Extracellular nucleotides can mediate a variety of cellular functions via interactions with purinergic receptors. We previously showed that mechanical ventilation (MV) induces airway IL-6 and ATP release, modifies luminal nucleotide composition, and alters lung purinoceptor expression. Here we hypothesize that extracellular nucleotides induce secretion of IL-6 by small airway epithelial cells (SAEC). Human SAEC were stimulated with nucleotides in the presence or absence of inhibitors. Supernatants were analyzed for IL-6 and lysates for p38 MAPK activity by ELISA. RNA was analyzed by real-time RT-PCR. Rats (n ϭ 51) were randomized to groups as follows: control, small-volume MV, largevolume MV, large-volume MV-intratracheal apyrase, or small-volume MV-intratracheal adenosine 5Ј-O-(3-thiotriphosphate) (ATP␥S). After 1 h of MV, bronchoalveolar lavage fluid was analyzed for ATP and IL-6 by luminometry and ELISA. ATP and ATP␥S increased SAEC IL-6 secretion in a time-and dose-dependent manner, an effect inhibited by apyrase. Agonists were ranked in the following order: ATP␥S Ͼ ATP ϭ UTP Ͼ ADP ϭ adenosine Ͼ 2-methylthio-ADP ϭ control. SB-203580, but not U-0126 or JNK1 inhibitor, decreased nucleotide effects. Additionally, nucleotides induced p38 MAPK phosphorylation. Inhibitors of Ca 2ϩ signaling, phospholipase C, transcription, and translation decreased IL-6 release. Furthermore, nucleotides increased IL-6 expression. In vivo, large-volume MV increased airway ATP and IL-6 concentrations. IL-6 release was decreased by apyrase and increased by ATP␥S. Extracellular nucleotides induce P2Y2-mediated secretion of IL-6 by SAEC via Ca 2ϩ , phospholipase C, and p38 MAPK-dependent pathways. This effect is dependent on transcription and translation. Our findings were confirmed in an in vivo model, thus demonstrating a novel mechanism of nucleotideinduced IL-6 secretion by airway epithelia. cytokine; inflammation; purine; purinergic; ventilator-associated lung injury; interleukin-6; mitogen-activated protein kinase

Background-Intestinal ischemia-reperfusion (IIR) injury is known to initiate the systemic inflammatory response syndrome which often progresses to multiple organ failure. We investigated changes in purinoceptor expression in clinically relevant extra-intestinal organs following IIR injury.

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The ngram CC classifier performed similarly to manually developed CC classifiers and has advantages of rapid automated creation and updating, and may be used independent of language or dialect.