title: Atrial natriuretic peptide attenuates agonist-induced pulmonary edema in mice with targeted disruption of the gene for natriuretic peptide receptor-A.
abstract: Atrial natriuretic peptide (ANP) inhibits agonist-induced pulmonary edema formation, but the signaling pathway responsible is not well defined. To investigate the role of the particulate guanylate cyclase-linked receptor, natriuretic peptide receptor-A (NPR-A), we measured acute lung injury responses in intact mice and pulmonary microvascular endothelial cells (PMVEC) with normal and disrupted expression of NPR-A. NPR-A wild-type (NPR-A+/+), heterozygous (NPR-A+/-), and knockout (NPR-A-/-) mice were anesthetized and treated with thrombin receptor agonist peptide (TRAP) or lipopolysaccharide (LPS). Lung injury was assessed by lung wet-to-dry (W/D) weight and by protein and cell concentration of bronchoalveolar lavage (BAL) fluid. No difference in pulmonary edema formation was seen between NPR-A genotypes under baseline conditions. TRAP and LPS increased lung W/D weight and BAL fluid cell counts more in NPR-A-/- mice than in NPR-A+/- or NPR-A+/+ mice, but no genotype-related differences were seen in TRAP-induced increases in bloodless lung W/D weight or LPS-induced increases in BAL protein concentration. Pretreatment with ANP infusion completely blocked TRAP-induced increases in lung W/D weight and blunted LPS-induced increases in BAL cell counts and protein concentration in both NPR-A-/- and NPR-A+/+ mice. Thrombin decreased transmembrane electrical resistance in monolayers of PMVECs in vitro, and this effect was attenuated by ANP in PMVECs isolated from both genotypes. Administration of the NPR-C-specific ligand, cANF, also blocked TRAP-induced increases in lung W/D weight and LPS-induced increases in BAL cell count and protein concentration in NPR-A+/+ and NPR-A-/- mice. We conclude that ANP is capable of attenuating agonist-induced lung edema in the absence of NPR-A. The protective effect of ANP on agonist-induced lung injury and pulmonary barrier function may be mediated by NPR-C.
authors.affiliation: Vascular Research Laboratory, Veterans Affairs Medical Center, Providence, RI, USA. James_Klinger@brown.edu
authors.forename: James R
authors.initials: JR
authors.lastname: Klinger
authors.forename: Shu-Whei
authors.initials: SW
authors.lastname: Tsai
authors.forename: Sabrina
authors.initials: S
authors.lastname: Green
authors.forename: Katie L
authors.initials: KL
authors.lastname: Grinnell
authors.forename: Jason T
authors.initials: JT
authors.lastname: Machan
authors.forename: Elizabeth O
authors.initials: EO
authors.lastname: Harrington
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D055370:Lung Injury / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020098:Natriuretic Peptide, C-Type / Q000235:genetics / Q000378:metabolism; D011654:Pulmonary Edema / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism*; D050705:Receptors, Guanylate Cyclase-Coupled / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D018179:Receptors, Thrombin / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology
chemical_list: D008070:Lipopolysaccharides; D018000:Receptors, Peptide; D018179:Receptors, Thrombin; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D013917:Thrombin; D017461:Receptors, Atrial Natriuretic Factor; D050705:Receptors, Guanylate Cyclase-Coupled; C091715:atrial natriuretic factor receptor A