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1 Division of Neonatology, University of Texas Medical Branch in Galveston, Galveston, Texas, USA
2 Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
3 Department of Genetics, University of North Carolina, Chapel Hill, NC, USA
4 Cystic Fibrosis/Pulmonary and Research Treatment Center, University of North Carolina, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: henry.akinbi{at}cchmc.org.
Purinergic receptors are expressed throughout the respiratory system in diverse cell types. The efficiency of mucus clearance in the airways, and the cascade leading to tissue injury and inflammation are modulated by autocrine/paracrine release of nucleotides and signaling by purinergic receptors. We assessed the role of purinergic receptors in innate host defense of the lung in vivo by infecting mice deficient in P2Y1, P2Y2 or both receptors with intratracheal instillation of Pseudomonas aeruginosa. Following P. aeruginosa challenge, all double knock-out (P2Y1/P2Y2-/-) mice succumbed within 30 h of challenge, whereas 85% of the wild-type mice survived. Thirty three percent of wild type mice survived beyond 96 h. Single knock-out mice, P2Y1-/- or P2Y2-/-, exhibited intermediate survivals. Twenty-four hours following intratracheal instillation of a sublethal dose of P. aeruginosa, the level of total protein in bronchoalveolar lavaged fluid was 1.8-fold higher in double knock-out than in wild type mice (p< 0.04). Total cell count in bronchoalveolar lavaged fluids at 4 h, and levels of interleukin-6 and MIP-2 in lung homogenates at 24 h post-challenge were significantly reduced in P2Y1/P2Y2-/- mice relative to wild-type mice. These findings suggest that purinergic receptors exert a protective role against infection of the lungs by P. aeruginosa by decreasing protein leak and enhancing pro-inflammatory cytokines response.
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