Connexin43 modulates neutrophil recruitment to the lung.
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.
Sarieddine
Maya Z Richani
MZ
Laboratory of Clinical Investigation III, Department of Pediatrics, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.
Scheckenbach
K E Ludwig
KE
Foglia
Bernard
B
Maass
Karen
K
Garcia
Irène
I
Kwak
Brenda R
BR
Chanson
Marc
M
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology*; D010455:Peptides / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
D018031:Connexin 43; D016207:Cytokines; C514423:Gap 26 peptide; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010455:Peptides