Increased susceptibility of purinergic receptor-deficient mice to lung infection with<i>Pseudomonas</i><i>aeruginosa</i>

Geary, Cara; Akinbi, Henry T.; Korfhagen, Thomas R.; Fabre, J; Boucher, Richard C.; Rice, Ward R.

doi:10.1152/ajplung.00428.2004

Cited by 42 publications

(32 citation statements)

References 41 publications

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“…Our data show that purinergic agonist ATP␥S applied intravenously produces a beneficial effect in an LPS-induced model of ALI, reducing accumulation of inflammatory cells and total protein in lungs. As a recent study showed, P2Y 1 /P2Y 2 Ϫ/Ϫ mice infected with P. aeruginosa accumulated more water and total protein in lungs than did wild-type mice, suggesting impaired epithelial/ endothelial barrier in purinergic receptor-deficient mice (11). Our in vitro data shows that ATP␥S promotes the restoration of endothelial barrier after LPS-induced injury.…”

Section: Discussionsupporting

confidence: 67%

“…Extracellular ATP is critical for survival of pulmonary endothelial and epithelial cells in high oxygen and ozone concentrations (3). A recent study on transgenic mice showed that P2Y 1 and P2Y 2 receptors exert a protective role against infection of the lungs by Pseudomonas aeruginosa by decreasing protein leak (11). ATP, either released from cells or exogenously applied, protects against reperfusion-induced failure of the coronary endothelial barrier (13).…”

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confidence: 99%

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Protective effect of purinergic agonist ATPγS against acute lung injury

Kolosova

Mirzapoiazova

Moreno‐Vinasco

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of acute respiratory failure associated with high morbidity and mortality. Although ALI/ARDS pathogenesis is only partly understood, pulmonary endothelium plays a major role by regulating lung fluid balance and pulmonary edema formation. Consequently, endothelium-targeted therapies may have beneficial effects in ALI/ARDS. Recently, attention has been given to the therapeutic potential of purinergic agonists and antagonists for the treatment of cardiovascular and pulmonary diseases. Extracellular purines (adenosine, ADP, and ATP) and pyrimidines (UDP and UTP) are important signaling molecules that mediate diverse biological effects via cell-surface P2Y receptors. We previously described ATP-induced endothelial cell (EC) barrier enhancement via a complex cell signaling and hypothesized endothelial purinoreceptors activation to exert anti-inflammatory barrier-protective effects. To test this hypothesis, we used a murine model of ALI induced by intratracheal administration of endotoxin/lipopolysaccharide (LPS) and cultured pulmonary EC. The nonhydrolyzed ATP analog ATP␥S (50 -100 M final blood concentration) attenuated inflammatory response with decreased accumulation of cells (48%, P Ͻ 0.01) and proteins (57%, P Ͻ 0.01) in bronchoalveolar lavage and reduced neutrophil infiltration and extravasation of Evans blue albumin dye into lung tissue. In cell culture model, ATP␥S inhibited junctional permeability induced by LPS. These findings suggest that purinergic receptor stimulation exerts a protective role against ALI by preserving integrity of endothelial cell-cell junctions.endotoxin/lipopolysaccharide; mice; inflammation; endothelial barrier THE ENDOTHELIAL LINING of blood vessels forms a selective barrier between plasma and interstitial spaces. In the course of acute lung injury (ALI), the endothelial barrier of the pulmonary microvasculature becomes compromised, leading to pulmonary edema, a characteristic feature of ALI. It is widely accepted that endothelial cell (EC) barrier dysfunction is initiated by agonist-induced cytoskeletal remodeling, which leads to disruption of cell-cell contacts and formation of paracellular gaps, allowing penetration of protein-rich fluid and inflammatory cells. Little is known about processes that determine barrier enhancement or protection. Recently, it has been shown that extracellular ATP stabilizes barrier function of endothelial monolayers (15,18,21) and attenuates barrier disruption caused by thrombin (12) and reperfusion (13). Extracellular purines (adenosine, ADP, and ATP) are important signaling molecules that mediate diverse biological effects via cellsurface receptors. Purinergic receptors are divided into two classes: P1 or adenosine receptors, and P2, which recognize primarily extracellular ATP, ADP, UTP, and UDP (26). The P2 receptors are further subdivided into two subclasses. P2X receptors are ATP-gated calcium-permeable nonselective cation channels. The P2Y receptors are coupled...

