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ASTHMA AND COPD

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					BRONCHIAL ASTHMA

  Dr. Romulo T. Uy
 Pulmonary Medicine
HISTORICAL BACKGROUND OF
         ASTHMA

   Referred to by Hippocrates (400 B.C.)
   Described in detail in second century
    – “facial anxiety, rapid, noisy respirations, fear of
      suffocation, and scanty foamy expectoration”
   From the Greek meaning “panting”
           OVERVIEW - ASTHMA

   Chronic inflammatory disease of the airways
    (mast cells, lymphocytes, eosinophils, epith
    cells) leading to:
               HYPERRESPONSIVENESS
              Worsening on exposure to various stimuli



                         OBSTRUCTION
                   Variable and usually reversible



                           SYMPTOMS
       Recurrent wheezing, shortness of breath, chest tightness,
                            and/or cough
      PREVALENCE OF ASTHMA

   A very common disease worldwide &
    increasing trend
   6% in USA
   Occurs predominantly in early life
   Philippines – 12% in children (13-14 yrs
    old); 17-22% older age group
   Male-female ratio <10 yrs 2:1; equal 30 yrs
   Highest prevalence in Australia, UK & New
    Zealand
    ASTHMA PREVALENCE IN ASIA
    ISAAC Study 1998
Country        Children        Adolescents
              (6-7 yrs old)   (13-14 yrs old)
CHINA                -            4.2%
HONGKONG          9.7%           12.4%
MALAYSIA          6.1%            9.6%
PHILIPPINES     11.3%            12.3%
SINGAPORE       15.7%              9.7%
KOREA           13.3%              7.7%
TAIWAN            9.6%             5.2%
Asthma is a variable disease


 Symptoms and use of
 reliever medication

         Exacerbation                       Exacerbation
                         Oral course of
                         corticosteroids

                          Effect of inhaled
                        corticosteroids during
                        periods of worsening




                                                           Time
Cellular effects of the
mono-components
Virus?
Adenosine
Exercise
Fog

                      Bronchoconstriction           Sensory nerve
            Mast cell                   Plasma leak
Antigen                                             activation
            Macrophage    Eosinophil
                                           Airway hyper-
                                           responsivene
                                           ss
  Virus?
                              T-
                              lymphocyte
Asthma - an inflammatory disease
  Normal                      Asthma
Laitinen LA et al, J Allergy Clin Immunol 1992
PATHOPHYSIOLOGY


                  Normal airway




              Airway during
               acute attack
                          REDUCTION IN AIRWAY
                                 DIAMETER
                         smooth mm contraction,
                         vascular congestion,
                         edema of bronchial wall, &
                         thick tenacious secretions.




                      INCREASE IN AIRWAY RESISTANCE
                      DECREASE IN FEV1 & FLOW RATES
                      HYPERINFLATION OF LUNGS
                         & THORAX
                      INCREASED WORK OF BREATHING
                      ALTERATIONS IN RESPIRATORY
                         MUSCLE FUNCTION
Post-mortem airways   V/Q MISMATCH
                      HYPOXEMIA, HYPERCAPNIA
                      RESPIRATORY ALKALOSIS
         AIRWAY REMODELING

   Increase in airway hyperresponsiveness
   Non-reversibility of airway obstruction &
    residual obstruction after bronchodilators
   Accelerated decline in FEV1
    STIMULI THAT INCITE ASTHMA
   Allergens
    – Activated by interaction of Ag with mast cell-bound IgE
      molecules  dendritic cells in airway epithelium 
      migrate to local lymph nodes  THo + IL4  TH2
    – Usually airborne
    – Usually seasonal and seen in children and young adults
    – Nonseasonal – animal danders, dust mites, molds
    – Early response occurs immediately
    – Late response – 6-10 hrs
   Pharmacologic
    – Aspirin and NSAID’s, beta-blockers, coloring agents,
      sulfiting agents
   Environmental
    – Air pollutants – ozone, nitrogen dioxide, sulfur dioxide
    STIMULI THAT INCITE ASTHMA
   Occupational
    – High mol wt compds – wood and vegetable dust, drugs
      (antibiotics, cimetidine), animal & insect dusts
    – Low mol wt – metal salts, industrial chemicals & plastics
   Infectious –
    – respiratory viruses > bacteria
   Exercise-induced – does not evoke any long term
    sequelae, nor does it increase airway reactivity
    – Severe attacks in increase ventilatory effort & cold air
   Emotional – bronchoconstriction thru vagal
    efferents or endorphins??
          CLINICAL FEATURES

