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Tierarztl Prax Ausg G Grosstiere Nutztiere 2021; 49(05): 320-325
DOI: 10.1055/a-1581-6231
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Remodeling beim equinen Asthma – Einfluss von Haltungsoptimierung und pharmakologischer Therapie

Remodeling in equine asthma – Effects of antigen avoidance and pharmacological therapy
Ann Kristin Barton
Klinik für Pferde, allgemeine Chirurgie und Radiologie, Freie Universität Berlin
,
Heidrun Gehlen
Klinik für Pferde, allgemeine Chirurgie und Radiologie, Freie Universität Berlin
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Zusammenfassung

Der Begriff Remodeling beschreibt den Prozess, der zu Veränderungen in Struktur und Aufbau im Vergleich zu gesundem Gewebe führt. Zumindest beim schweren equinen Asthma kommt es hauptsächlich, aber nicht ausschließlich, infolge der neutrophilen Entzündung zu einer Hypertrophie der glatten Bronchial- und arteriellen Gefäßmuskulatur sowie zu einer Fibrosierung der luftführenden Wege, aber auch des pulmonalen Interstitiums. Zur milden bis moderaten Form des equinen Asthmas ist bislang deutlich weniger bekannt. Lange wurde davon ausgegangen, dass das Remodeling irreversibel ist. Während dies für die glatte Bronchialmuskulatur weitgehend bis >heute gilt, gibt es beim Remodeling der extrazellulären Matrix der Lamina propria der Atemwege neue Erkenntnisse. Sowohl eine langfristige Remission durch konsequente Haltungsoptimierung als auch Glukokortikoide können den Kollagengehalt hier annähernd normalisieren. Das Remodeling der arteriellen Gefäßmuskulatur ist durch langfristige Haltungsoptimierung über mindestens 12 Monate und Bronchodilatatoren, nicht aber alleinig durch inhalative Glukokortikoide ebenfalls reversibel. Obwohl noch nicht abschließend geklärt, könnte die mit guter Prognose oft ausheilende milde bis moderate Form des equinen Asthmas eine Vorläuferform der schweren Form sein, bei der auch in der Phase der Remission Einschränkungen der Lungenfunktion nachweisbar sind, selbst wenn keine offensichtlichen klinischen Symptome vorliegen. Somit sind die frühzeitige Diagnosestellung des equinen Asthmas und ein früher Therapiebeginn entscheidend, damit zu Beginn der Behandlung möglichst wenige irreversible Veränderungen vorliegen. Der konsequenten Haltungsoptimierung kommt therapeutisch die größte Bedeutung zu, daneben sollten Glukokortikoide und Bronchodilatatoren eingesetzt werden.

Abstract

The term remodeling describes the process resulting in a tissue that is structurally and architecturally altered compared to its healthy counterpart. At least in severe equine asthma, this occurs mainly, but not exclusively, as a consequence of neutrophilic airway inflammation and is characterized by hypertrophy of the smooth muscle layers in airway and arterial walls as well as fibrosis of the bronchial walls and pulmonary interstitial tissue. To date, much less is known for mild to moderate equine asthma. For a long time it was assumed that these processes are irreversible, and at least for the remodeling of airway smooth muscle this is valid until today. In contrast, remodeling of the extracellular matrix disappears almost completely following long-term remission in consequence to strict antigen avoidance and environmental improvement as well as after glucocorticoid therapy. The remodeling of the arterial vasculature is also reversible following at least 12 months of antigen avoidance and bronchodilatory therapy, but not by inhaled glucocorticoids alone. Although not proven to date, the mild to moderate forms with a good prognosis for complete recovery may be a progenitor for severe equine asthma, in which lung function is restricted even during disease remission despite the absence of obvious clinical signs. Early diagnosis and therapy are, therefore, essential for the management of equine asthma prior to the development of irreversible remodeling, in particular of the bronchial smooth muscle. Antigen avoidance is of highest importance, and should be supported by glucocorticoids and bronchodilators.

