title: Systemic inhibition of the angiotensin-converting enzyme limits lipopolysaccharide-induced lung neutrophil recruitment through both bradykinin and angiotensin II-regulated pathways.
abstract: Recruitment of neutrophils to the lung is a sentinel event in acute lung inflammation. Identifying mechanisms that regulate neutrophil recruitment to the lung may result in strategies to limit lung damage and improve clinical outcomes. Recently, the renin angiotensin system (RAS) has been shown to regulate neutrophil influx in acute inflammatory models of cardiac, neurologic, and gastrointestinal disease. As a role for the RAS in LPS-induced acute lung inflammation has not been described, we undertook this study to examine the possibility that the RAS regulates neutrophil recruitment to the lung after LPS exposure. Pretreatment of mice with the angiotensin-converting enzyme (ACE) inhibitor enalapril, but not the anti-hypertensive hydralazine, decreased pulmonary neutrophil recruitment after exposure to LPS. We hypothesize that inhibition of LPS-induced neutrophil accumulation to the lung with enalapril occurred through both an increase in bradykinin, and a decrease in angiotensin II (ATII), mediated signaling. Bradykinin receptor blockade reversed the inhibitory effect of enalapril on neutrophil recruitment. Similarly, pretreatment with bradykinin receptor agonists inhibited IL-8-induced neutrophil chemotaxis and LPS-induced neutrophil recruitment to the lung. Inhibition of ATII-mediated signaling, with the ATII receptor 1a inhibitor losartan, decreased LPS-induced pulmonary neutrophil recruitment, and this was suggested to occur through decreased PAI-1 levels. LPS-induced PAI-1 levels were diminished in animals pretreated with losartan and in those deficient for the ATII receptor 1a. Taken together, these results suggest that ACE regulates LPS-induced pulmonary neutrophil recruitment via modulation of both bradykinin- and ATII-mediated pathways, each regulating neutrophil recruitment by separate, but distinct, mechanisms.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80206, USA. arndt108@umn.edu
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Arndt
authors.forename: Scott K
authors.initials: SK
authors.lastname: Young
authors.forename: Katie R
authors.initials: KR
authors.lastname: Poch
authors.forename: Jerry A
authors.initials: JA
authors.lastname: Nick
authors.forename: Sandor
authors.initials: S
authors.lastname: Falk
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schrier
authors.forename: G Scott
authors.initials: GS
authors.lastname: Worthen
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000502:physiology*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001920:Bradykinin / Q000819:agonists / Q000502:physiology*; D002464:Cell Migration Inhibition; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000378:metabolism; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008168:Lung / Q000201:enzymology* / Q000276:immunology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000276:immunology; D017395:Plasminogen Activator Inhibitor 1 / Q000008:administration & dosage / Q000096:biosynthesis / Q000378:metabolism; D018002:Receptors, Bradykinin / Q000819:agonists; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D018925:Chemokines; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D018002:Receptors, Bradykinin; D000804:Angiotensin II; D019808:Losartan; D001920:Bradykinin