   Triad – cough, dyspnea & wheezing
   Attacks – prolonged expiration, tachypnea,
    tachycardia, mild increase in SBP;
   Severe obstruction – use of accessory
    muscles and paradoxical pulse
   Cyanosis – late
         CLINICAL FEATURES

   Curschmann’s spirals  eosinophils &
    Charcot-Leyden crystals
   In severe attacks – wheezing absent,
    ineffective cough, gasping
   Pneumothorax or pneumomediastinum
        STATUS ASTHMATICUS

   Severe asthmatic attacks not
    responsive to drugs and associated
    with signs and symptoms of potential
    acute respiratory failure
        DIAGNOSIS OF ASTHMA

   History – triad, temporal waxing and waning
    of sx, a positive family history, provoked by
    exogenous factors, & improvement of
    symptoms with bronchodilators
   PE – maybe normal, wheezing is non-
    specific for asthma & doesn’t correlate with
    severity
   Objective measurement
               DIAGNOSIS
         Objective Measurements

   Spirometry - > 12% (200 ml
    in adults) improvement in
    FEV1 postbronchodilator
   Serial measures of peak expiratory flow rates (PEFR) – >20%
    change post BD over time
   Pre and post BD PEFR - >15% change after using inhaled BD
    in clinic
   Methacholine challenge – provocative doses of methacholine
    resulting in a 20% fall in FEV1 from the baseline (PC20) < 8
    mg/ml
                       SPIROMETRY
                          FEV1 FVC FEV1/FVC
    0         Normal 4.150 5.200       80 %
        Obstructive  2.350 3.900       60 %
    1
    2
Liter




            FEV1
    3
                               obstructive
    4   FEV1                         FVC
                 Normal
    5                   FVC
        1    2     3   4   5     6 Seconds
PEAK EXPIRATORY FLOW RATE

   Greatest flow velocity produced during a forced
    expiration from fully inflated lungs
   Advantages:
    –   Simple and reproducible
    –   Portable
    –   Quantitative
    –   Correlates with spirometry (FEV1)
   Disadvantages:
    – Effort dependent
    – Lung volumes are not measured
    – Absence of printed record
               DIAGNOSIS
         Objective Measurements
   Spirometry - > 12% (200 ml in adults) improvement in FEV1
    postbronchodilator

   Serial measures of peak expiratory
    flow rates (PEFR) – >20% change
    post BD over time
   Pre and post BD PEFR - >15%
    change after using inhaled BD in clinic
   Methacholine challenge – provocative doses of methacholine
    resulting in a 20% fall in FEV1 from the baseline (PC20) < 8
    mg/ml
Monitor Peak Expiratory
         Flow




    Keep an
  Asthma diary
              DIAGNOSIS
        Objective Measurements
   Spirometry - > 12% (200 ml in adults)
    improvement in FEV1 postbronchodilator
   Serial measures of peak expiratory flow rates
    (PEFR) – >20% change post BD over time
   Pre and post BD PEFR - >15% change after using
    inhaled BD in clinic
   Methacholine challenge – provocative
    doses of methacholine resulting in a
    20% fall in FEV1 from the baseline
    (PC20) < 8 mg/ml
  TABLE 1.3. Severity-Based Classification Of Chronic
                       Asthma


                       Intermittent                     Persistent

                                           Mild-Moderate          Severe**

Daytime sympts        Monthly             Weekly                Daily
Nocturnal             < monthly           Monthly to weekly     Nightly
awakening
Rescue b2 use         < weekly            Weekly to daily     Several times a
                                                              day
PEF or FEV1*          > 80% predicted     60-80% predicted    < 60% predicted
Treatment needed to   Occasional prn b2   Regular ICS +       Combination ICS +
control asthma        only                LABA combination    LABA + OCS
GOALS OF TREATMENT

   Maintain adequate oxygenation
   Relieve airflow obstruction
   Reduce airway inflammation
   Prevent future relapses
    – Elimination of causative agents from the
      environment of an allergic individual
              THERAPY

   QUICK-RELIEF MEDICATIONS
   LONG-TERM CONTROL MEDICATIONS
Asthma is a chronic inflammatory lung disease


                       Smooth          Airway
                       muscle      inflammation/
  B2 Agonists        dysfunction    remodelling                      ICS




        • Bronchoconstriction       • Inflammatory cell
       • Bronchial hyper-            infiltration/activation      
           reactivity                • Mucosal oedema               
        • Hyperplasia               • Cellular proliferation       
        • Inflammatory              • Epithelial damage            
           mediator release          • Basement membrane            
                                       thickening


                      Symptoms\exacerbations
                                        Johnson M. Current Allergy Clin Immunol 2002
    What is the first line of therapy in
       acute asthmatic attack?

