PCTH 325Mechanisms and consequences of airway remodeling in Asthma

Why is asthma a hot topic?Asthma is still common, increasing, and expensive & inflammation/remodeling starts in early childhood Testable hypothesis: that CD4+ Th2 lymphocytes associated with asthma (Th1/Th2 hypothesis) & Hygiene Hypothesis; role of eosinophils, epithelial damage etc.There is no cure. Treatment relieves symptoms.Is a primary focus of pharma because of its chronicity.

CDC Press Release9 million children <18 have been diagnosed with asthma>4 million have had an asthma attack in the past 12 months12% of children <18 have been diagnosed with asthmaBoys 14%, Girls 10%Poor families 16%, Not poor families 11%www.cdc.gov/nchs released 3/2004

The Morbidity of AsthmaMost common illness in childrenMost common cause - off school5-10% of asthma is occupational Impacts on everyday lifesport, work, school & socialPermanent lung damage - a realityMedication costs - always in top 5

People with a genetic predisposition to asthmaInappropriate immune response (Th2 cell cytokines)Airways inflammation (Th2 cells, mast cells, eosinophils)Asthma symptoms (wheeze, cough, chest tightness)AllergensBronchoconstricting stimuli (allergens, histamine, irritants,etc.)Genetic and environmental influences in asthmaInducersTriggers

Asthma EtiologyAsthma is a complex traitHeritable and environmental factors contribute to its pathogenesisMultiple interacting genesAt least 20 distinct chromosomal regions with linkage to asthma and asthma related traits have been identified Chromosome 5q – cytokine gene clusterADAM33 – bronchial hyperresponsivenessPHF11 – total IgE

Asthma Patient DemographicsUS Population = 277.8 Million (US Census, 3/01)Asthma Patients = 5.6% Prevalence (ALA, 2/01)1. Morbidity & Mortality Weekly Report, 2001.2. Asthma Physician Market Dynamics Study, 2001.3. National Center for Health Statistics, 1986-1999.4. Scott Levin, PDDA, MAT 12/01.Age1Age 18 y 12.1 million 68%Age 0-17 y 5.6 million 32%Severe 18%Moderatepersistent34%Mildpersistent22%Mildintermittent26%17.7 million patients with asthma2.7 m AA7.2%4.2 million Hispanic11.7% 10.8 million Caucasian5.4% prevalencePatients With Asthma1Severity2Race3Gender4Male45%Female55%

The prevalence of asthma continues to increase

Adults with severe asthma continue to show progressive declines in FEV1 , especially if their asthma began in childhood.Duration of AsthmaJenkins HA et al J Allergy Clin Immunol 2002; 109: 3-13Asthma as a Progressive Lung Disease

Its all about timing!

Airway Remodeling; A Featureof Pediatric Asthmatic AirwaysAsthmaticMale11YNormalMale11Y

Etiological Factors – Gene and EnvironmentWills-Karp M, et al. Nature Reviews Immunology; 2001; 1: 69-75

What Causes Asthma? The exact causes of asthma are not known Currently thought to be combination of:Genetics – Atopy = “high levels of the chemical IgE” Mother’s smoking during: pregnancy1st two years of child’s lifeEarly childhood exposure to allergensEarly childhood respiratory infections

What Happens During an Episode of Asthma?The lining of the airways becomes swollenThe airways produce a thick mucusThe muscles around the airways tighten and make airways narrower

Bronchial hyperresponsivenessSpasmogens;Histamine,MethacholineFEV1 = forced expiratoryvolume in 1 second. Theamount air you can forceout in 1 second. A low FEV1 means obstructed airways.

