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fbtwitterlinkedinvimeoflicker grey 14rssslideshare1
Languages: English
Types: Doctoral thesis
Subjects: RC, QP

Classified by OpenAIRE into

mesheuropmc: endocrine system, hormones, hormone substitutes, and hormone antagonists
The\ud acute\ud respiratory\ud distress\ud syndrome\ud (ARDS)\ud is\ud an\ud important\ud cause\ud of\ud respiratory\ud failure\ud in\ud critically\ud ill\ud patients\ud characterised\ud by\ud severe\ud inflammation\ud within\ud the\ud lungs.\ud This\ud inflammation\ud is\ud limited\ud by\ud anti-­inflammatory\ud glucocorticoid\ud hormones\ud released\ud from\ud the\ud hypothalamus-pituitary-adrenal\ud (HPA)\ud system.\ud This\ud thesis\ud reports\ud a\ud series\ud of\ud investigations\ud into\ud glucocorticoid\ud concentrations\ud and\ud glucocorticoid\ud metabolism\ud within\ud the\ud lungs\ud of\ud patients\ud with\ud ARDS.\ud It\ud also\ud contains\ud an\ud investigation\ud into\ud a\ud potential\ud biomarker\ud for\ud ARDS.\ud Our\ud study\ud of\ud glucocorticoid\ud concentrations\ud in\ud alveolar\ud epithelial\ud lining\ud fluid\ud showed\ud increased\ud cortisol\ud concentrations\ud within\ud the\ud lungs\ud at\ud onset\ud of\ud ARDS.\ud These\ud concentrations\ud have\ud a\ud positive\ud relationship\ud with\ud critical\ud illness\ud severity\ud indices,\ud but\ud negative\ud relationships\ud with\ud alveolar\ud permeability\ud and\ud alveolar\ud neutrophil\ud counts.\ud In\ud peripheral\ud tissues\ud cortisone\ud and\ud cortisol\ud are\ud inter-converted\ud by\ud iso-­enzymes\ud of\ud 11β-­hydroxysteroid\ud dehydrogenase\ud (11β-­HSD).\ud We\ud have\ud shown\ud that\ud healthy\ud primary\ud resident\ud alveolar\ud macrophages\ud increase\ud their\ud production\ud of\ud active\ud cortisol\ud by\ud the\ud oxo-­reduction\ud of\ud inactive\ud cortisone\ud in\ud response\ud to\ud inflammatory\ud stimuli.\ud Alveolar\ud macrophages\ud are\ud responsible\ud for\ud the\ud removal\ud of\ud spent\ud and\ud apoptotic\ud inflammatory\ud cells,\ud failure\ud of\ud this\ud process\ud causes\ud further\ud inflammation.\ud We\ud have\ud shown\ud that\ud glucocorticoids\ud increase\ud the\ud rate\ud of\ud uptake\ud of\ud apoptotic\ud cells\ud by\ud alveolar\ud macrophages,\ud and\ud that\ud macrophage\ud 11β-HSD\ud production\ud of\ud cortisol\ud increases\ud this\ud process.\ud We\ud have\ud shown\ud however\ud that\ud alveolar\ud macrophages\ud extracted\ud from\ud patients\ud with\ud established\ud ARDS\ud have\ud decreased\ud 11β-HSD\ud oxo-reductase\ud activity.\ud This\ud decreased\ud conversion\ud of\ud cortisone\ud to\ud cortisol\ud will\ud cause\ud a\ud diminished\ud response\ud to\ud the\ud anti-inflammatory\ud signal\ud of\ud the\ud HPA\ud system.\ud The\ud implications\ud of\ud this\ud are\ud that\ud they\ud will\ud have\ud a\ud limited\ud capacity\ud to\ud up-­regulate\ud efferocytosis\ud and\ud a\ud diminished\ud anti-­inflammatory\ud potential.\ud The\ud receptor\ud for\ud advanced\ud glycation\ud end-­products\ud (RAGE)\ud is\ud a\ud potential\ud biomarker\ud in\ud ARDS.\ud We\ud have\ud shown\ud that\ud RAGE\ud concentrations\ud in\ud plasma\ud and\ud BALF\ud had\ud excellent\ud diagnostic\ud compatibility\ud with\ud ARDS\ud diagnostic\ud criteria.\ud The\ud use\ud of\ud a\ud threshold\ud RAGE\ud concentration\ud could\ud assure\ud pulmonary\ud inflammation\ud in\ud future\ud investigations.
  • The results below are discovered through our pilot algorithms. Let us know how we are doing!