   Beta 2 agonists
   Epinephrine
   Anticholinergic agents
   Theophylline
   Steroids
BRONCHODILATORS

   QUICK – RELIEF MEDICATIONS – drugs
    that inhibit smooth muscle contraction
    – Beta-agonists
    – Anticholinergics
    – Methylxanthines
B2 AGONISTS – Short-acting beta2
agonists (SABA)

   First line therapy in the ER
   Interact with beta2 receptors of cells 
    increase cAMP  bronchodilatation
   Onset of action is rapid (5 min)
   Duration of action – 6 hrs
   Side effects are usually well tolerated
             BETA2 AGONISTS

   Catecholamines - Short-acting beta 2
    agonists (SABA) – terbutaline, salbutamol
   Resorcinols - fenoterol
   Saligenins – albuterol
   Major side effects – tremors
   Active via all routes (oral, IV or inhalation)
   Lasts 4-6 hours
   Inhalation route is preferred – maximal
    bronchodilatation with fewer side effects
BETA2 AGONISTS

   Catecholamines - Short-acting beta 2
    agonists (SABA) – terbutaline, salbutamol
   4-6 hours
   Long-acting beta 2 agonists (LABA) lasting
    for 12 hours - Salmeterol & Formoterol
   Combination of LABA + inhaled steroids
    – Symbicort (formoterol & budesonide)
    – Seretide (sslmeterol & fluticasone)
     B2 AGONISTS – Areas of debate

   Which route? Inhaled vs intravenous
   Which device? pMDI’s, wet nebulizers, DPI’s
   Which beta 2 agonist? Short-acting vs long-
    acting beta2 agonists
   What dose and intervals of administration?
    B2 AGONISTS – Inhaled vs
    Intravenous
   Meta-analysis 584 patients in 15 trials
   Inhaled route recommended than IV –
    faster onset, fewer adverse effects and
    more effective than IV (Level I)
   No clinical benefit of IV beta agonist
    either as adjunct to or replacement of
    inhaled bronchodilator (Level I)
                           Travers, et. al., Chest 2002; 122
                           Cochrane Database 2002
    B2 AGONISTS – Which inhaler device?


   There is no clear evidence that any one
    device is superior over the other.
   Although lung deposition studies show
    superiority of some inhaler devices, it is
    not clear whether this translates to better
    efficacy. (Level II)


                              PCCP Asthma Consensus 2004
B2 AGONISTS – Which inhaler device?


   pMDI’s vs nebulizers
     – 3 RCT’s compared NEB vs pMDI + spacer in adults
       with mod to severe attacks
     – Equally efficacious in improving FEV1, PEFR &
       symptoms (Level I)
     – NEB grp – more headaches, palpitations, tremors
     – Use nebulizers if patient unable to coordinate

                              Colacone, Chest 1993
                              Mandelberg, Chest 1997
                              Rodrigo, Am J Emer Med 1998
B2 AGONISTS – Which inhaler
         device?
                 pMDI’s + large-volume
                  spacers  more rapid
                  bronchodilation (1-2 min
                  compared to 15-20 min
                  with nebulizers), fewer
                  side effects
                  (Level I)




                     Rodrigo, Chest 2004
INHALER DEVICES

           MDI’s compared to
            other handheld inhaler
            devices to deliver
            beta2 agonists in non-
            acute asthma – no
            difference between
            devices (Level I)




            Cochrane Library 2002
B2 AGONISTS – What dose/interval?

