Nitric oxide blocks nuclear factor-kappa B activation in alveolar macrophages

Nitric oxide (NO) is an important endogenous regulatory molecule implicated in both proinflammatory and antiinflammatory processes in the lung. Previo usly, we demonstrated that in human alveolar phages (AM), NO decreased infl ammatory cytokine production, including that of interleukin-1 beta, tumor n ecrosis factor-alpha and macrophage inflammatory protein-lot. One mechanism by which NO could regulate such diverse cytokine production is through eff ects on the transcription factor nuclear factor-kappa B (NF-kappa B), which controls the expression of the genes for these inflammatory cytokines and growth factors. We therefore investigated whether NO affects NF-kappa B act ivation in AM in vitro and in vivo. In vitro studies with AM showed that NF -kappa B activation by lipopolysaccharide (LIPS) is decreased by NO in a do se-dependent manner. NO prevented an LPS-mediated decrease in the NF-kappa B inhibitory protein I kappa B-alpha. In asthma, airway NO levels are incre ased, whereas in primary pulmonary hypertension (PPH), airway NO levels are lower than in healthy lungs. In vivo investigations were conducted with fr eshly isolated AM from healthy controls, asthmatic individuals, and PPH pat ients. Healthy individuals had airway NO levels of 8 +/- 2 ppb (mean +/- SE M), which is associated with low NF-KB activation. Asthma patients with air way NO levels > 17 ppb showed minimal NF-kappa B activation, whereas asthma tic individuals with NO levels less than or similar to 17 ppb showed greate r NF-kappa B activation. PPH patients with low NO (1 +/- 1 ppb) had promine nt NF-kappa B activation. These in vivo studies in asthma and PPH support t he in vitro observation of an inverse relationship between NO and NF-kappa B activation. One mechanism by which NO blocks cytokine production involves I kappa B.