The two phases of asthmaFEV1; forced expiratory volume in 1 second

How many triggers of asthma

House Dust Mite allergensHouse dust mites are arachnids, related to spiders, scorpions etc. live in bedding, carpets etc. feed off human skin scales void faecal pellets (10-50 m) that contain large amounts of digestive enzymes[These faecal pellets are dry and can be readily inhaled] Der P1 is a cysteine proteaseislolated from a common house dust mite, Der P.Dermatophagoides pteronyssinus (Der P)… with faecal pellets containing allergens, such as Der P1

To the asthmatic airways, allergens are foreign invaders. Inhaled allergens can be trapped by mucus, which lines the epithelium, and swept away by the rapidly beating cilia If not, then the allergen meets the next line of defense, tight junctions between the cells of the epithelium.

These tight junctions act as ‘gate-keepers’, controlling outward flow of fluid and the inward flow of macromolecules such as allergens.

Principal types of cell junctionsThree classes of cell junctions:Tight jns- prevent diffusion between lumen and blood in extracellular spaceGap jns- allow small molecules and ions between adj cellsAnchoring jns: adherens jns, spot desmosomes and hemidesmosomes- cell-cell; cell-matrix; and signalingDer p1

Antigen presenting cells Although some other cells act as APCs, the most important APC in lung is the dendritic cell (DC). DCs are starfish-shaped cells that form an extensive network throughout the epithelium. DCs are wildly phagocytic (take up about 4 times their volume in extracellular fluid per hour). Allergen taken up into DCs is chopped into small peptides, which are loaded into a MHC II-peptide, and transported to the surface for display. [ MHC II is like a billboard that displays what peptides are present outside the cell ].

The end result of this process is bronchoconstrictionBefore10 minutes after allergen challengeP Howarth

Thick mucous plugs

Lungs following asthma death - Hyperinflation

So, most commonly used anti-asthma therapies appear to be effective in controlling symptoms and even inflammation.Questions: Why do susceptible asthmatics continue to exhibit airway remodeling over time?Is it due to a lack of efficacy of currently used therapy on facets of airway remodelling?Notice – no “preventers” or “reversers”?

Airway remodeling-Mucus secretion-Edema formation-cellular infiltration-vessel dilatation-muscle contraction Has both reversible (either spontaneously or with drugs) and irreversible componentsReversible components include:

-phenotypic changes in cells: The presence and increased number of (myo)-fibroblasts immediately underneath the basement membrane correlates with the basement membranethickening and airway hyperreactivity. Frequently damaged epithelial cells may undergo metaplasia and in some cases de-differentiate into mucus secreting cells.-angiogenesis: blood vessels have been reported to be increased in size and number in autopsy specimens from patients dying of asthma. This would have implications for tissue edema.IRREVERSIBLE (?) COMPONENTS

IRREVERSIBLE (?) C OMPONENTS-H ypertrophy/hyperplasia Airway smooth muscle: A 20-1 5 0 % increase in the area of of asm has been demonstrated. H owever, whether theincrease is due to hyperplasia (more cells) or hypertrophy (biggercells) is controversial. submucosal glands: Glandular hypertrophy is a wellrecognized component of airway wall thickening. In addition,goblet cell metaplasia is frequently seen.-scar formation or fibrosis: thickening of the sub-epithelial basement membrane is a common occurrence. The patho-physiological significance is unclear, although correlation withmethacholine sensitivity has been reported.

Targets and mechanismsCellular proliferationExtra-cellular matrix increaseCell recruitmentEpithelial damageEarly structural changesBronchoconstrictionOedemaSecretionsCoughAcuteInflammationAirwayRemodelling ChronicInflammationhttp://www.mc.uky.edu/ahec/skyahec/RTAMR.htm

BronchoconstrictionOedemaSecretionsCoughAcuteInflammation

Pharmacologic TherapyReliever Medications:Rapid-acting inhaled β2-agonistsSystemic glucocorticosteroidsAnticholinergicsMethylxanthinesShort-acting oral β2-agonists

What Are Relievers?Rescue medicationsQuick relief of symptomsUsed during acute attacksAction lasts 4-6 hrs

RELIEVERSShort acting 2 agonists Salbutamol Levosalbutamol Anti-cholinergics Ipratropium bromide Xanthines TheophyllineAdrenaline injections