   Doses of administration
    – Should be individualized using objective
      measures of obstruction
    – Studies support use of high & repeated
      doses
    – Induce maximal stimulation of B2
      receptors without causing side effects
                             Rodrigo et al., Chest 2004
            BETA 2 AGONISTS

               INHALER            NEBULE


Ventolin       100mcg/dose        0.5 mg/2.5 ml



Berodual       Feno 50 mcg        Feno – 1.25 mg
               IB – 20 mcg        IB – 0.5 mg

Bricanyl       Turbuhaler – 500   2.5 mg/ml
               mcg


Combivent      IB – 20 mcg        IB – 500 mcg
               Salb – 120 mcg     Salb – 2.5 mg
            USE OF INHALERS

   Patient instruction on proper use of device is
    important
   All clinicians should understand the correct
    use of aerosol devices
If patient does not respond to beta2
  agonist, what is your next drug of
               choice?
   Theophylline
   Anticholinergic drugs
   Another beta 2 agonist
   Singulair
ANTICHOLINERGIC DRUGS

   Cholinergic-induced bronchoconstriction
    involves the large airways; B2 agonists relax
    small airways
   Muscarinic receptors:
     – M1 – within parasympathetic ganglia
     – M2 – postganglionic sympathetic nerves/
       act as negative feedback
     – M3 – airway smooth muscles
Nonselective anticholinergic agents – inhibits M1, M2
      & M3. Ex: atropine, ipratropium bromide

Selective anticholinergic drugs – inhibit M1 & M3
        Ex: tiotropium bromide
      ANTICHOLINERGIC DRUGS
        Ipratropium Bromide

   Use of ipratropium bromide (IB) as the
    initial bronchodilator in adult asthmatics –
    inferior to beta2 agonists
   Addition of IB to beta2 agonists provided
    additional benefits to asthmatics (Level I)
   IB is a quaternary ammonium compd
    currently the only inhaled anticholinergic
    bronchodilator licensed in USA
   Slow onset of action – 30 minutes
      ANTICHOLINERGIC DRUGS
         Ipratropium Bromide

   Insoluble in lipids/less than 1% absorbed
    systemically
    – Does not exert unwanted side effects/stays in
      airways
    – 10X recommended dose – no side effects
   Slow onset of action – 30 minutes but
    longer duration of action (6 hrs)
           METHYXANTHINES -
              Theophylline
   Mild to moderate bronchodilatation
   Mechanism of action – uncertain
   Convenient long-acting oral dosage forms & IV
    form
   Therapeutic plasma concentration 5-15 ug/ml
   Side effects – GIT symptoms (nausea, vomiting)
    most common & CNS (stimulation/seizures) &
    cardiac (tachycardia/arrhythmia)
                  THEOPHYLLINE

   Decreased metabolism (         blood levels)
    –   Liver diseases
    –   Congestive heart failure
    –   Cimetidine
    –   Quinolone
    –   Febrile illness
    –   Old age
   Increased metabolism (         blood levels)
    – Cigarette smoking
    – Young age
    – Phenytoin
                 THEOPHYLLINE

   IV aminophylline should not be used as a first
    line of treatment in AAA (Level I)
   IV aminophyllined showed no clinical benefit
    compared to beta2 agonists
   Addition to beta-2 agonists  no significant
    benefits but increase side effects (tremors,
    nausea, anxiety and tachyarrhythmias)
   As an option for patients where all other
    modalities have failed but should be used
    cautiously
                                    Cochrane Review 2002
                     THERAPY

   LONG-TERM CONTROL MEDICATIONS –
    agents that prevent/reverse inflammation
    –   Glucocorticoids
    –   Long-acting beta 2 agonists (LABA)
    –   Mast-cell stabilizing agents
    –   Leukotriene modifiers
    –   methylxanthines
Asthma is a chronic inflammatory lung disease


                        Smooth          Airway
                        muscle      inflammation/
   B2 Agonists        dysfunction    remodelling                      ICS




         • Bronchoconstriction       • Inflammatory cell
        • Bronchial hyper-            infiltration/activation      
            reactivity                • Mucosal oedema               
         • Hyperplasia               • Cellular proliferation       
         • Inflammatory              • Epithelial damage            
            mediator release          • Basement membrane            
                                        thickening


                       Symptoms\exacerbations
                                         Johnson M. Current Allergy Clin Immunol 2002
            GLUCOCORTICOIDS

   Most potent & most effective anti-inflammatory
    agent available
   Mechanism of action:
    – Inhibit synthesis of most cytokines
    – Reduce vascular permeability
    – Inhibit mediator synthesis and release
   Available – IV, oral or inhaled
   Effects not immediate - >6 hrs
   Dose should be tapered – ½ the dose every 3-5
    days over 10-12 days
   Prednisone, methyprednisolone, prednisolone
            CORTICOSTEROIDS

   Reduction of symptoms
   Diminish airway hyperresponsiveness
   Prevention of exacerbations
   Possibly prevention of airway remodelling
                      (Level 1)
CORTICOSTEROIDS

   Do corticosteroids improve pulmonary
    function tests within 24 hours?
   Does parenteral (IV or IM) route
    improve outcome compared to oral or
    inhaled administration?
   What is the relative efficacy of the
    different doses – high dose vs low
    dose?
What is the lag time for IV steroids
          to take effect?

