Airway remodeling in asthma


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Airway remodeling in asthma

Presented by Suparat Sirivimonpan, MD.

May17, 2013

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  • BD, Budesonide; BDP, beclomethasonedipropionate; FP, fluticasone propionate.
  • To achieve the best results
  • Airway remodeling in asthma

    1. 1. Airway remodeling in asthma17/5/2013 Suparat Sirivimonpan, MD
    2. 2. Outline• Introduction• Histopathological features of remodeling• Mechanism of airway remodeling• Clinical relevance of remodeling• Effect of asthma therapy on airway remodeling
    3. 3. IntroductionAsthma• common chronic disorder of the airway• is characterized by the complex interaction of– airway obstruction– bronchial hyperresponsiveness (BHR)– airway inflammation leads to recurrent episodes of wheezing, breathlessness,chest tightness, and coughingManuyakorn W,et al. APJAI 2013;31:3-10
    4. 4. Introduction• The airway inflammation is typically eosinophillic ,elevation of Th2 cytokines• However, TH2 inflammation alone cannot explain allfeatures of asthma• Furthermore, whilst recognized to modify eosinophilicinflammation, inhaled corticosteroid treatment in atopicchildren with recurrent wheezing has been shown tohave no effect on decline in lung function and the naturalhistory of asthma over timeManuyakorn W,et al. APJAI 2013;31:3-10
    5. 5. N Engl J Med 2006;354:1985-97.
    6. 6. Introduction• Airway remodeling is strongly suspected to result in thephysiologic subphenotypes of irreversible or partiallyreversible airflow obstruction and accelerated lungfunction declineCurr Opin Allergy Clin Immunol 2013, 13:203–210J Allergy. 2012;2012:316049InflammationandRemodeling !!
    7. 7. Histopathological features ofremodeling
    8. 8. Airway remodeling• Airway remodeling : structural alterations• wide array of pathophysiologic featuresAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-621. Epithelial changes2. Increased smooth muscle mass3. Increased numbers of activatedfibroblasts/myofibroblasts4. Subepithelial fibrosis5. Vascular changes (angiogenesis)
    9. 9. Epithelial alterations• Morphologic changes to airwayepithelium : key feature• Epithelial alterations :– shedding of the epithelium– loss of ciliated cells– goblet cell hyperplasia– upregulation of growthfactors, cytokines, andchemokinesAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62Epithelialshedding
    10. 10. Epithelial alterations• Barrier function of the airway epithelium in asthmaticpatients is dysfunctional– breakdown in epithelial tight junction integrity– impaired repair after injury• However, epithelial changes are not necessarily specificto asthma– can be observed in patients with various pathologic conditions ofthe lungAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62J Allergy Clin Immunol 2007;120: -
    11. 11. Mucus secretion and goblet cells• Mucus hypersecretion of the mucins MUC5AC andMUC5B by goblet cells• Upregulation of mucin synthesis and development ofgoblet cell hyperplasia- TH2 cytokines (predominantly IL-9 and IL-13)- IL-1β, TNF-- COX-2 and their associated intracellular signalingpathwaysAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    12. 12. Subepithelial layer thickening• increased deposition of extracellular matrix proteins(ECMs)• Subepithelial basement membrane thickening isconfined to the lamina reticularis (reticular basementmembrane - RBM)Manuyakorn W,et al. APJAI 2013;31:3-10The true basement membrane(lamina rara and laminadensa) is not altered in thickness in asthma
    13. 13. Subepithelial layer thickening• consists of a dense layer of fibrillar collagens• composed of collagen I, III and V and fibronectin• Laminin and collagen IV is unaltered in asthmaManuyakorn W,et al. APJAI 2013;31:3-10