Beta Adrenergic AgentsShort Acting Long actingsalbutamol (albuterol)terbutalineadrenaline (epinephrine)(isoprenaline)Minutes - 4 hoursformoterolsalmeterolLast up to 12 hours

Useful Beta Adrenergic EffectsRelax bronchial smooth muscleInhibit mediator release from mast cells, eosinophils, macrophagesIncrease mucous secretion (submucosal gl)Increase mucociliary transportInhibit bronchial oedemaInhibit cholinergic transmisssionDecrease airway hyperresponsiveness

Beta agonist and xanthines: Mechanisms of ActionBeta2 Agonists:↓ chemical mediator release causing dilatation via ↓ Ca++: Ca++ is reduced when cyclic AMP is elevatedVia ↑ adenylate cyclase activity → ↑ cAMP which reduces Ca++ concentrationTheophylline (less common now):Inhibits phosphodiesterase, which inhibits cAMP, therefore Cyclic AMP is elevated

Salbutamol v MethacholineRelaxation of bronchial smooth muscle mediated through action of Salbutamol on Beta receptors may be used to reverse the bronchial constriction induced by methacholine challenge (muscarinic effect)This is example of functional antagonism

Unwanted Beta Adrenergic EffectsTachycardiaSkeletal muscle tremorHypokalemia (K shift into muscle tissue)Hyperglycaemia (glycogenolysis)Hypoxia (pulmonary vasodilation causing increased ventilation/perfusion mismatch)

Anti-Cholinergic AgentsIpratropium - short-acting with action 30 mins to 4 hoursTiotropium - long-acting to 24+ hoursBoth administered only by inhalationSome additive effect with beta-agonistsPrimarily used for COPD but useful in asthma also

C ell recruitmentEpithelial damageEarly structural changesC hronicInflammation

C ontroller Medications:Inhaled glucocorticosteroidsSystemic glucocorticosteroidsC romones MethylxanthinesLong-acting inhaled β2-agonistsLeukotriene modifiersAnti-IgEPharmacologic Therapy

C ontrollersC orticosteroids Anti-leukotrienesPrednisolone, Betamethasone Montelukast, ZafirlukastBeclomethasone, Budesonide Fluticasone Xanthines Theophylline SRLong acting 2 agonists Mast cell stabilisersBambuterol, Salmeterol Sodium cromoglycateFormoterol C OMBINATIONSSalmeterol/FluticasoneFormoterol/BudesonideSalbutamol/Beclomethasone

Anti-Inflammatory - Controllersused to treat the inflammation that is caused by exposure to inducers . inducers cause both airway inflammation and airway hyperresponsiveness Inducers result in symptoms which may last longer, are delayed and less easily reversible than those caused by triggers.The most common inducers are allergens & respiratory viral infections

Why are long-acting beta-adrenoceptor agonists long-acting? Anderson et al Eur Respir J 1994; 7: 569-578

Anti-leukotriene Drugs

ZileutonXXSingulair

Pizzichini et al, Eur Respir J 1999; 14: 12-18The effect of LT receptor antagonists on sputum eosinophils

Broncho-constriction+++++++++++–Plasmaproteinexudation–++?+/–+–Neuralstimulation++––++––Glandularsecretion–?–+++/–++Cromonesß2-agonistsTheophyllineH1-antihistaminesCyst-LT1-receptorantagonistsAnti-muscarinic agentsComparative effects of drugs acting on acute inflammation

Glucocorticoids (GCS) - Primary anti-inflammatoryTherapy for asthma and related disorders.Transrepressiontransrepression.negative modulation of gene transcription by GCS via non genomic mechanisms.Transrepression is due at least in part to direct, physical interactions between monomeric GR and transcription factors

Laitinen et al Am Rev Resp Dis 1992* budesonide 800µg bd for 3 months300250010050200150BeforeAfter250010050200150300EpitheliumLamina propriaEosinophils per mm2BeforeAfterEffect of inhaled budesonide* on airway eosinophils

So, most commonly used anti-asthma therapies appear to be effective in controlling symptoms and even inflammation.Questions: Why do susceptible asthmatics continue to exhibit airway remodeling over time?Is it due to a lack of efficacy of currently used therapy on facets of airway remodelling?

