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Beta-adrenergic agonist stimulat by pengxiang

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									The latest developments in research
              in ARDS:
 Implications for novel drug therapy
              Danny McAuley

        Royal Victoria Hospital and
      The Queen’s University of Belfast

      Intensive Care Society of Ireland
                 June 2007
   Developments in ALI/ARDS:
    Emerging drug treatment
• In vivo models of ALI
• Phase 2/3 clinical studies
   – Beta agonists
   – Statins
   – APC
• Novel therapeutic targets
              Pathogenesis of acute lung injury
                     LPS

   Vessel
                                                          Coagulation
   lumen
                              Cell activation     Gap      Proteases
                                and injury

Endothelium
 Epithelium



    Alveoli
                     Toxins



                                                    Alveolar
                                                    oedema
                       Scanning EM
                                                Respiratory failure
Regulation of lung endothelial cell barrier function
  Barrier disruption                                                           Barrier protection

       Thrombin

                                         Occludin


                                                    ZO-1
               Rho                                          Cortactin             Rac

       Actin stress fibers                 Ca2+                      P60src
                                                           MLCK
                                                       a-catenin
                                                      catenin b/g        Adherens
MLCK                             MLCK                                     junction
                                         Cadherin
                      MLC
          Myosin   phosphatase
                           X                                                              Focal
                            Rho Kinase                                PAX TalinVinculin   adhesion
                                                                    GIT1 FAK              assembly/
                                                                                          disassembly
                        Integrin                                       Integrin
                   ba                                                             ab
          Actin/Myosin contraction                                  Cellular adhesion

                     Barrier                                   Barrier integrity
                   dysfunction               Adapted from Jacobson et al. AJRCMB 2004;30:662
LPS inhalation as a model of lung injury


                       BAL           Plasma

                6 hr         24 hr




   LPS inhalation
Neutrophil activity upregulated in BAL following
           low dose LPS inhalation




    Saline
    LPS
                           Maris N et al. AJRCCM 2005;172:878
Similar qualitative cytokine overexpression
between LPS-induced response and ARDS




           LPS-induced   ARDS
            response
 Similar qualitative MAPK overexpression
between LPS-induced response and ARDS

  ERK2
  JNK2

                                  p38α
  p38δ
  RSK1
  GSK-3α/β




             LPS-induced   ARDS
              response
      One lung ventilation as a model of
                 lung injury

Overdistension                         Ischaemia-
                                       reperfusion
Hyperperfusion
                                       Atelectotrauma
Hyperoxia
                                       Surgical trauma
                                       (contusion &
                                       lymphatic
                                       disruption)




 Local and systemic release of inflammatory mediators
Lung injury after oesophagectomy


  40
  35
  30
                                  Ascot 2003
  25                              Schilling 1998
  20                              Duprat 1987
  15                              NCEPOD 1997
                                  Tandon 2000
  10
                                  Millikan 1995
   5
   0
       Incidence of lung injury
         Pulmonary inflammation associated
             with one lung ventilation
                                                                                *
                                                            3




                          Expiratory flow                   2




                                               H2O 2 (M)
                          to ventilator
Cooling tube and
                                                            1
insulating jacket
                          RTube, Respiratory
                          Research Inc                      0
                                                                Pre Lobectomy       Post Lobectomy


Connection to patient     One-way valve                                         *
via endo-tracheal tube                                      7



                                                            6




                                                    pH
                         Inspiratory flow
                                                            5
                         from ventilator

                                                            4
                                                                Pre Lobectomy       Post Lobectomy



                                                                Moloney et al. 2004 AJRCCM 169:64
        Salmeterol attenuates acid-induced
            experimental lung injury
              600

              500
Excess lung   400
 water (μl)
              300
                                                        *
              200
              100

                0
                    2 hours                    4 hours

                          Saline   Salmeterol (10-6M)

                                      McAuley et al. CCM 2004;32:1470
         IV salbutamol reduced extravascular lung
                          water
                 20



                                                                      Salbutamol
                 15
EVLWI ml kg -1




                                                                      Placebo

                 10



                                                                  P=0.04
                  5
                  0
                      0   1   2   3   4   5   6     7          days



                                                  Perkins et al. AJRCCM 2006;173: 281
     Salbutamol did not reduce BAL neutrophil
  adhesion molecule / activation marker expression
            80


            70


            60


            50
    Median                                               ARDS d0
Fluorescence 40                                          Salbutamol d4
   Intensity                                             Placebo d4
            30


            20


            10


             0
                  Cd11b   CD18   CD49    CD64
                                        Perkins et al. Thorax 2007;62:36
     IV salbutamol reduced alveolar-capillary permeability
             measured by IgG : total protein ratio
                             0.12   P=0.09   P=0.8                    P=0.021

