Increased susceptibility of purinergic receptor-deficient mice to lung infection with Pseudomonas aeruginosa.
Purinergic receptors are expressed throughout the respiratory system in diverse cell types. The efficiency of mucus clearance in the airways, 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. After P. aeruginosa challenge, all double knockout (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 knockout 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 lavage fluid was 1.8-fold higher in double knockout than in wild-type mice (P < 0.04). Total cell count in bronchoalveolar lavage fluids at 4 h and levels of IL-6 and macrophage inflammatory protein-2 in lung homogenates at 24 h postchallenge 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 proinflammatory cytokine response.
Geary
Cara
C
Division of Neonatology, University of Texas Medical Branch, Galveston, Texas, USA.
Akinbi
Henry
H
Korfhagen
Tom
T
Fabre
Jean-Etienne
JE
Boucher
Richard
R
Rice
Ward
W
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D007113:Immunity, Innate; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018410:Pneumonia, Bacterial / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D011552:Pseudomonas Infections / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000503:physiopathology; D018048:Receptors, Purinergic P2 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2; D015398:Signal Transduction
D016207:Cytokines; D018836:Inflammation Mediators; C546383:P2ry1 protein, mouse; C546386:P2ry2 protein, mouse; D018048:Receptors, Purinergic P2; D058472:Receptors, Purinergic P2Y1; D058473:Receptors, Purinergic P2Y2