Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of polarized duodenal enterocytes is mediated by the divalent metal transporter, DMTi. A second transporter has been postulated to export iron across the basolateral surface to the circulation. Here we have used positional cloning to identify the gene responsible for the hypochromic anaemia of the zebrafish mutant weissherbst. The gene, ferroportin1, encodes a multiple-transmembrane domain protein, expressed in the yolk sac, that is a candidate for the elusive iron exporter. Zebrafish ferroportin1 is required for the transport of iron from maternally derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes. Human Ferroportin1 is found at the basal surface of placental syncytiotrophoblasts, suggesting that it also transports iron from mother to embryo. Mammalian Ferroportin1 is expressed at the basolateral surface of duodenal enterocytes and could export cellular iron into the circulation. We propose that Ferroportin1 function may be perturbed in mammalian disorders of iron deficiency or overload.

Nitric oxide (NO) can be detected in exhaled gas in human subjects. It is produced by nitric oxide synthase (NOS) and is rapidly metabolized to nitrite and nitrate (NO2/NO3). Exhaled NO is reported to be elevated in patients with asthma, bronchiectasis, or upper respiratory tract infection. Recent reports have shown no increase of exhaled NO in stable cystic fibrosis (CF). We hypothesized that NOS activity is increased in patients with acute pulmonary exacerbation of CF. We therefore measured exhaled NO and sputum NO2/NO3 in three subject categories: patients with acute pulmonary exacerbation of CF, patients with stable CF, and healthy control subjects. Mean +/- SD exhaled NO was significantly higher in control subjects (8.8 +/- 4.9 ppb) than in both acute (3.8 +/- 3.9 ppb) and stable (5.0 +/- 2.5 ppb) patients. Sputum NO2/NO3 was significantly higher in acute patients (774 +/- 307 micromol/L) when compared with both stable patients (387 +/- 203 micromol/L) and control (421 +/- 261 micromol/L) subjects. Sputum NO2/NO3 did not return to normal in a subgroup of patients assessed after 2 wk of intensive antibiotic and glucocorticoid treatment. These results confirm that exhaled NO is not a useful measure of airway inflammation in CF. Elevated levels of sputum NO2/NO3 suggest that NOS is activated during acute pulmonary exacerbations of CF.

We hypothesized that abnormal ventilation-perfusion matching in chronically infected lungs was in part due to excess nitric oxide (NO) production after upregulation of inducible NO synthase (iNOS) expression. Rats were anesthetized and inoculated intratracheally with Pseudomonas aeruginosa incorporated into agar beads (chronically infected) or with sterile agar beads (placebo inoculated) and killed 10–15 days later. Immunohistochemistry demonstrated increased expression of iNOS and reduced expression of endothelial NOS (eNOS) in chronically infected compared with placebo-inoculated or noninoculated lungs. In isolated lungs from chronically infected rats, NOS inhibition with N ω-nitro-l-arginine methyl ester increased the mean perfusion pressure (14.4 ± 2.7 mmHg) significantly more than in the placebo-inoculated (4.8 ± 1.0 mmHg) or noninoculated (5.3 ± 0.8 mmHg) lungs ( P < 0.01). Although the chronically infected lungs were more sensitive to NOS inhibition, further evidence suggested that the increased iNOS expression was not associated with enhanced iNOS activity. Selective inhibitors of iNOS did not produce an increase in vascular resistance similar to that produced by nonselective inhibitors. Accumulation of nitrate/nitrite in the perfusate of isolated lungs was unchanged by chronic infection. Thus although iNOS expression was increased in chronic pulmonary infection, iNOS activity in the intact lung was not. Nonetheless, endogenous NO production was essential to maintain normal vascular resistance in these lungs.

Increased exhaled nitric oxide (NO) may reflect respiratory tract inflammation in untreated asthmatics. We compared exhaled NO and bronchoalveolar lavage (BAL) nitrate/nitrite (NO3-/NO2-) in 10 patients who had untreated, active pulmonary sarcoidosis with those of normal control subjects. Exhaled NO concentrations, determined by chemiluminescence, were similar in patients and control subjects (peak NO concentration of patients [mean +/- SD]: 13.6 +/- 5.9 parts per billion [ppb], peak NO concentration of control subjects: 11.2 +/- 5.7 ppb, p = 0.32; mean alveolar NO concentration of patients: 7.8 +/- 4.4 ppb, mean alveolar NO concentration of control subjects: 7.1 +/- 4.2 ppb, p = 0.70; end-tidal NO concentration of patients: 6.9 +/- 4.5 ppb, end-tidal NO concentration of control subjects: 6.6 +/- 4.0 ppb, p = 0.60). BAL NO2- was assayed using a modified Griess reaction after reduction of NO3- to NO2-. There was no significant difference in mean BAL NO2- concentrations, expressed as nanomoles per milliliter of epithelial lining fluid (patients: 544 nmol/ml, control subjects: 579 nmol/ml, p = 0.81) or as nanomoles per milliliter of BAL fluid (patients: 6.7 nmol/ml, control subjects: 5.7 nmol/ml, p = 0.41). These data suggest that excess NO generation does not accompany the respiratory tract inflammation of pulmonary sarcoidosis.

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