Schlüsselwörter

Pferd - Lunge - Fibrosierung - Glukokortikoide - Bronchodilatatoren - Haltungsoptimierung

Key words

Horse - lung - fibrosis - bronchodilators - glucocorticoids - environmental improvement


Publication History

Received: 20 January 2021

Accepted: 26 July 2021

Article published online:
01 September 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • Literatur

  • 1 Pirie RS. Recurrent airway obstruction: A review. Equine Vet J 2014; 46 (03) 276-288
    CrossrefPubMedGoogle Scholar
  • 2 Bullone M, Lavoie JP. The equine asthma model of airway remodeling: from a veterinary to a human perspective. Cell Tissue Res 2020; 380 (02) 223-236
    CrossrefPubMedGoogle Scholar
  • 3 Huber HL, Koessler KK. The pathology of bronchial asthma. Arch Intern Med 1922; 30: 689-760
    CrossrefPubMedGoogle Scholar
  • 4 Thurlbeck WM, Lowell FC. Heaves in horses. Am Rev Respir Dis 1964; 89 (01) 82-88
    PubMedGoogle Scholar
  • 5 Kaup FJ, Drommer W, Deegen E. Ultrastructural findings in horses with chronic obstructive pulmonary disease (COPD). I: Alterations of the larger conducting airways. Equine Vet J 1990; 22 (05) 343-348
    CrossrefPubMedGoogle Scholar
  • 6 Kaup FJ, Drommer W, Damsch S. et al. Ultrastructural findings in horses with chronic obstructive pulmonary disease (COPD). II: Pathomorphological changes of the terminal airways and the alveolar region. Equine Vet J 1990; 22 (05) 349-355
    CrossrefPubMedGoogle Scholar
  • 7 Couetil L, Cardwell JM, Leguillette R. et al. Equine Asthma: Current Understanding and Future Directions. Front Vet Sci 2020; 7: 450
    CrossrefPubMedGoogle Scholar
  • 8 Ceriotti S, Bullone M, Leclere M. et al. Severe asthma is associated with a remodeling of the pulmonary arteries in horses. PLoS One 2020; 15 (10) e0239561
    CrossrefPubMedGoogle Scholar
  • 9 Bullone M, Beauchamp G, Godbout M. et al. Endobronchial ultrasound reliably quantifies airway smooth muscle remodeling in an equine asthma model. PLoS One 2015; 10: e0136284
    CrossrefPubMedGoogle Scholar
  • 10 Herszberg B, Ramos-Barbon D, Tamaoka M. et al. Heaves, an asthma-like equine disease, involves airway smooth muscle remodeling. J Allergy Clin Immunol 2006; 118 (02) 382-388
    CrossrefPubMedGoogle Scholar
  • 11 Leclere M, Lavoie-Lamoureux A, Gelinas-Lymburner E. et al. Effect of antigenic exposure on airway smooth muscle remodeling in an equine model of chronic asthma. Am J Respir Cell Mol Biol 2011; 45 (01) 181-187
    CrossrefPubMedGoogle Scholar
  • 12 Vargas A, Roux-Dalvai F, Droit A. et al. Neutrophil-derived exosomes: a new mechanism contributing to airway smooth muscle remodeling. Am J Respir Cell Mol Biol 2016; 55: 450-461
    CrossrefPubMedGoogle Scholar
  • 13 West JB. Respiratory Physiology: the Essentials. 8th ed. Baltimore: Lippincott Williams & Wilkins; 2008
    Google Scholar
  • 14 Bullone M, Chevigny M, Allano M. et al. Technical and physiological determinants of airway smooth muscle mass in endobronchial biopsy samples of asthmatic horses. J Appl Physiol 2014; 117 (07) 806-815
    PubMedGoogle Scholar
  • 15 Setlakwe EL, Lemos KR, Lavoie-Lamoureux A. et al. Airway collagen and elastic fiber content correlates with lung function in equine heaves. Am J Phys Lung Cell Mol Phys 2014; 307 (03) L252-260
    PubMedGoogle Scholar
  • 16 Dubuc J, Lavoie JP. Airway wall eosinophilia is not a feature of equine heaves. Vet J 2014; 202: 387-389
    CrossrefPubMedGoogle Scholar
  • 17 Grainge CL, Lau LC, Ward JA. et al. Effect of bronchoconstriction on airway remodeling in asthma. N Engl J Med 2011; 364 (21) 2006-2015
    CrossrefPubMedGoogle Scholar
  • 18 Shapiro SD, Endicott SK, Province MA. et al. Marked longevity of human lung parenchymal elastic fibers deduced from prevalence of D-aspartate and nuclear weapons-related radiocarbon. J Clin Invest 1991; 87 (05) 1828-1834
    CrossrefPubMedGoogle Scholar
  • 19 Foronjy RF, Okada Y, Cole R. et al. Progressive adult-onset emphysema in transgenic mice expressing human MMP-1 in the lung. Am J Physiol Lung Cell Mol Physiol 2003; 284 (05) 727-737
