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Connexin43 modulates neutrophil recruitment to the lung

Sarieddine, M. Z.
Scheckenbach, K. E.
Maass, Karen
Published in Journal of Cellular and Molecular Medicine. 2009, vol. 13, no. 11-12, p. 4560-4570
Abstract Transmigration of neutrophils through the microvascular endothelium is a cardinal event of acute inflammation. It has been suggested that gap junctions made of connexin43 (Cx43) may serve as a conducting pathway to spread inflammatory signals within the lung capillary network. To determine whether Cx43 contributes to neutrophil transmigration in vivo, the number of transmigrated neutrophils was monitored in lungs of Cx43 mouse models subjected to inflammation by intratracheal instillations of Pseudomonas aeruginosa lipopolysaccharide (LPS). Cx43 was detected in inflamed lungs independently of neutrophil recruitment, whereas Cx43 up-regulation was not detected in mice genetically protected from inflammation. Mice heterozygous for the Cx43 gene (gja1) showed a 56% (P < 0.01) reduction in airway neutrophil count. In contrast, increased (P < 0.05) neutrophil recruitment in response to LPS was observed in a mouse model expressing a mutant Cx43 with enhanced channel conductivity. In vitro adhesion assays showed that reduced conductivity of Cx43 channels with (43)Gap26, a Cx43 blocking peptide, decreased adhesion of neutrophils to endothelial cells. Finally, we found that instillation of (43)Gap26 in inflamed lungs reduced neutrophil transmigration by 65% (P < 0.05). These results indicate that inflammatory mediators up-regulate alveolar Cx43 to promote neutrophil recruitment to the airspace. Cx43 may therefore represent a pharmacological target in lung diseases characterized by excessive neutrophil recruitment to the airways.
Keywords AnimalsBronchoalveolar Lavage FluidCell Adhesion/drug effectsCell Communication/drug effectsCell LineConnexin 43/*metabolismCytokines/metabolismHumansInflammation/immunology/pathologyInflammation Mediators/metabolismLipopolysaccharides/administration & dosage/pharmacologyLung/drug effects/*immunology/pathologyLymphocyte CountMiceNeutrophil Infiltration/drug effects/*immunologyPeptides/pharmacologyPulmonary Alveoli/drug effects/metabolism/pathology
Stable URL http://archive-ouverte.unige.ch/unige:10974
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PMID: 19166484
Research groups Mucoviscidose et jonctions GAP (229)
L'athérosclérose (665)
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