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. 2006 Jun;2(2):399-408.
doi: 10.1007/s11302-006-9001-7. Epub 2006 May 30.

E-NTPDases in human airways: Regulation and relevance for chronic lung diseases

Lauranell H Burch  1 , Maryse Picher
Affiliations

E-NTPDases in human airways: Regulation and relevance for chronic lung diseases

Lauranell H Burch et al. Purinergic Signal. 2006 Jun.

Abstract

Chronic obstructive lung diseases are characterized by the inability to prevent bacterial infection and a gradual loss of lung function caused by recurrent inflammatory responses. In the past decade, numerous studies have demonstrated the importance of nucleotide-mediated bacterial clearance. Their interaction with P2 receptors on airway epithelia provides a rapid 'on-and-off' signal stimulating mucus secretion, cilia beating activity and surface hydration. On the other hand, abnormally high ATP levels resulting from damaged epithelia and bacterial lysis may cause lung edema and exacerbate inflammatory responses. Airway ATP concentrations are regulated by ecto nucleoside triphosphate diphosphohydrolases (E-NTPDases) which are expressed on the mucosal surface and catalyze the sequential dephosphorylation of nucleoside triphosphates to nucleoside monophosphates (ATP --> ADP --> AMP). The common bacterial product, Pseudomonas aeruginosa lipopolysaccharide (LPS), induces an acute reduction in azide-sensitive E-NTPDase activities, followed by a sustained increase in activity as well as NTPDase 1 and NTPDase 3 expression. Accordingly, chronic lung diseases, including cystic fibrosis (CF) and primary ciliary dyskinesia, are characterized by higher rates of nucleotide elimination, azide-sensitive E-NTPDase activities and expression VSports手机版. This review integrates the biphasic regulation of airway E-NTPDases with the function of purine signaling in lung diseases. During acute insults, a transient reduction in E-NTPDase activities may be beneficial to stimulate ATP-mediated bacterial clearance. In chronic lung diseases, elevating E-NTPDase activities may represent an attempt to prevent P2 receptor desensitization and nucleotide-mediated lung damage. .

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Figures (V体育安卓版)

Fig. 1
Fig. 1
Impact of chronic obstructive lung diseases on mucociliary clearance. The polarized epithelium is composed of columnar (ciliated or mucin-secreting) cells facing the lumen and basal cells facing the serosal compartment. Bacterial clearance in healthy lungs is maintained by coordinated cilia beating activity within the PCL layer, moving upward the overlying mucus and pathogens. In chronic obstructive lung diseases, cilia are collapsed under a thick layer of mucus containing bacteria and leukocytes.
Fig. 2
Fig. 2
Ectonucleotidases regulate nucleotide concentrations on airway epithelial surfaces. a Polarized primary cultures of human bronchial epithelial cells were assayed with 100 µM ATP added to the mucosal surface, as we previously described [10]. Buffer sample analysis by high-pressure liquid chromatography (10) shows that exogenous ATP (•) is dephosphorylated into ADP (▪), AMP (≆) and adenosine (○). b Similar experiments repeated on primary cultures of human nasal, bronchial and bronchiolar epithelial cells show that the elimination rate of ATP increases toward alveoli (N = 3, *, P < 0.05; Mann-Whitney test).
Fig. 3
Fig. 3
Expression level of NTPDase 1 and NTPDase 3 along human airways. Total RNA from excised epithelia was analyzed by real-time PCR using SYBR green assays and normalized to the expression level of the house-keeping gene, 18S, as we previously described [89]. The mRNA level of E-NTPDase 1 (□) and NTPDase 3 (▪) increases toward alveoli (N = 4, *, P < 0.05; Mann-Whitney test).
Fig. 4
Fig. 4
Chronic lung diseases enhance azide-sensitive E-NTPDases. Primary bronchial epithelial cultures from healthy donors (N) and patients diagnosed with primary ciliary dyskinesia (PCD), CF or α1-antitrypsin deficiency (α AT) were assayed with bilateral 1 mM ATP in the absence (▪) or presence (□) of 20 mM azide, as we previously described [10]. Analysis of buffer samples by high-pressure liquid chromatography showed that azide-sensitive E-NTPDases are concentrated on the mucosal surface under normal and pathological conditions (N = 4, *, P < 0.05; Mann-Whitney test).
Fig. 5
Fig. 5
Impact of P. aeruginisa LPS on NTPDase 1 and NTPDase 3. A The mucosal surface of primary bronchial epithelial cultures were exposed 0, 1, 8 or 24 h to 100 ng/ml LPS, then assayed for surface activity by high-pressure liquid chromatography, as we previously described [10]. The activities of azidesensitive mucosal E-NTPDases measured with 0.03 mM ATP were transiently reduced by LPS. B Quantification of their mRNA expression by real-time PCR using the house-keeping gene 18S, as we previously described (89). LPS induced a delayed increase in the expression level of both E-NTPDases (N = 5, *, P < 0.05; Mann-Whitney test).
Fig. 6
Fig. 6
Purine signaling and nucleotide salvage pathways on human airway epithelia. In normal lungs, basal adenosine levels maintain adequate PCL height for mucus transport through A2B receptor-mediated CFTR activity. Mechanical stimulation of the epithelial surface by an irritant, a pathogen, mechanical ventilation or cyclic compressive stress induces ATP release and elevates ASL concentrations above activation threshold level for P2Y2 receptor activation. This autocrine signal transiently enhances basal MCC through cilia beating, mucin secretion and ion/water efflux into the lumen. The signal is rapidly terminated by NTPDase 1 and/or NTPDase 3 dephosphorylating excess ATP to AMP. Ecto 5′-nucleotidase (ecto 5′-NT; CD73) produces ASL adenosine from the resulting AMP, and excess adenosine is transported back to the cytosol. Chronic lung diseases burdened by considerable tissue damage recruits additional receptors (P2X4, 5, 7) responding to higher ATP cocnentrations.
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