    CrossrefPubMedGoogle Scholar
  • 20 Furness MC, Bienzle D, Caswell JL. et al. Immunohistochemical identification of collagen in the equine lung. Vet Pathol 2010; 47 (05) 982-990
    CrossrefPubMedGoogle Scholar
  • 21 Gross J, Lapiere CM. Collagenolytic activity in amphibian tissues: a tissue culture assay. Proc Natl Acad Sci USA 1962; 48 (06) 1014-1022
    CrossrefPubMedGoogle Scholar
  • 22 Brinckerhoff CE, Matrisian LM. Matrix metalloproteinases: a tail of a frog that became a prince. Nat Rev Mol Cell Biol 2002; 3 (03) 207-214
    CrossrefPubMedGoogle Scholar
  • 23 Parks WC, Wilson CL, López-Boado YS. Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat Rev Immunol 2004; 4 (08) 617-629
    CrossrefPubMedGoogle Scholar
  • 24 Atkinson JJ, Lutey BA, Suzuki Y. et al. The role of matrix metalloproteinase-9 in cigarette smoke-induced emphysema. Am J Respir Crit Care Med 2011; 183 (07) 876-884
    CrossrefPubMedGoogle Scholar
  • 25 Russell RE, Culpitt SV, DeMatos C. et al. Release and activity of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 by alveolar macrophages from patients with chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol 2002; 26 (05) 602-609
    CrossrefPubMedGoogle Scholar
  • 26 Koivunen AL, Maisi P, Konttinen YT. et al. Gelatinolytic activity in tracheal aspirates of horses with chronic obstructive pulmonary disease. Acta Vet Scand 1997; 38 (01) 17-27
    CrossrefPubMedGoogle Scholar
  • 27 Raulo SM, Sorsa T, Tervahartiala T. et al. MMP-9 as a marker of inflammation in tracheal epithelial lining fluid (TELF) and in bronchoalveolar fluid (BALF) of COPD horses. Equine Vet J 2001; 33 (02) 128-136
    CrossrefPubMedGoogle Scholar
  • 28 Raulo SM, Sorsa TA, Kiili MT. et al. Evaluation of collagenase activity, matrix metalloproteinase-8, and matrix metalloproteinase-13 in horses with chronic obstructive pulmonary disease. Am J Vet Res 2001; 62 (07) 1142-1148
    CrossrefPubMedGoogle Scholar
  • 29 Barton A, Shety T, Bondzio A. et al. Metalloproteinases and their tissue inhibitors in comparison between different chronic pneumopathies in the horse. Mediators Inflamm 2015; 2015: 569512
    CrossrefPubMedGoogle Scholar
  • 30 Nevalainen M, Raulo SM, Brazil TJ. et al. Inhalation of organic dusts and lipopolysaccharide increases gelatinolytic matrix metalloproteinases (MMPs) in the lungs of heaves horses. Equine Vet J 2002; 34 (02) 150-155
    CrossrefPubMedGoogle Scholar
  • 31 Simonen-Jokinen T, Pirie RS, McGorum BC. et al. Effect of composition and different fractions of hay dust suspension on inflammation in lungs of heaves-affected horses: MMP-9 and MMP-2 as indicators of tissue destruction. Equine Vet J 2005; 37 (07) 412-417
    PubMedGoogle Scholar
  • 32 Simonen-Jokinen T, Pirie RS, McGorum B. et al. Dose responses to inhalation of endotoxin, hay dust suspension and Aspergillus fumigatus extract in horses as measured by levels and activation of matrix metalloproteinase-9. Equine Vet J 2005; 37 (02) 155-160
    CrossrefPubMedGoogle Scholar
  • 33 Barton A, Shety T, Bondzio A. et al. Metalloproteinases and their inhibitors are influenced by inhalative glucocorticoid therapy in equine recurrent airway obstruction. BMC Vet Res 2016; 12 (01) 282
    CrossrefPubMedGoogle Scholar
  • 34 Bourboulia D, Stetler-Stevenson WG. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion. Semin Cancer Biol 2010; 20 (03) 161-168
    CrossrefPubMedGoogle Scholar
  • 35 Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta 2010; 1803 (01) 55-71
    CrossrefPubMedGoogle Scholar
  • 36 Bessonnat A. Évaluation du remodelage des voies respiratoires centrales de chevaux asthmatiques [Dissertation]. Montreal: Department of Clinical Sciences, University of Montreal; 2018
    Google Scholar
  • 37 Ter Woort F, Caswell JL, Arroyo LG. et al. Histologic investigation of airway inflammation in postmortem lung samples from racehorses. Am J Vet Res 2018; 79 (03) 342-347
