Increased progenitor cell proliferation in the peripheral blood of patients with bronchial asthma: The role of nitric oxide

Background: Asthma exacerbation is associated with increased numbers of circulating CD34⁺ progenitor cells, which may migrate to airways and develop into mature cells under the effects of cytokines and hematopoietic factors. Nitric oxide (NO) generation is enhanced in asthma and is known to suppress human hematopoiesis. Objectives: We studied circulating progenitor cells in the blood of patients with varying severity of asthma and examined the contribution of NO to their proliferation into eosinophil-forming colonies ex vivo. Methods: With use of multiparameter flow cytometric analyses, the cell numbers and intracellular inducible NO synthase (iNOS) immunoreactivity of circulating CD34⁺ cells in peripheral blood was measured. The serum level of GM-CSF or IL-5 was also determined. The colonies grown from progenitor cells were cultured in methylcellulose either in the presence or absence of growth factors, including GM-CSF, stem cell factor, and IL-3. Results: A significantly greater number of circulating CD34⁺ cells increased together with higher intracellular iNOS immunoreactivity in moderate asthmatics compared with mild intermittent asthmatics and healthy subjects. There was no significant difference in iNOS immunoreactivities or CD34⁺ progenitor cell numbers between healthy subjects and those with mild intermittent asthma. Serum levels of GM-CSF or IL-5 were significantly higher in all asthmatics compared with healthy subjects and correlated with circulating CD34⁺ cells. A greater number of colonies was grown either in the presence or absence of growth factors with a higher percentage of cells of eosinophil lineage in asthmatics than in health subjects. N^G-nitro-L-arginine methyl ester potentiated and sodium nitroprusside inhibited the colony growth in both asthmatic and healthy subjects without a significant change in the percentage of eosinophil lineage. Conclusions: The production of NO from progenitor cells or other circulating cells may act in an autocrine or paracrine fashion to regulate progenitor cell growth and colony forma-tion. However, this is not sufficient to control the increased proliferation of progenitor cells observed in asthma.