Gap junction protein connexin43 exacerbates lung vascular permeability

• Published in: PloS one Vol. 9; no. 6; p. e100931
• Main Authors: O'Donnell, 3rd, James J, Birukova, Anna A, Beyer, Eric C, Birukov, Konstantin G
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.06.2014; Public Library of Science (PLoS)
• Subjects: Adult respiratory distress syndrome; Alveolar Epithelial Cells - drug effects; Alveolar Epithelial Cells - metabolism; Biology and Life Sciences; Biophysics; Capillary Permeability - drug effects; Capillary Permeability - genetics; Carbenoxolone - pharmacology; Cell culture; Cell cycle; Cell Line; Cell signaling; Connexin 43; Connexin 43 - genetics; Connexin 43 - metabolism; Connexins; Critical care; Edema; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Gap junctions; Gap Junctions - drug effects; Gap Junctions - metabolism; Gene Expression; Gene Knockdown Techniques; Health aspects; Humans; Immunoglobulins; Inflammation; Inflammation Mediators - metabolism; Intracellular Space - metabolism; Lipopolysaccharides; Lipopolysaccharides - pharmacology; Lung - metabolism; Lungs; Medicine; Medicine and Health Sciences; Morbidity; Mortality; mRNA; Muscle proteins; Myosin; Myosin Light Chains - metabolism; Oxygenation; Permeability; Phosphorylation; Proteins; Pulmonary arteries; Respiratory distress syndrome; RNA; RNA, Small Interfering - genetics; Rodents; Sepsis; siRNA; Thrombin; Thrombin - pharmacology; Tight junctions
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0100931

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.