    • 4.4.3   Glucocorticoid  concentration  and  severity  scores . ................................... 1 08  
    • 4.4.4   Glucocorticoid  concentration  and  changes  in  severity  scores . ................. 1 12  
    • 4.4.5   Glucocorticoid  concentration  and  mortality . ............................................ 1 15  
    • 4.4.6   Glucocorticoid  concentrations  and  cellular  inflammation . ....................... 1 16  
    • 4.4.7   Glucocorticoid  concentrations  and  protein  permeability . ........................ 1 19  
    • 4.4.8   The  cortisol:  cortisone  ratio  ...................................................................... 1 21  
    • 5.4.7   Effect  of  salbutamol  on  the  11β-­‐HSD  activity  induced  by  pro-­‐inflammatory  
    • mediators. .............................................................................................................. 1 47  
    • 5.4.8   BALF  from  patients  with  ARDS  increases  alveolar  macrophage  11β-­‐HSD  
    • oxo-­‐reductase  activity. ........................................................................................... 1 50  
    • 6.3.1   Sample  collection,  processing  and  cell  culture  ......................................... 1 60  
    • 6.3.2   Efferocytosis  assay  .................................................................................... 1 61  
    • 6.3.3   Statistical  analysis. ..................................................................................... 1 61  
    • 6.4.1   Glucocorticoids  up-­‐regulate  efferocytosis  ................................................ 1 62  
    • 6.4.2   Effect  of  salbutamol  on  efferocytosis. ....................................................... 1 65  
    • 6.4.3   Effect  of  LPS  on  efferocytosis . ................................................................... 1 67  
    • 6.4.4   TNF  increases  efferocytosis  of  apoptotic  neutrophils  by  alveolar  
    • macrophages  ......................................................................................................... 1 68  
    • 6.4.5   HMGB-­‐1  decreases  efferocytosis  of  apoptotic  neutrophils  by  alveolar  
    • macrophages  ......................................................................................................... 1 69  
    • 6.4.6   BALF  from  patients  with  ARDS  and  efferocytosis. ..................................... 1 72  
    • 2.     Petty  TL.  Acute  respiratory  distress  syndrome  (ARDS).  Dis  Mon  1990;  36(1):1-­‐58.  
    • 3.     Bernard  GR,  Artigas  A,  Brigham  KL  et  al.  The  American-­‐European  Consensus   Conference  on  ARDS.  Definitions,  mechanisms,  relevant  outcomes,  and  clinical   trial  coordination.  Am  J  Respir  Crit  Care  Med  1994;  149(3  Pt  1):818-­‐824.  
    • 4.     Rubenfeld  GD,  Caldwell  E,  Peabody  E  et  al.  Incidence  and  outcomes  of  acute   lung  injury.  N  Engl  J  Med  2005;  353(16):1685-­‐1693.  
    • 5.     Thomsen  GE,  Morris  AH.  Incidence  of  the  adult  respiratory  distress  syndrome  in   the  state  of  Utah.  Am  J  Respir  Crit  Care  Med  1995;  152(3):965-­‐971.  
    •   16.     Meduri  GU,  Tolley  EA,  Chrousos  GP,  Stentz  F.  Prolonged  methylprednisolone   treatment  suppresses  systemic  inflammation  in  patients  with  unresolving  acute   respiratory  distress  syndrome:  evidence  for  inadequate  endogenous   glucocorticoid  secretion  and  inflammation-­‐induced  immune  cell  resistance  to   glucocorticoids.  Am  J  Respir  Crit  Care  Med  2002;  165(7):983-­‐991.  
    •   17.     Bajwa  EK,  Cremer  PC,  Gong  MN  et  al.  An  NFKB1  Promoter  Insertion/Deletion   Polymorphism  Influences  Risk  and  Outcome  in  Acute  Respiratory  Distress   Syndrome  among  Caucasians.  PLoS  One  2011;  6(5):e19469.  
    •   18.     Paterson  RL,  Galley  HF,  Dhillon  JK,  Webster  NR.  Increased  nuclear  factor  kappa  B   activation  in  critically  ill  patients  who  die.  Crit  Care  Med  2000;  28(4):1047-­‐1051.  
    •   19.     Steinberg  KP,  Milberg  JA,  Martin  TR,  Maunder  RJ,  Cockrill  BA,  Hudson  LD.   Evolution  of  bronchoalveolar  cell  populations  in  the  adult  respiratory  distress   syndrome.  Am  J  Respir  Crit  Care  Med  1994;  150(1):113-­‐122.  
    •   20.     Gattinoni  L,  Caironi  P,  Pelosi  P,  Goodman  LR.  What  has  computed  tomography   taught  us  about  the  acute  respiratory  distress  syndrome?  Am  J  Respir  Crit  Care   Med  2001;  164(9):1701-­‐1711.  