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Section: Discussionsupporting

confidence: 67%

mentioning

confidence: 99%

Protective effect of purinergic agonist ATPγS against acute lung injury

Kolosova

Mirzapoiazova

Moreno‐Vinasco

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Interestingly, while most of the purinergic receptors in KO mice display no aberrant phenotype under homeostatic conditions (48), the phenotypic consequences of their deficiencies become evident when KO mice are subjected to ischemia (49), infection (50), or bleeding (51,52), suggesting the pivotal roles of purinergic receptor in a variety of pathophysiological conditions. UDP-glucose (UDP-Glc) has been proposed as a ligand for the P2Y 14 receptor (53).…”

Section: Discussionmentioning

confidence: 99%

Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence

Cho¹,

Yusuf²,

Kook³

et al. 2014

J. Clin. Invest.

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Purinergic receptors of the P2Y family are G protein-coupled surface receptors that respond to extracellular nucleotides and can mediate responses to local cell damage. P2Y-dependent signaling contributes to thrombotic and/or inflammatory consequences of tissue injury by altering platelet and endothelial activation and immune cell phagocytosis. Here, we have demonstrated that P2Y 14 modifies cell senescence and cell death in response to tissue stress, thereby enabling preservation of hematopoietic stem/progenitor cell function. In mice, P2Y 14 deficiency had no demonstrable effect under homeostatic conditions; however, radiation stress, aging, sequential exposure to chemotherapy, and serial bone marrow transplantation increased senescence in animals lacking P2Y 14 . Enhanced senescence coincided with increased ROS, elevated p16 INK4a expression, and hypophosphorylated Rb and was inhibited by treatment with a ROS scavenger or inhibition of p38/MAPK and JNK. Treatment of WT cells with pertussis toxin recapitulated the P2Y 14 phenotype, suggesting that P2Y 14 mediates antisenescence effects through Gi/o protein-dependent pathways. Primitive hematopoietic cells lacking P2Y 14 were compromised in their ability to restore hematopoiesis in irradiated mice. Together, these data indicate that P2Y 14 on stem/progenitor cells of the hematopoietic system inhibits cell senescence by monitoring and responding to the extracellular manifestations of tissue stress and suggest that P2Y 14 -mediated responses prevent the premature decline of regenerative capacity after injury.

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“…For example, ATP receptor (P2Y 1 -R and P2Y 2 -R)-deficient mice exhibit impaired inflammatory responses and difficulty eradicating Pseudomonas from the lung [21]. Similarly, mouse strains with modest increases in lung adenosine have enhanced interleukin (IL)-4-mediated inflammatory responses [22], and higher lung AFFILIATIONS *Pediatric Pulmonology, adenosine levels lead to airway inflammation and pulmonary fibrosis [23,24].…”

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confidence: 99%

Extracellular purines are biomarkers of neutrophilic airway inflammation

Esther¹,

Alexis²,

Clas³

et al. 2008

Eur Respir J

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Purinergic signalling regulates airway defence mechanisms, suggesting that extracellular purines could serve as airway inflammation biomarkers in cystic fibrosis (CF).The purines adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and adenosine were measured in sputum from 21 adults (spontaneously expectorated from seven CF patients, induced from 14 healthy controls) to assess normal values and CF-associated changes. Subsequently, purine levels were measured in bronchoalveolar lavage fluid (BALF) from 37 children (25 CF patients, 12 disease controls) and compared with neutrophil counts, presence of airway infection and lung function. To noninvasively assess airway purines, ATP levels were measured using luminometry in exhaled breath condensate (EBC) from 14 children with CF and 14 healthy controls, then 14 CF children during a pulmonary exacerbation.Both ATP and AMP were elevated in sputum and BALF from CF subjects compared with controls. In BALF, ATP and AMP levels were inversely related to lung function and strongly correlated with neutrophil counts. In EBC, ATP levels were increased in CF relative to controls and decreased after treatment of CF pulmonary exacerbation.The purines adenosine triphosphate and adenosine monophosphate are candidate biomarkers of neutrophilic airways inflammation. Measurement of purines in sputum or exhaled breath condensate may provide a relatively simple and noninvasive method to track this inflammation.

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Increased susceptibility of purinergic receptor-deficient mice to lung infection withPseudomonasaeruginosa

Abstract: Rice. Increased susceptibility of purinergic receptor-deficient mice to lung infection with Pseudomonas aeruginosa. Am

Cited by 42 publications

References 41 publications

Protective effect of purinergic agonist ATPγS against acute lung injury

Protective effect of purinergic agonist ATPγS against acute lung injury

Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem/progenitor cell senescence

Extracellular purines are biomarkers of neutrophilic airway inflammation

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