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This Article Full Text Full Text (PDF) All Versions of this Article: 296/6/L901    most recent 90549.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kiefmann, R. Articles by Bhattacharya, J. PubMed PubMed Citation Articles by Kiefmann, R. Articles by Bhattacharya, J.

Paracrine purinergic signaling determines lung endothelial nitric oxide production

Lung Biology Laboratory, Department of Medicine, College of Physicians and Surgeons, Columbia University, St. Luke's-Roosevelt Hospital Center, New York, New York

Submitted 5 November 2008 ; accepted in final form 13 March 2009

Although the vascular bed is a major source of nitric oxide (NO) production, factors regulating the production remain unclear. We considered the role played by paracrine signaling. Determinations by fluorescence microscopy in isolated, blood-perfused rat and mouse lungs revealed that a brief lung expansion enhanced cytosolic Ca²⁺ (Ca²⁺cyt) oscillations in alveolar epithelial (AEC) and endothelial (EC) cells, and NO production in EC. Furthermore, as assessed by a novel microlavage assay, alveolar ATP production increased. Intra-alveolar microinfusion of the purinergic receptor antagonist, PPADS, and the nucleotide hydrolyzing enzyme, apyrase, each completely blocked the Ca²⁺cyt and NO responses in EC. Lung expansion induced Ca²⁺cyt oscillations in mice lacking the P2Y1, but not the P2Y2, purinergic receptors, which were located in the perivascular interstitium basolateral to AEC. Prolonged lung expansion instituted by mechanical ventilation at high tidal volume increased EC expression of nitrotyrosine, indicating development of nitrosative stress in lung microvessels. These findings reveal a novel mechanism in which mechanically induced purinergic signaling couples cross-compartmental Ca²⁺cyt oscillations to microvascular NO production.

pulmonary circulation; calcium; DAF; imaging; fluorescence