                              0.1
Protein Permeability index
    (Ig G : Tot protein)




                             0.08


                             0.06


                             0.04


                             0.02


                               0
                                      0       1                       4
                                             Day     Placebo          Salbutamol

                                                     Perkins et al. Thorax 2005;60:S16
Pleiotropic effects of statins
Simvastatin reduces thrombin-induced
          endothelial injury




                        Jacobson et al. AJRCMB 2004;30:662
Statins modulate mechanisms important in
      ventilator associated lung injury
          Cell membrane                                                Nucleus



      ?                                                                          IL-8 mRNA
               cRaf   MEK1     ERK1/2    p90 RSK                cFos




                  Mitochondrial ROS                                    Nucleus



                               IKK        IκB
      ?                                                                          IL-8 mRNA
                                                      p65 p50
                 GSH/GSSG               p65 p50        NFkB
                    Trx

          Cell membrane




                                                  Adapted from Pinhu et al, AJRCCM 2004;169:A707
  Simvastatin reduces IL-8 production from
endothelial cells exposed to mechanical strain
Simvastatin attenuates LPS-induced
     experimental lung injury




                     Jacobson et al. AJP Lung 2005;288:L1026
  Pre-treatment with simvastatin attenuates
systemic inflammation following LPS challenge




                           Steiner et al. Circulation 2005; 111:1841
HMGCoA reductase inhibition in prevention and
            treatment of ALI
     (http://www.controlled-trials.com/ISRCTN0127774)
    (http://www.controlled-trials.com/ISRCTN56543987)

• Phase II, double blind, placebo controlled, single
  centre studies
• Study population
   – Patients undergoing oesphagectomy
   – Within 48 hours of onset of ALI/ARDS
• Simvastatin 80mg or placebo
• Endpoints:
   – Extravascular lung water, pulmonary dead
     space, respiratory compliance
   – Biological markers in plasma and BAL or EBC
      Macrovascular obstruction in ARDS:
     detection with pulmonary angiography




• Filling defects in 19 of 40
  patients with ARDS
• Associated with
   – 1) severity of ARDS
   – 2) PA HTN
   – 3) mortality
                                  Green et al ARRD 1982
    Procoagulant activity associated with worse
             outcomes in ALI/ARDS

     Survived
      Died                                            *
 > 14 Vent free days
<= 14 Vent free days                                  *
                                                                       * p < 0.05
  < 2 organ failures
 >= 2 organ failures                                 *
     No shock
      Shock                                           *
                       0   10      20     30    40        50     60      70

     N = 45                     Plasma Protein C (% Control)
                                                Ware et al. AJP Lung 2003;285:L514
Pulmonary fibrinolysis is inhibited in ALI/ARDS

                10000
                                                     * p < .001
Pulmonary oedema 8000
    fluid PAI-1
      (ng/ml)
                 6000

                4000

                2000

                  0
                        Hydrostatic          ALI/ARDS
                          n = 25              N = 26
                                  Prabhakaran et al. AJP Lung 2003;285:L20
Protein C and PAI-1 additive risk factors for
              mortality in ALI

              5.0                     4.1


                                                              3.7
   Excess
   Relative   4.0
   Risk of                                                                        2.9


    Death
              3.0

                                1.8

                                                        1.6
              2.0         1.8
                                                                                                           1.3

                                                  1.5                       1.1


              1.0   1.2                                               1.1
                                                                                                                 1st
                                            1.0
                                                                                                    0.3

                                                                0.7
                                                                                                           2nd
                                                                                              0.2
              0.0                                                                                    3rd         Protein C
                    4th
                                        3rd
                                                                                        0.0
                                                                                               4th               Quartile
                                                                2nd                     1st
                                  PAI-1 Quartile
Mechanisms of action of APC
Intratracheal APC in bleomycin
       induced lung injury




                    Howell et al. Am J Path 2001;159:1383
 Activated protein C in severe sepsis
• Decreased mortality
     Placebo APC
     30.8% 24.7% P < 0.005
• D-dimers and IL-6 decreased
• 1690 patients
   – 75% ventilated
   – 75% pneumonia
   – Increase in resolution of respiratory
     dysfunction
• ? Prevalence ALI/ARDS – uncertain
                                             NEJM 2001;344:699
     Activated Protein C in ALI/ARDS

• NIH sponsored phase II clinical trial of Activated
  Protein C in patients with ALI/ARDS
• Randomized, placebo controlled with stratification
  for sepsis - 72 of the planned 90 patients enrolled
• End points
   – ventilator and organ failure free days
   – pulmonary vascular dysfunction
   – biological markers in plasma and BAL
• Study stopped by Data Monitoring Committee
Role of renin-angiotensin system in
             ALI/ARDS
         Sepsis
       Pneumonia
         SARS
          +
  AI                   AII             A1-7
          ACE                   ACE2


