ANP attenuates inflammatory signaling and Rho pathway of lung endothelial permeability induced by LPS and TNFalpha.
We have previously reported protective effects of atrial natriuretic peptide (ANP) against endothelial cell (EC) permeability induced by thrombin via suppression of Rho GTPase pathway of barrier dysfunction by protein kinase A and Epac-Rap1-Tiam1-Rac signaling cascades. This study tested effects of ANP on EC barrier dysfunction induced by inflammatory mediators lipopolysaccharide (LPS) and TNFalpha and linked them with activation of mitogen-activated protein kinase (MAPK) and NFkappaB signaling cascades known to promote EC hyperpermeability in the models of lung inflammation and sepsis. LPS and TNFalpha increased permeability in human pulmonary EC monitored by measurements of transendothelial electrical resistance, and caused disruption of EC monolayer integrity monitored by immunofluorescence staining for adherens junction marker protein VE-cadherin. Both disruptive effects were markedly attenuated by ANP. Both LPS and TNFalpha caused sustained activation of p38 and ERK1/2 MAP kinases, increased phosphorylation and degradation of negative regulator of NFkappaB signaling IkBalpha, and increased Rho-kinase mediated phosphorylation of myosin phosphatase MYPT1 leading to accumulation of phosphorylated myosin light chains. Consistent with protective effects on EC permeability and monolayer integrity, ANP dramatically attenuated activation of inflammatory signaling by LPS and TNFalpha in pulmonary EC. These results strongly suggest inhibitory effects of ANP on the LPS and TNFalpha induced inflammatory signaling as additional mechanism of EC barrier preservation in the models of acute lung injury and sepsis.
Xing
Junjie
J
Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
Birukova
Anna A
AA
D022005:Adherens Junctions / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D009320:Atrial Natriuretic Factor / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability; D002478:Cells, Cultured; D017097:Electric Impedance; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism*; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism*; D008168:Lung / Q000098:blood supply*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D054460:rho-Associated Kinases / Q000378:metabolism*; D000099152:Cadherin 5
D015703:Antigens, CD; D009320:Atrial Natriuretic Factor; D015820:Cadherins; D020672:I-kappa B Proteins; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D020928:Mitogen-Activated Protein Kinases; D043263:Myosin-Light-Chain Phosphatase; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D054460:rho-Associated Kinases; D000099152:Cadherin 5; C000606204:NFKBIA protein, human; C490372:PPP1R12A protein, human