title: Gap junction protein connexin43 exacerbates lung vascular permeability.
abstract: Increased vascular permeability causes pulmonary edema that impairs arterial oxygenation and thus contributes to morbidity and mortality associated with Acute Respiratory Distress Syndrome and sepsis. Although components of intercellular adhesive and tight junctions are critical for maintaining the endothelial barrier, there has been limited study of the roles of gap junctions and their component proteins (connexins). Since connexins can modulate inflammatory signaling in other systems, we hypothesized that connexins may also regulate pulmonary endothelial permeability. The relationships between connexins and the permeability response to inflammatory stimuli were studied in cultured human pulmonary endothelial cells. Prolonged treatment with thrombin, lipopolysaccharide, or pathological cyclic stretch increased levels of mRNA and protein for the major connexin, connexin43 (Cx43). Thrombin and lipopolysaccharide both increased intercellular communication assayed by transfer of microinjected Lucifer yellow. Although thrombin decreased transendothelial resistance in these cells, the response was attenuated by pretreatment with the connexin inhibitor carbenoxolone. Additionally, the decreases of transendothelial resistance produced by either thrombin or lipopolysaccharide were attenuated by reducing Cx43 expression by siRNA knockdown. Both carbenoxolone and Cx43 knockdown also abrogated thrombin-induced phosphorylation of myosin light chain. Taken together, these data suggest that increased lung vascular permeability induced by inflammatory conditions may be amplified via increased expression of Cx43 and intercellular communication among pulmonary endothelial cells.
authors: Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America; Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors: James J
authors: JJ
authors: O'Donnell
authors: Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America; Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors: Anna A
authors: AA
authors: Birukova
authors: Department of Pediatrics, University of Chicago, Chicago, Illinois, United States of America.
authors: Eric C
authors: EC
authors: Beyer
authors: Section of Pulmonary and Critical Care, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America; Lung Injury Center, Department of Medicine, University of Chicago, Chicago, Illinois, United States of America.
authors: Konstantin G
authors: KG
authors: Birukov
mesh_terms: D056809:Alveolar Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics; D002229:Carbenoxolone / Q000494:pharmacology; D002460:Cell Line; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000235:genetics; D013917:Thrombin / Q000494:pharmacology
chemical_list: D018031:Connexin 43; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D018994:Myosin Light Chains; D034741:RNA, Small Interfering; D013917:Thrombin; D002229:Carbenoxolone