The current pharmacotherapeutic approaches to asthma have several limitations. There is no known asthma cure and little evidence that prevention is possible in susceptible persons. Patients continue to be at risk of symptoms and exacerbations. Mortality remains a severe problem. Current medications have adverse effects. Novel Therapies

Multiple levels to targetnovel molecular therapiesAntigen presentation2. Th-2 cell stimulation and release of Th-2 cytokinesMast cell activation (IgE)4. Eosinophil recruitment and activation.5. Upregulation of adhesionmolecule expression in bloodvessels and epithelium.6. Activation of resident cellssuch as fibroblasts.

Other therapeutic strategiesTargeting specific elements, thought to be crucial, butat the same time specific, for the inflammatory cascade in asthma.These would include inhibitors/antagonists/antibodies to IL-9IL-5IgEIL-4/ IL-13Transcription factors (NFkB)New understanding of the molecular pathology of asthma has identified several novel therapeutic targets

humanized chimeric monoclonal antibody against high-affinity receptor-binding domain of human IgE. acts by complexing free IgE, preventing its binding to effector cells. Initial human studies -diminished early- and late-phase responses to allergen, diminished sputum eosinophilia, decreased airway hyperresponsiveness, and decreased levels of the relevant receptor (Fc-epsilon-R1) in circulating basophils. high-dose intravenous injections were administered on days 0 and 4 (half-dose) and day 7 (full-dose), and then once every two weeks for 20 weeksAnti-IgE: Omalizumab

Anti-IgE: OmalizumabA humanized monoclonal antibody given SQ - binds IgECan reduce asthma exacerbations & decrease use of ICS in patients with allergic asthmaCost: $10,000 - $12,000 per yearRemote risk of anaphylaxis within 2h of injection (3 patients)Malignant neoplasms reported in 0.4% of those exposed to drug & 0.1% of controls

B ronchodilatorsNon-Steroidal Anti-inflamatory MedicationSteroidal C ompoundsInhaled beta-2 adrenergicssalbutamol / Ventolinfenoterol / Berpotecprocaterol / Pro-Airquick-relief; take as you need2-4 /day: if more required, more medical therapy requiredSome are ‘slow’ actingSide Effects:tremors, palpatations (all rare)Theophylline Bronchodilators(Uniphyl, Theodur)pill form: used less oftenIpratropium Bromide(Atrovent)used in conjunction with beta-2 adrenergic agent (ventolin)C romoglycate / chromolyn intalpreventative: mild asthma, childreninhaled nedocrimil sodium (Tilade)Oral Ketotifen (Zaditen)Inhaled Steroidsbeclovent, budesonidereduces and prevents inflammationimproves sleep/ exercise performanceSide Effects: weight gain, burning sensation (all rare and mild)Oral Steriodsprednisonefor poorly managed asthma and emergency situationsnow prescribed more oftensafer than once thought

Cellular proliferationExtra-cellular matrix increaseAirwayRemodelling What about Answer: None

Rhen T and Cidlowski J. N Engl J Med 2005;353:1711-1723Three General Mechanisms of Action of G C S and the G C Receptor in the Inhibition of InflammationHowever, The majoritory of cellular effects mediated by growth factors and extracellular matrix proteins associated with remodeling are not blunted by GCS.

Eder W et al. N Engl J Med 2006;355:2226-2235Effect of the Interaction between Various Types of Exposures and Various Genetic Backgrounds in a Range of Racial and Ethnic Groups on the Prevalence of Asthma through Pathways Involving Atopy, Airway Inflammation, Airway Hyperresponsiveness (AHR), or Other, Unknown Factors