    14. 14. Subepithelial layer thickening• Major cells (ECMs production) are fibroblasts,myofibroblasts• In an inflammatory environmentManuyakorn W,et al. APJAI 2013;31:3-10epithelial cells release growth factors (TGF-β)fibroblasts are activated/differentiated into myofibroblastssecrete proinflammatory mediators and ECM proteins“Epithelial mesenchymaltrophic unit (EMTU)”as an integrated component within theairways of relevance to asthma
    15. 15. Airway smooth muscle hyperplasiaand hypertrophy• Smooth muscle layer in the airways is increased by– 50-200% in fatal asthma– 25-55% in non-fatal asthmacompared with normal subjects• These changes could be from smooth muscle cellhyperplasia, hypertrophy or increased ECMs betweencellsManuyakorn W,et al. APJAI 2013;31:3-10Clin Exp Allergy. 2005;35:703-7
    16. 16. Airway smooth muscle hyperplasiaand hypertrophy• ASM cells are biologically active and may participate inthe remodeling process through the synthesis of ECMsin response to growth factors (TGF-β, VEGF, and CTGF)and serum from asthmatic patients• Increased airway smooth muscle mass has beensuggested to be responsible for the pathophysiology ofairway hyperresponsivenessManuyakorn W,et al. APJAI 2013;31:3-10
    17. 17. Angiogenesis• abnormal increase in the number and size ofmicrovessels within bronchial tissue in remodeled airways• mainly below the basal lamina in the space between themuscle layer and the surrounding parenchyma• An imbalance between vascular endothelial growth factor(VEGF) and angiopoietin-1 has been shown to beinvolved in these abnormalitiesAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    18. 18. Angiogenesis• VEGF : increasing the permeability of these abnormalblood vessels– vessel dilation and edema  airway narrowing– source of inflammatory cells and plasma-derivedmediators and cytokinesAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    19. 19. • role for tissue factor (TF), a primary initiator of blood coagulation,secreted by bronchial epithelium after mechanical stress onangiogenesis of asthmatic airwayJ Allergy Clin Immunol. 2012;130:1375-83
    20. 20. Mechanisms of AirwayRemedeling
    21. 21. Mechanisms of airway remodeling• Inflammation and Inflammatory mediators• Epithelial injury• Physical forces• Cell-cell interactions• Imbalance between repair and removal of ECMproteins
    22. 22. Inflammation• driving force behind most features of airway remodeling• Multiple cytokines, chemokines, and growth factorsreleased from both inflammatory and structural cells inthe airway tissue create a complex signalingenvironment that drives airway remodelingAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    23. 23. Inflammation• IgE and mast cells : acute response• Eosinophils , T-cell esp TH2 cells : late response– Eosinophils : highly basic granule-associated proteins– TH2 cells : cytokines, such as IL-4, IL-5, IL-9, and IL-13• Eosinophils play a critical role in tissue remodeling– main source of the profibrotic cytokine TGF-β  tissueremodeling– support fibroblast proliferation, collagen synthesis, andmyofibroblast maturationAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    24. 24. Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62Inflammation
    25. 25. Al-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    26. 26. Stephen T. Holgate, .Middleton’s Allergy 7’th edition ,893-915.important role for airway epithelial cells in initiating and maintaining the remodelingprocess through their interactions with subepithelial mesenchymal cells
    27. 27. Epithelial-Mesenchymal Trophic Dysfunction• associated with broad functional activation of the airwayepithelium, with expression of many molecules that arerelevant to the remodeling process– transcription factors nuclear factor kappa B (NF-κB)– STAT-1, and STAT-6– enzymes COX-2– inducible nitric oxide synthase (iNOS);– peptide endothelin– proinflammatory cytokines such as IL-1β and GM-CSF– growth factors such as PDGF, bFGF, and TGF-βStephen T. Holgate, .Middleton’s Allergy 7’th edition ,893-915.
