title: Monocyte chemoattractant protein-1 released from alveolar macrophages mediates the systemic inflammation of acute alveolar hypoxia.
abstract: Alveolar hypoxia produces rapid systemic inflammation in rats. Several lines of evidence suggest that the inflammation is not initiated by low systemic tissue partial pressure of oxygen (Po(2)) but by a mediator released into the circulation by hypoxic alveolar macrophages. The mediator activates tissue mast cells to initiate inflammation. Monocyte chemoattractant protein-1/Chemokine (C-C motif) ligand 2 (MCP-1/CCL2) is rapidly released by hypoxic alveolar macrophages. This study investigated whether MCP-1 is the mediator of the systemic inflammation of alveolar hypoxia. Experiments in rats and in alveolar macrophages and peritoneal mast cells led to several results. (1) Alveolar hypoxia (10% O(2) breathing, 60 minutes) produced a rapid (5-minute) increase in plasma MCP-1 concentrations in conscious intact rats but not in alveolar macrophage-depleted rats. (2) Degranulation occurred when mast cells were immersed in the plasma of hypoxic intact rats but not in the plasma of alveolar macrophage-depleted rats. (3) MCP-1 added to normoxic rat plasma and the supernatant of normoxic alveolar macrophages produced a concentration-dependent degranulation of immersed mast cells. (4) MCP-1 applied to the mesentery of normoxic intact rats replicated the inflammation of alveolar hypoxia. (5) The CCR2b receptor antagonist RS-102895 prevented the mesenteric inflammation of alveolar hypoxia in intact rats. Additional data suggest that a cofactor constitutively generated in alveolar macrophages and present in normoxic body fluids is necessary for MCP-1 to activate mast cells at biologically relevant concentrations. We conclude that alveolar macrophage-borne MCP-1 is a key agent in the initiation of the systemic inflammation of alveolar hypoxia.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Chao
authors.forename: Paula
authors.initials: P
authors.lastname: Donham
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: John G
authors.initials: JG
authors.lastname: Wood
authors.forename: Norberto C
authors.initials: NC
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D015550:Cell Degranulation / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000276:immunology*; D000860:Hypoxia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008407:Mast Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D011650:Pulmonary Alveoli / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054390:Receptors, CCR2
references.citation: Crit Care Med. 2005 Jun;33(6):1351-8
references.pmid: 15942355
references.citation: Cytokine Growth Factor Rev. 1996 Jun;7(1):47-64
references.pmid: 8864354
references.citation: Am J Respir Crit Care Med. 2001 Sep 1;164(5):826-30
references.pmid: 11549540
references.citation: Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3652-6
references.pmid: 8170963
references.citation: J Biol Chem. 1995 May 19;270(20):11703-6
references.pmid: 7744810
references.citation: Environ Health Perspect. 2006 Mar;114(3):412-9
references.pmid: 16507465
references.citation: J Am Coll Cardiol. 2008 Aug 26;52(9):719-26
references.pmid: 18718418
references.citation: Lancet. 2003 Jun 7;361(9373):1967-74
references.pmid: 12801752
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Jul;291(1):L102-10
references.pmid: 16461432
references.citation: Am J Physiol Heart Circ Physiol. 2007 May;292(5):H2285-94
references.pmid: 17208999
references.citation: Immunology. 1995 Nov;86(3):434-40
references.pmid: 8550082
references.citation: Circulation. 2008 Apr 29;117(17):2270-8
references.pmid: 18413499
references.citation: Life Sci. 2006 Aug 22;79(13):1293-300
references.pmid: 16712875
references.citation: J Exp Med. 1992 Sep 1;176(3):781-6
references.pmid: 1512541
references.citation: Blood. 2000 Jul 1;96(1):34-40
references.pmid: 10891427
references.citation: Clin Diagn Lab Immunol. 2003 Sep;10(5):813-20
references.pmid: 12965910
references.citation: J Appl Physiol (1985). 1993 Apr;74(4):1994-2003
references.pmid: 8514721
references.citation: J Appl Physiol (1985). 1999 Nov;87(5):1734-40
references.pmid: 10562616
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Jan;288(1):L3-15
references.pmid: 15591040
references.citation: J Immunol. 1995 Dec 15;155(12):5769-76
references.pmid: 7499865
references.citation: J Appl Physiol (1985). 2003 Jun;94(6):2323-9
references.pmid: 12598489
references.citation: Am J Respir Cell Mol Biol. 2001 Dec;25(6):780-7
references.pmid: 11726405
references.citation: Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L360-7
references.pmid: 12388372
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Jul;295(1):L79-85
references.pmid: 18469117
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Jul;293(1):L105-13
references.pmid: 17416740
references.citation: J Appl Physiol (1985). 2003 Jan;94(1):325-34
references.pmid: 12391033
references.citation: Chest. 2003 Aug;124(2):548-53
references.pmid: 12907541
references.citation: J Appl Physiol (1985). 2001 Sep;91(3):1160-7
references.pmid: 11509511
references.citation: J Appl Physiol (1985). 2003 Dec;95(6):2495-502
references.pmid: 12949012
references.citation: Ann Thorac Surg. 2002 Sep;74(3):899-905; discussion 905
references.pmid: 12238858
references.citation: Cardiovasc Res. 1996 Oct;32(4):699-708
references.pmid: 8915188
references.citation: Ann Hematol. 1995 May;70(5):251-8
references.pmid: 7541256
references.citation: Am J Physiol. 1993 Mar;264(3 Pt 2):R610-4
references.pmid: 8457016
references.citation: Am J Respir Cell Mol Biol. 2009 Nov;41(5):573-82
references.pmid: 19244200
references.citation: J Immunol Methods. 1994 Sep 14;174(1-2):83-93
references.pmid: 8083541
references.citation: Physiol Rev. 1997 Oct;77(4):1033-79
references.pmid: 9354811
references.citation: J Appl Physiol (1985). 2007 Oct;103(4):1386-94
references.pmid: 17656628
references.citation: Br J Pharmacol. 2003 Feb;138(4):698-706
references.pmid: 12598424
references.citation: COPD. 2008 Apr;5(2):133-8
references.pmid: 18415812
references.citation: Prostaglandins Leukot Essent Fatty Acids. 2008 Feb;78(2):137-46
references.pmid: 18093816
references.citation: Respir Res. 2005 Aug 01;6:87
references.pmid: 16053532
references.citation: J Appl Physiol (1985). 2005 Jul;99(1):290-7
references.pmid: 15746296
references.citation: Respir Res. 2009 Jun 22;10:54
references.pmid: 19545431
references.citation: J Appl Physiol (1985). 1999 Sep;87(3):873-81
references.pmid: 10484552
references.citation: J Appl Physiol (1985). 2000 Oct;89(4):1561-8
references.pmid: 11007596
references.citation: Am J Respir Cell Mol Biol. 1995 Oct;13(4):399-409
references.pmid: 7546769