    •   21.     Craig  TR,  Duffy  MJ,  Shyamsundar  M  et  al.  Extravascular  lung  water  indexed  to   predicted  body  weight  is  a  novel  predictor  of  intensive  care  unit  mortality  in   patients  with  acute  lung  injury.  Crit  Care  Med  2010;  38(1):114-­‐120.  
    •   22.     Berkowitz  DM,  Danai  PA,  Eaton  S,  Moss  M,  Martin  GS.  Accurate  characterization   of  extravascular  lung  water  in  acute  respiratory  distress  syndrome.  Crit  Care   Med  2008;  36(6):1803-­‐1809.  
    •   23.     Ware  LB,  Matthay  MA.  The  acute  respiratory  distress  syndrome.  N  Engl  J  Med   2000;  342(18):1334-­‐1349.  
    •   24.     Tomashefski  JF,  Jr.  Pulmonary  pathology  of  acute  respiratory  distress  syndrome.   Clin  Chest  Med  2000;  21(3):435-­‐466.  
    •   30.     Rhen  T,  Cidlowski  JA.  Antiinflammatory  action  of  glucocorticoids-­‐-­‐new   mechanisms  for  old  drugs.  N  Engl  J  Med  2005;  353(16):1711-­‐1723.  
    •   31.     Marik  PE,  Pastores  SM,  Annane  D  et  al.  Recommendations  for  the  diagnosis  and   management  of  corticosteroid  insufficiency  in  critically  ill  adult  patients:   consensus  statements  from  an  international  task  force  by  the  American  College   of  Critical  Care  Medicine.  Crit  Care  Med  2008;  36(6):1937-­‐1949.  
    •   32.     Jurney  TH,  Cockrell  JL,  Jr.,  Lindberg  JS,  Lamiell  JM,  Wade  CE.  Spectrum  of  serum   cortisol  response  to  ACTH  in  ICU  patients.  Correlation  with  degree  of  illness  and   mortality.  Chest  1987;  92(2):292-­‐295.  
    •   33.     HAMMOND  GL.  Molecular  Properties  of  Corticosteroid  Binding  Globulin  and  the   Sex-­‐Steroid  Binding  Proteins.  Endocr  Rev  1990;  11(1):65-­‐79.  
    •   34.     Hamrahian  AH,  Oseni  TS,  Arafah  BM.  Measurements  of  Serum  Free  Cortisol  in   Critically  Ill  Patients.  New  England  Journal  of  Medicine  2004;  350(16):1629-­‐1638.  
    •   35.     Pemberton  PA,  Stein  PE,  Pepys  MB,  Potter  JM,  Carrell  RW.  Hormone  binding   globulins  undergo  serpin  conformational  change  in  inflammation.  Nature  1988;   336(6196):257-­‐258.  
    •   36.     Barnes  PJ,  Adcock  IM.  Glucocorticoid  resistance  in  inflammatory  diseases.   Lancet  2009;  373(9678):1905-­‐1917.  
    •   37.     Meduri  GU,  Muthiah  MP,  Carratu  P,  Eltorky  M,  Chrousos  GP.  Nuclear  factor-­‐ kappaB-­‐  and  glucocorticoid  receptor  alpha-­‐  mediated  mechanisms  in  the   regulation  of  systemic  and  pulmonary  inflammation  during  sepsis  and  acute   respiratory  distress  syndrome.  Evidence  for  inflammation-­‐induced  target  tissue   resistance  to  glucocorticoids.  Neuroimmunomodulation  2005;  12(6):321-­‐338.  
    •   38.     Marik  PE.  Critical  illness-­‐related  corticosteroid  insufficiency.  Chest  2009;   135(1):181-­‐193.  
    •   45.     Yau  JL,  Noble  J,  Kenyon  CJ  et  al.  Lack  of  tissue  glucocorticoid  reactivation  in   11beta  -­‐hydroxysteroid  dehydrogenase  type  1  knockout  mice  ameliorates  age-­‐ related  learning  impairments.  Proc  Natl  Acad  Sci  U  S  A  2001;  98(8):4716-­‐4721.  
    •   46.     Silverman  MN,  Sternberg  EM.  Neuroendocrine-­‐immune  interactions  in   rheumatoid  arthritis:  mechanisms  of  glucocorticoid  resistance.   Neuroimmunomodulation  2008;  15(1):19-­‐28.  
    •   47.     Cohen  J,  Deans  R,  Dalley  A,  Lipman  J,  Roberts  MS,  Venkatesh  B.  Measurement  of   tissue  cortisol  levels  in  patients  with  severe  burns:  a  preliminary  investigation.   Crit  Care  2009;  13(6):R189.  
    •   48.     Tomlinson  JW,  Stewart  PM.  Cortisol  metabolism  and  the  role  of  11beta-­‐ hydroxysteroid  dehydrogenase.  Best  Pract  Res  Clin  Endocrinol  Metab  2001;   15(1):61-­‐78.  