   1   hr
   2   hrs
   4   hrs
   6   hrs
     How Soon Do Steroids Work?
                                                          140
                                                          120         Hydrocortisone




                                        FEV1 Change (%)
   20 asthmatics, 31–32 yr                               100         Placebo        *
   Hydrocortisone 2 mg/kg                                 80
    bolus, then 0.5 mg/kg/hr                               60                      *
   × 24 hr vs placebo                                     40
   Results                                                20
    – Initial 6 hr lag, followed by                         0
      progressive improvement
                                                          –20
    – No  in PaO2 response
                                                                 –5     0     5 10 15 20
                                                                            Time (hr)
    Fanta CH et al. Am J Med. 1983;74:845                  *P<0.025 vs placebo
     META-ANALYSIS: RESULTS

   Pulmonary function 1st 24 hours
     – Patients required at least 6-24 hours to show
       moderate improvement in lung function
     – Only high doses of inhaled corticosteroids
       significantly improved lung function compared
       to placebo (ES=0.56 CI 0.15-0.97) within 3
       hours



                             Rodrigo et al., Chest 1999: 116
    EFFECTS OF CORTICOSTEROID
    IN ACUTE ASTHMA
VARIABLE     SYSTEMIC              INHALED STEROIDS
             STEROIDS
Effects      Anti-inflammatory     Topical


Time delay   > 6 hours             < 3 hours


Mechanism    Induce                Up-regulate postsynap.
             transcriptional       adrenergic receptors  airway
             effects  synthesis   mucosa vasoconstrict  airway
             of new proteins       mucosa bld flow mucosal
                                   decongestion
CORTICOSTEROIDS:
Oral vs Parenteral

   4 studies, RCT, 157 patients
   Compared MTP IV and po, IV
    hydrocortisone and Prednisone po
   Conclusion: oral route provided similar
    beneficial effects on pulmonary
    function when compared to IV
    (Level 1)
                      Rodrigo et al., Chest 1999: 116
    How much IV hydrocortisone will
              you give?

   50 mg IV q 6 hrs
   100 mg IV q 6 hrs
   250 mg IV q 6 hrs
   500 mg IV q 6 hrs
CORTICOSTEROIDS: Meta-analysis
High vs Low Dose

   5 RCT’s:
         Low dose – 50 mg hydrocort q 6h or 15 mg
          MTP q 6h
         Medium dose – 100 mg q 6h or 40 mg MTP q
          6h
         High dose – 500 mg q 6h or 125 mg MTP q
          6h
   Pooled results showed a nonsignificant favorable
    trend toward improve outcome with medium and
    high doses (Level I)


                              Rodrigo et al., Chest 1999
    INHALED CORTICOSTEROIDS

   Potent local/topical anti-inflammatory with
    minimal systemic toxicity
   Control inflammation
   Prevention of symptoms
   Reduce need for oral steroids
   Prevent hospitalization
    INHALED CORTICOSTEROIDS

   Agents – budesonide, fluticasone,
    beclomethasone, triamcinolone, flunisolide
   Oral steroid sparing effects
   Combination with long acting beta2 agonists
    (LABA) – synergistic
   Seretide – salmeterol & fluticasone
   Symbicort – formoterol & budesonide
    INHALED CORTICOSTEROIDS
   Local side effects:
     – Oral thrush
     – Cough/hoarseness
     – Can be reduced with use of spacer or rinsing
       mouth
   Systemic side effects
     – Infrequent at currently recommended doses
     – Mild adrenal suppression possible with higher
       doses
     – Cataract formation, decreased growth in
       children, purpura, interference with bone
       metabolism
       MAST CELL STABILIZING
             AGENTS
   Cromolyn sodium and nedocromil sodium
   Inhibit degranulation of mast cells
   Nonsteroidal
   Effectively prophylactically inhibit both early
    and late phase reactions
   4-6 weeks trial therapy
   Side effects of cromolyn – cough;
    nedocromil – unpleasant taste,
    nausea/vomiting
             LEUKOTRIENES