                     AT1R
                      +
                 Inflammation
              Vascular permeability
ACE2 deletion associated with worse lung
                 injury




                            Imai et al. Nature 2005;436:112
Recombinant human ACE2 attenuates acid
         induced murine ALI
  ACE inhibition attenuates pulmonary
inflammation in LPS-induced ALI/ARDS




                       Arndt PG et al. J Immunol 2006;177:7233
AII receptor blockade attenuates pulmonary
  inflammation in LPS-induced ALI/ARDS
  ACE inhibition attenuates pulmonary
inflammation in LPS-induced ALI/ARDS
  ALI/ARDS and stem cell research

• Characterised by extensive damage to the
  alveolar epithelium and endothelial injury
• Survivors of ARDS demonstrate restoration of
  lung architecture and function
   – Could pluripotent stem cells be involved in
     lung repair?
   – Is there any therapeutic potential?
      • Upregulate resident stem cells
      • Administration of stem cells
Evidence for haematopoeitic stem cell
             engraftment




                        Krause DS et al. Cell 2001;105:369
            ARDS and stem cells
• 45 patients with ALI, 10 intubated controls and 7
  healthy volunteers
• Venous blood within 72 hrs and day 7 in patients
• Endothelial progenitor cells (EPCs) higher in ALI
  and intubated controls than healthy controls
• Improved survival in ALI patients correlated with
  higher EPC count
• EPCs mobilised from bone marrow in inflammatory
  lung disease and contribute to repair?

                                Burnham et al. AJRCCM 2005;172:854
      Upregulate resident stem cells

• Variety of cytokines can induce mobilisation of
  resident stem cells
   – G-CSF, SDF-1
• Interfere with interaction between BM stromal and
  stem cells allowing stem cells to enter circulation
• ? cytokine therapy to upregulate EPC in patient
  with ALI
Atorvastatin upregulates endothelial
          progenitor cells
  Endothelial progenitor cells (%)




                                     Treatment with atorvastatin 40mg (days)

                                                             Vasa M et al. Circulation 2001;103:288
   Matrix metalloproteinases (MMPs)
• Family of structurally related enzymes
   - Degrade extracellular matrix proteins (ECM)
      - ECM remodelling
   - Modulation of inflammatory response
      - Cleavage of cytokines/chemokines
        (activation/inactivation)
      - Control of cellular migration
   - Tissue repair

• Inhibited in vivo by the Tissue Inhibitors of
  Metalloproteinases (TIMPs)
Increased MMP-9 and TIMP-1 in ALI




                          Ricou et al. AJRCCM 1996
          MMP inhibition in ALI

• MMP inhibitors decrease lung injury
  – Abdominal sepsis
  – VILI
  – Pancreatitis
  – Cardiopulmonary bypass


• Non-specific
MMP-9 deletion reduces mortality after
          LPS challenge




                           Dubois et al. Eur J Immunol 2002
MMP-9 deletion increases ALI after
       abdominal sepsis




                        Renckens et al. J immunol 2006
             Salbutamol upregulates BAL MMP-9




  MMP9 Std   Placebo   Salbutamol   Normal




92kDa




                 P= 0.03
              (Mann Whitney)
                                             Placebo   Salbutamol
  Salbutamol upregulates BAL MMP-9 activity

                                P=0.01
           350
MMP 9
activity   300
(ng/ml)
           250

           200

           150

           100

           50

             0
                 Day 0          Day 4

                                Placebo   Salbutamol
 BAL fluid from salbutamol treated
patients enhances in-vitro epithelial
            wound repair


                                                  P=0.117
                    70
                                     P=0.07                      P=0.008
                    60
Wound closure (%)




                    50

                    40

                    30

                    20

                    10

                    0
                         All day 0            Salbutamol day 4        Placebo day 4


                                                         Perkins et al. Thorax 2005;60:S16
                Conclusions

Ashbaugh et al. described using “a clinical trial
of a variety of drugs, respirators and fluid
regimes” with limited success

                                   Lancet 1967
                  Conclusions
• Beta agonists
  – Potential benefit in phase II study
  – Phase III multi-centre clinical trials planned
• Potential therapeutic interventions in phase II trials
  – Statins
  – APC?
• Novel potential future treatments
  – Modulation of renin-angiotensin system
  – Stem cell therapy
  – MMP modulation
              Acknowledgements
Queen’s University of        West Midlands Critical
Belfast                      Care Research Centre
• Richard Arnold             • Gavin Perkins
• Thelma Craig               • David Thickett
• Martin Duffy               • Fang Gao
• Gerarde McArdle            Imperial College London
• Scott McKeown              • Mark Griffiths
• Cecilia O’Kane             UC San Francisco
                             • James Frank
Funding                      • Michael Matthay
Peel Medical Research Trust
UK Intensive Care Society
Intensive Care Society of Ireland
Northern Ireland R&D research office

								
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