title: Opposite effects of ANP receptors in attenuation of LPS-induced endothelial permeability and lung injury.
abstract: Atrial natriuretic peptide (ANP) has been recently identified as a modulator of acute lung injury (ALI) induced by pro-inflammatory agonists. While previous studies tested effects of exogenous ANP administration, the role of endogenous ANP in the course of ALI remains unexplored. This study examined regulation of ANP and its receptors NPR-A, NPR-B and NPR-C by LPS and involvement of ANP receptors in the modulation of LPS-induced lung injury. Primary cultures of human pulmonary endothelial cells (EC) were used in the in vitro tests. Expression of ANP and its receptors was determined by quantitative RT-PCR analysis. Agonist-induced cytoskeletal remodeling was evaluated by immunofluorescence staining, and EC barrier function was characterized by measurements of transendothelial electrical resistance. In the murine model of ALI, LPS-induced lung injury was assessed by measurements of protein concentration and cell count in bronchoalveolar lavage fluid (BAL). LPS stimulation significantly increased mRNA expression levels of ANP and NPR-A in pulmonary EC. Pharmacological inhibition of NPR-A augmented LPS-induced EC permeability and blocked barrier protective effects of exogenous ANP on LPS-induced intercellular gap formation. In contrast, pharmacological inhibition of ANP clearance receptor NPR-C significantly attenuated LPS-induced barrier disruptive effects. Administration of NPR-A inhibitor in vivo exacerbated LPS-induced lung injury, whereas inhibition of NPR-C suppressed LPS-induced increases in BAL cell count and protein content. These results demonstrate for the first time opposite effects of NPR-A and NPR-C in the modulation of ALI and suggest a compensatory protective mechanism of endogenous ANP in the maintenance of lung vascular permeability in ALI.
authors: Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors: Junjie
authors: J
authors: Xing
authors: Bakhtiyor
authors: B
authors: Yakubov
authors: Valeriy
authors: V
authors: Poroyko
authors: Anna A
authors: AA
authors: Birukova
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000378:metabolism; D004195:Disease Models, Animal; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005455:Fluorescent Antibody Technique; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D008070:Lipopolysaccharides; D008168:Lung / Q000098:blood supply* / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D006727:Hormone Antagonists; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C482199:lipopolysaccharide, E coli O55-B5; D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor