title: Age influences inflammatory responses, hemodynamics, and cardiac proteasome activation during acute lung injury.
abstract: BACKGROUND
  Acute lung injury (ALI) is a significant source of morbidity and mortality in critically ill patients. Age is a major determinant of clinical outcome in ALI. The increased ALI-associated mortality in the older population suggests that there are age-dependent alterations in the responses to pulmonary challenge. The objective of this observational study was to evaluate age-dependent differences in the acute (within 6 hours) immunological and physiological responses of the heart and lung, to pulmonary challenge, that could result in increased severity.
  
  
  METHODS
  Male C57Bl/6 mice (young: 2-3 months, old: 18-20 months) were challenged intratracheally with cell wall components from Gram-positive bacteria (lipoteichoic acid and peptidoglycan). After 6 hours, both biochemical and physiological consequences of the challenge were assessed. Alveolar infiltration of inflammatory cells and protein, airspace and blood cytokines, cardiac function and myocardial proteasome activity were determined.
  
  
  RESULTS
  In young mice, there was a dose-dependent response to pulmonary challenge resulting in increased airspace neutrophil counts, lung permeability, and concentrations of cytokines in bronchoalveolar lavage fluid and plasma. A midrange dose was then selected to compare the responses in young and old animals. In comparison, the old animals displayed increased neutrophil accumulation in the airspaces, decreased arterial oxygen saturation, body temperatures, plasma cytokine concentrations, and a lack of myocardial proteasome response, following challenge.
  