   Cysteinyl leukotrienes (LTC4, LTD4, LTE4)
    induce airway obstruction, bronchovascular
    leak, mucous gland secretion, proliferation
    of smooth muscles & granulocyte infiltration
   One of potent molecules  airway
    obstruction
   Produced by eosinophils, mast cells &
    neutrophils
      LEUKOTRIENE INHIBITORS

   5 lipo-oxygenase (5-LO) inhibitor – Zileuton
   Inhibitors of LTD4 at receptor – Montelukast
    (Singulair) and Zafirlukast (Accolate)
   Modest brochodilation, effective in exercise-
    induced asthma (EIA) and nocturnal
    symptoms
   Effective in aspirin-induced asthma
   Limited effectiveness against allergens
   Inhaled CS (ICS) superior to leukotriene
    inhibitors; add-on to ICS improved lung
    function
      LEUKOTRIENE INHIBITORS

   Hepatic enzymes elevate but reversed with drug
    withdrawal
   Montelukast – lesser elevation of liver enzymes
   Rare complication – Churg Strauss syndrome (CSS)
    – systemic vasculitis, peripheral eosinophilia,
    pulmonary infiltrates, & myocarditis
   CSS not direct result of leukotriene inhibitors but
    due to unmasking of pre-existing CSS as a result of
    steroid withdrawal
    Severity-Based Classification Of Chronic Asthma


                       Intermittent                     Persistent

                                           Mild-Moderate          Severe**

Daytime sympts        Monthly             Weekly                Daily
Nocturnal             < monthly           Monthly to weekly     Nightly
awakening
Rescue b2 use         < weekly            Weekly to daily     Several times a
                                                              day
PEF or FEV1*          > 80% predicted     60-80% predicted    < 60% predicted
Treatment needed to   Occasional prn b2   Regular ICS +       Combination ICS +
control asthma        only                LABA combination    LABA + OCS
        Chronic Treatment based on Severity*
               Daily             Alternative         Reliever
               controller        controller          medications
               medications
Intermittent   None necessary                        SABA prn


Mid-           ICS + LABA as     ICS high dose       SABA prn
               single inhaler    or ICS regular
Moderate       combination       dose + any of
Persistent                       the following:
                                      -SR
                                      -Theophyl
                                       line
                                      -Anti-LT
                                      -Oral SR b2-
                                      agonist
Severe         Oral steroids +                       SABA prn
               ICS + LABA +
Persistent     any of the
               above drugs
        GOALS OF TREATMENT
          GINA GUIDELINES
   Minimally (ideally no) chronic symptoms including
    nocturnal symptoms
   Minimal (infrequent) exacerbations
   No ED visits
   Minimal (ideally no) use of prn beta agonists
   No limitations of activities, including exercise
   PEFR circadian variations <20%
   Near normal PEFR
   Minimal (or no) side effects from medications
               CONCLUSION

   Asthmatic – chronic inflammatory disease of
    the airways  airway obstruction &
    hyperresponsiveness
   The mainstay of treatment – LABA +
    INHALED CORTICOSTEROIDS
   In AAA, use SABA initially; may add
    anticholinergic drugs
               CONCLUSION

   Quick relief medications - SABA & LABA
   Controller medications – inhaled steroids
    mainly; for attacks, oral route is effective;
    low dose IV steroid.
   Proper use of inhalers/ avoid triggers
   Ensure proper follow-up care after patients
    are discharged from the ER to prevent
    relapse
Neutrophils
     INFLAMMATORY MEDIATORS

                         STIMULI



                                CYTOKINES          GROWTH
                 MEDIATORS
  MEDIATORS                    (GMCSF, IL-8       FACTORS
                 (NO, PGE2,
(ENDOTHELIN I)                   RANTES,         (EGF, IGF-1,
                  15-HETE)
                                 EOTAXIN            PDGF)




BRONCHOCONSTRICTION           INFLAMMATION

                                              FIBROSIS
             VASODILATATION                   SMOOTH MUSCLE
                                                HYPERPLASIA

				
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posted:10/10/2011
language:English
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