Exhaled breath condensate cytokines and pH in pediatric asthma and atopic dermatitis

Department of Biomedicina dell'Eta' Evolutiva, Pediatric Unit S.Maggiore, University of Bari, Bari, Italy.
Allergy and Asthma Proceedings (Impact Factor: 3.06). 08/2008; 29(5):461-7. DOI: 10.2500/aap.2008.29.3152
Source: PubMed


Some studies have proposed exhaled breath condensate (EBC) as a noninvasive tool for monitoring airway inflammation in children. Moreover, atopic dermatitis (AD) has been considered a risk factor for the development of asthma. This study was designed to assess the EBC pH and the exhaled concentration of cytokines produced by T-helper (Th) 1, Th2, and T regulatory cells in asthmatic children and AD and to verify if their concentrations are affected by a short course of treatment with inhaled corticosteroids (ICS). We assessed the mean levels of pH, interferon (IFN) gamma, interleukin (IL)-4, and IL-10 in EBC of children with asthma (n=20) and AD (n=12) and healthy controls (n=20) by enzyme-linked immunosorbent assay (ELISA). Variations of pH and cytokine concentration in response to ICS (flunisolide, 500 microg/day, for 2 weeks), were also investigated in asthmatic patients. We found that the mean condensate pH value in patients with asthma and AD was significantly lower when compared with that of controls (6.9+/-0.2 and 7.0+/-0.2 versus 7.4+/-0.4; p<0.0001) and it significantly increased in asthmatic patients after treatment (7.2+/-0.2 versus 6.9+/-0.2; p=0.003). In addition, the IL-4/IFN-gamma ratio was significantly higher in children with asthma and in those with AD when compared with controls (9.72+/-2.00 and 9.70+/-2.0 versus 8.04+/-2.6; p<0.001) and that it decreased in asthmatic patients after ICS (6.4+/-5.4 versus 9.72+/-2.00; p<0.01). We observed that exhaled IL-10 levels were significantly higher in children with asthma compared with those of controls (18.8+/-8.9 versus 4.2+/-1.0; p<0.002). IL-10 did not significantly increase after treatment with steroids. No such finding was documented in children with AD. Our data suggest that EBC IL-10 levels are different in asthmatic patients compared with healthy children, but they are insensitive markers in monitoring therapy with ICS. Moreover, children with AD show an EBC pH and an exhaled pattern of Th2/Th1 cytokines similar to that of asthmatic patients.

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    • "Numerous recent studies have suggested alterations in airway pH contribute to the pathophysiology of obstructive airway disease (reviewed in Ricciardolo et al., 2004). Airway acidification caused by either exogenous acids (polluted air constituting an 'acid fog') (Honma et al., 2000), endogenous acids (gastroesophageal reflux with microaspiration) (Ricciardolo, 2001; Hunt and Gaston, 2008), or as a consequence of airway inflammation (Kostikas et al., 2002; Brunetti et al., 2008) can reduce the pH of the airway and increase airway smooth muscle (ASM) contractility and airway resistance. Two major mechanisms mediating acid-induced bronchoconstriction have been identified. "
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    ABSTRACT: Previous studies have linked a reduction in pH in airway, caused by either environmental factors, microaspiration of gastric acid or inflammation, with airway smooth muscle (ASM) contraction and increased airway resistance. Neural mechanisms have been shown to mediate airway contraction in response to reductions in airway pH to < 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown. Intracellular signalling events stimulated by reduced pHo in human cultured ASM cells were examined by immunoblotting, phosphoinositide hydrolysis and calcium mobilization assays. ASM cell contractile state was examined using magnetic twisting cytometry. The expression of putative proton-sensing GPCRs in ASM was assessed by real-time PCR. The role of ovarian cancer G protein-coupled receptor 1 (OGR1 or GPR68) in acid-induced ASM signalling and contraction was assessed in cultures subjected to siRNA-mediated OGR1 knockdown. ASM cells responded to incremental reductions in pHo (from pH 8.0 to pH 6.8) by activating multiple signalling pathways, involving p42/p44, PKB, PKA and calcium mobilization. Coincidently, ASM cells contracted in response to decreased pHo with similar 'dose'-dependence. Real-time PCR suggested OGR1 was the only proton-sensing GPCR expressed in ASM cells. Both acid-induced signalling (with the exception of PKB activation) and contraction were significantly attenuated by knockdown of OGR1. These studies reveal OGR1 to be a physiologically relevant GPCR in ASM cells, capable of pleiotropic signalling and mediating contraction in response to small reductions in extracellular pH. Accordingly, ASM OGR1 may contribute to asthma pathology and represent a therapeutic target in obstructive lung diseases.
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