  
  CONCLUSIONS
  Age-dependent differences in the onset of systemic response and in maintenance of vital functions, including temperature control, oxygen saturation, and myocardial proteasome activation, are evident. We believe a better understanding of these age-related consequences of ALI can lead to more appropriate treatments in the elderly patient population.
authors.affiliation: 1Center for Heart and Lung Research, The Feinstein Institute for Medical Research, Manhasset, New York, USA.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Linge
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Lee
authors.forename: Kanta
authors.initials: K
authors.lastname: Ochani
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Koga
authors.forename: Nina
authors.initials: N
authors.lastname: Kohn
authors.forename: Kaie
authors.initials: K
authors.lastname: Ojamaa
authors.forename: Saul R
authors.initials: SR
authors.lastname: Powell
authors.forename: Edmund J
authors.initials: EJ
authors.lastname: Miller
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D000367:Age Factors; D000375:Aging / Q000276:immunology / Q000378:metabolism; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D006439:Hemodynamics; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides; D008168:Lung / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000201:enzymology* / Q000276:immunology; D020556:Neutrophil Infiltration; D010457:Peptidoglycan; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012307:Risk Factors; D012720:Severity of Illness Index; D013682:Teichoic Acids; D013997:Time Factors
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D013682:Teichoic Acids; C009900:lipoteichoic acid; D046988:Proteasome Endopeptidase Complex
keywords: aging; inflammatory response; myocardial proteasome; pulmonary challenge
references.citation: Am J Physiol Heart Circ Physiol. 2010 Sep;299(3):H868-75
references.pmid: 20601465
references.citation: Circ Res. 2006 Dec 8;99(12):1315-28
references.pmid: 17158347
references.citation: Mol Ther. 2010 Jun;18(6):1143-54
references.pmid: 20372109
references.citation: Chest. 1995 Nov;108(5):1303-14
references.pmid: 7587434
references.citation: Crit Care Med. 2007 Jan;35(1):246-51
references.pmid: 17133178
references.citation: Front Biosci. 2006 Jan 01;11:15-22
references.pmid: 16146710
references.citation: J Intensive Care Med. 2009 Sep-Oct;24(5):293-316
references.pmid: 19703817
references.citation: Am Rev Respir Dis. 1992 Aug;146(2):427-32
references.pmid: 1489135
references.citation: Am J Respir Crit Care Med. 1996 Mar;153(3):1072-9
references.pmid: 8630547
references.citation: PLoS One. 2012;7(5):e35361
references.pmid: 22586448
references.citation: N Engl J Med. 2006 Jun 15;354(24):2564-75
references.pmid: 16714767
references.citation: Methods Mol Biol. 2014;1172:147-62
references.pmid: 24908302
references.citation: Am J Respir Cell Mol Biol. 2011 May;44(5):725-38
references.pmid: 21531958
references.citation: Int J Infect Dis. 2011 Jan;15(1):e58-62
references.pmid: 21111647
references.citation: Respir Res. 2009 May 04;10:33
references.pmid: 19413900
references.citation: Crit Care. 2002 Dec;6(6):500-8
references.pmid: 12493071
references.citation: Mech Ageing Dev. 2000 Jan 24;113(1):61-70
references.pmid: 10708250
references.citation: N Engl J Med. 2006 May 25;354(21):2213-24
references.pmid: 16714768
references.citation: Exp Gerontol. 2006 Mar;41(3):289-95
references.pmid: 16413724
references.citation: J Crit Care. 2010 Mar;25(1):176.e7-13
references.pmid: 19592208
references.citation: Lancet. 1993 Mar 13;341(8846):643-7
references.pmid: 8095568
references.citation: Eur Respir J. 1999 Jan;13(1):197-205
references.pmid: 10836348
references.citation: Crit Care Med. 2006 Feb;34(2):344-53
references.pmid: 16424713
references.citation: J Infect Dis. 1989 Feb;159(2):189-94
references.pmid: 2644368
references.citation: Intensive Care Med. 2004 Jan;30(1):68-74
references.pmid: 14634726
references.citation: Crit Care Med. 2009 Jan;37(1):1-6
references.pmid: 19050621
references.citation: Am J Physiol Lung Cell Mol Physiol. 2005 Feb;288(2):L266-74
references.pmid: 15475382
references.citation: Geriatrics. 1978 Jun;33(6):68-74
references.pmid: 648879
references.citation: Shock. 2002 Feb;17(2):104-8
references.pmid: 11837784
references.citation: Intensive Care Med. 2012 Oct;38(10):1573-82
references.pmid: 22926653
references.citation: Mo Med. 2010 Jul-Aug;107(4):252-8
references.pmid: 20806836
references.citation: N Engl J Med. 2005 Oct 20;353(16):1685-93
references.pmid: 16236739
references.citation: J Leukoc Biol. 2000 Jan;67(1):40-5
references.pmid: 10647996
references.citation: Am J Respir Crit Care Med. 2010 Nov 1;182(9):1123-8
references.pmid: 20558628
references.citation: Neuromolecular Med. 2008;10(3):179-86
references.pmid: 18338270
references.citation: Am J Med. 1982 Jul;73(1):25-34
references.pmid: 7091171
references.citation: Mediators Inflamm. 2012;2012:204250
references.pmid: 22363101
references.citation: Am J Respir Crit Care Med. 1994 Sep;150(3):710-6
references.pmid: 8087341
references.citation: Surgery. 2004 Jan;135(1):87-98
references.pmid: 14694305
references.citation: JAMA. 2012 Jun 20;307(23):2526-33
references.pmid: 22797452
references.citation: Sci Rep. 2014 Jul 02;4:5543
references.pmid: 24986487
references.citation: Biochem Pharmacol. 2010 Mar 1;79(5):706-14
references.pmid: 19835847
references.citation: J Mol Cell Cardiol. 2007 Jan;42(1):265-9
references.pmid: 17140599
references.citation: Shock. 2006 May;25(5):472-84
references.pmid: 16680012
references.citation: Am J Physiol Heart Circ Physiol. 2011 Dec;301(6):H2207-19
references.pmid: 21949118
references.citation: Arch Biochem Biophys. 2002 Jan 15;397(2):298-304
references.pmid: 11795886
references.citation: Proc Natl Acad Sci U S A. 2013 Feb 26;110(9):3507-12
references.pmid: 23401516
references.citation: Prog Mol Biol Transl Sci. 2012;109:75-112
references.pmid: 22727420
references.citation: Antioxid Redox Signal. 2011 Apr 1;14(7):1191-202
references.pmid: 20831446
references.citation: Am J Physiol Heart Circ Physiol. 2006 Jul;291(1):H1-H19
references.pmid: 16501026
references.citation: Aging Dis. 2014 Apr 01;5(2):126-36
references.pmid: 24729938
references.citation: J Crit Care. 2011 Aug;26(4):395-401
references.pmid: 21036521
references.citation: Cell Res. 2010 Dec;20(12):1372-85
references.pmid: 20805844
references.citation: Proc Natl Acad Sci U S A. 2015 Jan 27;112(4):1167-72
references.pmid: 25092317