    28. 28. Epithelial lossReticular basement membrane thicknessAm J Respir Crit Care Med. 2008;178:476-82
    29. 29. Number of vesselsEosinophilsAm J Respir Crit Care Med. 2008;178:476-82
    30. 30. IL-4+ cellsIL-5+ cellsAm J Respir Crit Care Med. 2008;178:476-82All pathologic features examined weresimilar in nonatopic and atopic children
    31. 31. J Allergy Clin Immunol 2012;129:974-82Severe therapy resistantasthma
    32. 32. J Allergy Clin Immunol 2012;129:974-82Airway remodeling
    33. 33. J Allergy Clin Immunol 2012;129:974-82STRA ControlEosinophilia
    34. 34. J Allergy Clin Immunol 2012;129:974-82Remodeling can occur independently ofTh2 inflammationTH2 cytokine
    35. 35. Epithelial injury• Both inflammatory and functionally active structuralcomponents are equally involved• Asthma primarily develops because of serious defects inthe epithelial layer environmental allergens, microorganisms, and toxinsgreater access to the airway tissue impaired repair process that drives the inflammatoryand remodeling responses in the underlying submucosaAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    36. 36. Epithelial injuryEnvironmental (pathogens, allergens, pollutants, and cigarette smoke)or mechanical stress factors resulting in epithelial injuryAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62release of mediators from the epitheliumex. TGF-β and chemokinessubepithelial fibrosis and increased ASM mass“Epithelial-mesenchymal interactions”
    37. 37. Physical forces• may potentially arise in several ways, such as– during inspiration-expiration– Cough– Bronchoconstriction from airway smooth musclecontraction during asthma exacerbation• Airway smooth muscle contraction produces acompressive stress on the airway epithelium, fibroblastsand smooth muscle itself airway structural changes or airway remodelingManuyakorn W,et al. APJAI 2013;31:3-10
    38. 38. Physical forces• Role of physical forces on airway structural cellsresponses involved in airway remodeling– increased cell proliferation– increased deposition of ECMS– subepithelial layer thickness– promoted smooth muscle cells migration– production of contractile enzyme and VEGFManuyakorn W,et al. APJAI 2013;31:3-10
    39. 39. N Engl J Med 2011;364:2006-15
    40. 40. Mild atopic asthma4 group• dust-mite allergen (Dermatophagoides pteronyssinus)• methacholine• albuterol followed by methacholine• salineN Engl J Med 2011;364:2006-15
    41. 41. N Engl J Med 2011;364:2006-15Airway eosinophil recruitmentEpithelial repair & structural remodeling
    42. 42. Before;Collagen type IIIAfter;Collagen type IIIBefore;Goblet cellsAfter;Goblet cellsMethacholine ChallengeBronchoconstriction induces epithelialstress and initiates a tissue response thatleads to structural airway changes
    43. 43. Cell-cell interactions• critical for the interaction of many inflammatory andstructural cells leading to airway tissue remodeling• CD4+ T cells might directly enhance ASM proliferationthrough cell cell interactions increased AHR• activated T lymphocytes, eosinophils, neutrophils, and mastcells interact with ASM cells through ICAM-1 ,VCAM-1 upregulation of cell adhesion molecules and the stimulation ofDNA synthesis in ASM cellsAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    44. 44. Imbalance between repair and removalof ECM proteins• ECM proteins form a network of collagenous andnoncollagenous structures that surrounds cells in theairway tissue• The main ECM elements include– collagens, elastic fibers, fibronectin– MMP (metalloprotease): MMP-1, MMP-2, MMP-9, MMP-12– TIMP-1 and TIMP-2, which are inhibitors of MMPsAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    45. 45. Subepithelial layer thickening• The interaction between– inflammatory cells– structural cells (e.g. epithelial cells and fibroblasts)– turnover rate of extracellular matrix proteins (ECMs)determines the net balance of remodeling and fibrosiswithin the airways• ASM cells secrete MMPs,TIMPsManuyakorn W,et al. APJAI 2013;31:3-10
    46. 46. Imbalance between repair and removalof ECM proteins• Abnormal deposition of ECM elements in– submucosal and adventitial areas of the large and small airways– ASM layer• ECM composition within the ASM layer might constrainshortening of the ASM bundles and prevent excessiveairway narrowingAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62 fibrosis of the airway wall might protect against thecollapse of the airway lumen by an exaggeratedcontraction of the increased ASM mass
    47. 47. Clinical relevance ofremodeling
    48. 48. Structural-physiologic relationship• Remodeling is assumed to result in– persistent airflow limitation– decrease in lung function– AHR• Structural changes in the asthmatic airway , particularlyincreased smooth muscle mass, angiogenesis, andsubepithelial fibrosis  airflow limitation• cellular infiltration in the asthmatic airways  decreasein lung functionAl-Muhsen S,et al. J Allergy Clin Immunol 2011;128:451-62
    49. 49. Am J Respir Crit Care Med. 2003;168:983-8The airway wall thickness as assessed by HRCT in the asthmatic airway wasdemonstrated to inversely correlate with airway hyperresponsivenessIt was proposed that the thickening with deposition ofthe matrix proteins may exert a protective mechanismby increasing the stiffness of the airways to attenuatethe sporadic bronchoconstriction
    50. 50. Current asthma medicationand Airway remodeling
    51. 51. Asthma medication• Inhaled corticosteroids (ICS)• ICS plus LABA• Leukotriene receptor antagonists• Omalizumab
    52. 52. ICSN Engl J Med 2006;354:1985-97.