    •   49.     Walker  EA,  Clark  AM,  Hewison  M,  Ride  JP,  Stewart  PM.  Functional  Expression,   Characterization,  and  Purification  of  the  Catalytic  Domain  of  Human  11-­‐+¦-­‐ Hydroxysteroid  Dehydrogenase  Type  1.  Journal  of  Biological  Chemistry  2001;   276(24):21343-­‐21350.  
    •   50.     Bujalska  IJ,  Draper  N,  Michailidou  Z  et  al.  Hexose-­‐6-­‐phosphate  dehydrogenase   confers  oxo-­‐reductase  activity  upon  11  beta-­‐hydroxysteroid  dehydrogenase   type  1.  J  Mol  Endocrinol  2005;  34(3):675-­‐684.  
    •   51.     Cooper  MS,  Walker  EA,  Bland  R,  Fraser  WD,  Hewison  M,  Stewart  PM.  Expression   and  functional  consequences  of  11beta-­‐hydroxysteroid  dehydrogenase  activity   in  human  bone.  Bone  2000;  27(3):375-­‐381.  
    •   52.     Jamieson  PM,  Chapman  KE,  Edwards  CR,  Seckl  JR.  11  beta-­‐hydroxysteroid   dehydrogenase  is  an  exclusive  11  beta-­‐  reductase  in  primary  cultures  of  rat   hepatocytes:  effect  of  physicochemical  and  hormonal  manipulations.   Endocrinology  1995;  136(11):4754-­‐4761.  
    •   53.     Rauz  S,  Walker  EA,  Shackleton  CH,  Hewison  M,  Murray  PI,  Stewart  PM.   Expression  and  putative  role  of  11  beta-­‐hydroxysteroid  dehydrogenase  isozymes   within  the  human  eye.  Invest  Ophthalmol  Vis  Sci  2001;  42(9):2037-­‐2042.  
    •   55.     Bujalska  IJ,  Walker  EA,  Hewison  M,  Stewart  PM.  A  Switch  in  Dehydrogenase  to   Reductase  Activity  of  11+¦-­‐Hydroxysteroid  Dehydrogenase  Type  1  upon   Differentiation  of  Human  Omental  Adipose  Stromal  Cells.  Journal  of  Clinical   Endocrinology  &  Metabolism  2002;  87(3):1205-­‐1210.  
    •   56.     Friedberg  M,  Zoumakis  E,  Hiroi  N,  Bader  T,  Chrousos  GP,  Hochberg  Z.   Modulation  of  11+¦-­‐Hydroxysteroid  Dehydrogenase  Type  1  in  Mature  Human   Subcutaneous  Adipocytes  by  Hypothalamic  Messengers.  Journal  of  Clinical   Endocrinology  &  Metabolism  2003;  88(1):385-­‐393.  
    •   57.     Hundertmark  S,  Dill  A,  Buhler  H  et  al.  11beta-­‐hydroxysteroid  dehydrogenase   type  1:  a  new  regulator  of  fetal  lung  maturation.  Horm  Metab  Res  2002;   34(10):537-­‐544.  
    •   58.     Shimojo  M,  Ricketts  ML,  Petrelli  MD  et  al.  Immunodetection  of  11  beta-­‐ hydroxysteroid  dehydrogenase  type  2  in  human  mineralocorticoid  target   tissues:  evidence  for  nuclear  localization.  Endocrinology  1997;  138(3):1305-­‐ 1311.  
    •   66.     Zbankova  S,  Bryndova  J,  Leden  P,  Kment  M,  Svec  A,  Pacha  J.  11beta-­‐ hydroxysteroid  dehydrogenase  1  and  2  expression  in  colon  from  patients  with   ulcerative  colitis.  J  Gastroenterol  Hepatol  2007;  22(7):1019-­‐1023.  
    •   91.     Domenighetti  G,  Suter  PM,  Schaller  MD,  Ritz  R,  Perret  C.  Treatment  with  N-­‐ acetylcysteine  during  acute  respiratory  distress  syndrome:  a  randomized,   double-­‐blind,  placebo-­‐controlled  clinical  study.  J  Crit  Care  1997;  12(4):177-­‐182.  
    •   156.     Bucher  HC,  Guyatt  GH,  Cook  DJ,  Holbrook  A,  McAlister  FA,  for  the  Evidence-­‐ Based  Medicine  Working  Group.  Users'  Guides  to  the  Medical  Literature.  JAMA:   The  Journal  of  the  American  Medical  Association  1999;  282(8):771-­‐778.  
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    The results below are discovered through our pilot algorithms. Let us know how we are doing!

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