and colleagues (9), show an inverse correlation between exhaled levels of NO and NF- k B activity in alveolar macrophages obtained from patients with asthma or PPH. What conclusions can we draw from these new insights? NF- k B regulates many of the genes involved in the immune response, including tumor necrosis factor- a (TNF- a ), interleukin (IL)-8, intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and the cytokine-inducible NO-synthase (NOS 2) (10). The prototypic form of NF- k B is the p50-p65 heterodimer. (Although other dimeric forms exist [e.g., p50-p50, p65-cRel], their function in transcriptional regulation is less clear.) In its inactive state, NF- k B (p50-p65) is bound by an inhibitory protein, I- k B a and is sequestered in the cytoplasm. Upon stimulation by inflammatory mediators (e.g., TNF- a , lipopolysaccharide [LPS]), NF- k B is released from I- k B a and translocates to the nucleus where it can activate target gene transcription. NF- k B function is regulated by NO or related molecules. NO primarily inhibits NF- k B activation, but the effects are