Bronchial asthma is associated with increased levels of exhaled nitric oxide which are suppressible by glucocorticosteroid inhalation. Children with bronchial asthma were studied to elucidate the relation between endogenous NO release and recent symptoms of bronchial obstruction.Twenty-five children with atopic asthma and 11 healthy control subjects were enrolled and exhaled NO was studied using chemiluminescence analysis. The subjects breathed purified air (<0.5 parts per billion (ppb) NO) exclusively through their mouths. Orally expired NO was measured during continuous nasal aspiration (1.3 L . min -1 ) to remove nasally produced NO. Nasal NO concentration was determined within the aspirated gas.Orally expired NO concentration was 2.50.3 ppb (meanSEM) in healthy control subjects, 3.190.88 ppb (NS) in symptom-free children, and 8.280.81 ppb (p#0.01) in children with bronchial asthma who had had recent symptoms of bronchial obstruction. Similarly, in the subgroup of children treated regularly with inhaled glucocorticosteroids those with recent symptoms had significantly higher orally exhaled NO concentrations than healthy control subjects (9.51.5 ppb, p<0.05). The nasal NO concentration was 152.812.7 ppb in healthy control subjects and not significantly different in asthmatic children.In this group of asthmatic children, recent symptoms of bronchial obstruction were linked to significantly higher concentrations of NO in orally exhaled gas and to increased oral NO excretion rates. If substantiated by further studies, measurement of orally exhaled NO during nasal aspiration may become useful to monitor disease control in asthmatic children. Eur Respir J 1999; 13: 1396±1401. Nitric oxide can be detected in exhaled gas of various mammals including humans [1] and is increased in patients with bronchial asthma [2±8]. In adults, the increase is mainly due to increased production in the lower airways [9,10] although at present it is not clear whether the increased exhaled NO in asthmatics reflects a beneficial response counterbalancing bronchoconstrictor stimuli or contributes to increased tissue damage and perpetuation of immune responses [11,12]. There is sufficient evidence to conclude that NO synthesis is induced by the underlying chronic inflammatory process in bronchial asthma: in vitro studies have shown the inducibility of NO synthesis by inflammatory cytokines relevant to asthma [13,14]. Inducible NO synthase (iNOS) has been detected immunohistochemically in bronchial epithelial cells of asthmatic patients [13] and in alveolar macrophages from areas of chronic inflammation [15]. The inhalation of a pulmonary irritant has been shown to enhance NO production by alveolar macrophages in rats [16]. Furthermore, antigen-induced bronchoconstriction specifically affects exhaled NO levels and is antagonized by endogenous NO in animal studies [17,18]. Treatment with glucocorticosteroids reduces the expression of iNOS in macrophages in vitro [19] and leads to a decrease of exhaled NO levels in adults and childr...

Cathepsin S is a cysteine protease with potent endoproteolytic activity and a broad pH profile. Cathepsin S activity is essential for complete processing of the MHC class II-associated invariant chain within B cells and dendritic cells, and may also be important in extracellular matrix degradation in atherosclerosis and emphysema. Unique among cysteine proteases, cathepsin S activity is up-regulated by IFN-gamma. Given its importance, we sought to elucidate the pathway by which IFN-gamma increases cathepsin S expression. Our data demonstrate that the cathepsin S promoter contains an IFN-stimulated response element (ISRE) that is critical for IFN-gamma-induced gene transcription in a cell line derived from type II alveolar epithelial (A549) cells. IFN response factor (IRF)-2 derived from A549 nuclear extracts associates with the ISRE oligonucleotide in gel shift assays, but is quickly replaced by IRF-1 following stimulation with IFN-gamma. The time course of IRF-1/ISRE complex formation correlates with increased levels of IRF-1 protein and cathepsin S mRNA. Overexpression of IRF-1, but not IRF-2, markedly augments cathepsin S promoter activity in A549 cells. Furthermore, overexpression of IRF-1 increases endogenous cathepsin S mRNA levels in 293T epithelial cells. Finally, freshly isolated bone marrow cells from IRF-1(-/-) mice fail to up-regulate cathepsin S activity in response to IFN-gamma. Thus, IRF-1 is the critical transcriptional mediator of IFN-gamma-dependent cathepsin S activation. These data elucidate a new pathway by which IRF-1 may affect MHC class II processing and presentation.

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