    53. 53. ICSDurrani SR,et al. J Allergy Clin Immunol 2011;128:439-48
    54. 54. ICSDurrani SR,et al. J Allergy Clin Immunol 2011;128:439-48
    55. 55. Corticosteroids• Role of corticosteroids in reversing airway remodelingremains controversial• Corticosteroid dose and duration of administration areimportant considerations when evaluating the effects oftreatment on remodeling• The doses needed to affect a change are thus beyondthe dose clinically used by many patients• The use of such high doses : potential for adverseeffects esp. growth in childrenDurrani SR,et al. J Allergy Clin Immunol 2011;128:439-48Manuyakorn W,et al. APJAI 2013;31:3-10
    56. 56. ICS plus LABA• 30 moderate asthmatic patients (adults) VS 30 controlsubjects• Symbicort 4.5/160 μg twice daily for one year• Result :– decreases in MMP-9, TIMP-1, and TGF-β levels insputum samples– decreased airway wall thickness, as assessed bymeans of HRCT with ICS/LABA treatmentActa Pharmacol Sin. 2011;32:126-32
    57. 57. ICS plus LABA• There is an absence of studies comparing combinationtherapy versus ICSs alone on human airway remodeling• β-adrenergic agents could affect aspects of remodeling anti-bronchoconstrictor influence protecting againstairway mechanotransductive effectsDurrani SR,et al. J Allergy Clin Immunol 2011;128:439-48
    58. 58. LTRA• Murine model• Montelukast– reduction in airway eosinophilic infiltration and goblet cellmetaplasia– reversal in the established increase in ASM mass andsubepithelial collagen depositionSaline MontelukastOVAAm J Respir Crit Care Med. 2006;173:718-28.
    59. 59. Omalizumab• Severe persistant allergic asthma– reduce airway wall thickness in severe asthmatic subjects asevaluated by HRCTChanges in airway measurements after 16 weeks of treatment with and without omalizumab versus baselineData are expressed as medians. p < 0.01Respiration. 2012;83:520-8
    60. 60. Novel treatment• Anti IL-5 : Mepolizumab• Anti IL-13 : Lebrikizumab• Anti-TNFα : Etanercept, Golimumab ?
    61. 61. Conclusion• inflammation and remodeling can occur as separate butparallel aspects of the asthmatic process• Airway remodeling represents complex multicellularprocessesStephen T. Holgate, .Middleton’s Allergy 7’th edition ,893-915.
    62. 62. Conclusion• Remodeling is assumed to result in– persistent airflow limitation– decrease in lung function– AHR• Inhaled corticosteroids– limited influence on remodeling– dose and duration of treatment
    63. 63. Conclusion• Despite advancements in the recognition of key cellularand molecular mechanisms involved in remodelingit is unclear as to– when is the best time to initiate treatments to modifyremodeling?– which components to target?– how best to monitor interventions on remodeling?need to develop new therapeutic approaches orinterventions to specifically target components of airwayremodeling to either prevent or reverse these processes
    64. 64. Thank you