    CrossrefPubMedGoogle Scholar
  • 38 Williams KJ, Derksen FJ, de Feijter-Rupp H. et al. Regional pulmonary veno-occlusion: a newly identified lesion of equine exercise-induced pulmonary hemorrhage. Vet Pathol 2008; 45 (03) 316-26
    CrossrefPubMedGoogle Scholar
  • 39 Stack A, Derksen FJ, Williams KJ. et al. Regional heterogeneity in the reactivity of equine small pulmonary blood vessels. J Appl Physiol 1985; 120 (06) 599-607
    PubMedGoogle Scholar
  • 40 Girodet PO, Allard B, Thumerel M. et al. Bronchial smooth muscle remodeling in nonsevere asthma. Am J Respir Crit Care Med 2016; 193 (06) 627-633
    CrossrefPubMedGoogle Scholar
  • 41 James AL, Elliot JG, Jones RL. et al. Airway smooth muscle hypertrophy and hyperplasia in asthma. Am J Respir Crit Care Med 2012; 185 (10) 1058-1064
    CrossrefPubMedGoogle Scholar
  • 42 Bullone M, Vargas A, Elce Y. et al. Fluticasone/salmeterol reduces remodeling and neutrophilic inflammation in severe equine asthma. Sci Rep 2017; 7 (01) 8843
    CrossrefPubMedGoogle Scholar
  • 43 Leclere M, Lavoie-Lamoureux A, Joubert P. et al. Corticosteroids and antigen avoidance decrease airway smooth muscle mass in an equine asthma model. Am J Respir Cell Mol Biol 2012; 47 (05) 589-596
    CrossrefPubMedGoogle Scholar
  • 44 Hoshino M, Takahashi M, Takai Y. et al. Inhaled corticosteroids decrease subepithelial collagen deposition by modulation of the balance between matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 expression in asthma. J Allergy Clin Immunol 1999; 104: 356-363
    CrossrefPubMedGoogle Scholar
  • 45 Yeganeh B, Xia C, Movassagh H. et al. Emerging mediators of airway smooth muscle dysfunction in asthma. Pulm Pharmacol Ther 2013; 26 (01) 105-111
    CrossrefPubMedGoogle Scholar
  • 46 Sergejeva S, Ivanov S, Lotvall J. et al. Interleukin-17 as a recruitment and survival factor for airway macrophages in allergic airway inflammation. Am J Respir Cell Mol Biol 2005; 33 (03) 248-253
    CrossrefPubMedGoogle Scholar
  • 47 Roussel L, Houle F, Chan C. et al. IL-17 promotes p38 MAPKdependent endothelial activation enhancing neutrophil recruitment to sites of inflammation. J Immunol 2010; 184 (08) 4531-4537
    CrossrefPubMedGoogle Scholar
  • 48 Lindén A. Role of interleukin-17 and the neutrophil in asthma. Int Arch Allergy Immunol 2001; 126 (03) 179-184
    CrossrefPubMedGoogle Scholar
  • 49 Prause O, Bozinovski S, Anderson GP. et al. Increased matrix metalloproteinase-9 concentration and activity after stimulation with interleukin-17 in mouse airways. Thorax 2004; 59 (04) 313-317
    CrossrefPubMedGoogle Scholar
  • 50 Debrue M, Hamilton E, Joubert P. et al. Chronic exacerbation of equine heaves is associated with an increased expression of interleukin-17 mRNA in bronchoalveolar lavage cells. Vet Immun Immunopathol 2005; 105 1–2 25-31
    CrossrefPubMedGoogle Scholar
  • 51 Ainsworth DM, Wagner B, Franchini M. Time-dependent alterations in gene expression of interleukin-8 in the bronchialepithelium of horses with recurrent airway obstruction. Am J Vet Res 2006; 67 (04) 669-677
    CrossrefPubMedGoogle Scholar
  • 52 Padoan E, Ferraresso S, Pegolo S. et al. Real time RT-PCR analysis of inflammatory mediator expression in recurrent airway obstruction-affected horses. Vet Immunol Immunopathol 2013; 156 3–4 190-199
    CrossrefPubMedGoogle Scholar
  • 53 Lindén A, Dahlén B. Interleukin-17 cytokine signaling in patients with asthma. The Eur Respir J 2014; 44 (05) 1319-1331
    CrossrefPubMedGoogle Scholar
  • 54 GINA report 2020: Global initiative for asthma. https://ginasthma.org/gina reports/gina-2020-full-report Stand: 18.12.2020
    PubMedGoogle Scholar
  • 55 Dauvillier J, Felippe MJ, Lunn DP. et al. Effect of long-term fluticasone treatment on immune function in horses with heaves. J Vet Intern Med 2011; 25 (03) 549-557
    PubMedGoogle Scholar
  • 56 Duvivier DH, Votion D, Vandenput S. et al. Aerosol therapy in the equine species. Vet J 1997; 154 (03) 189-202
    CrossrefPubMedGoogle Scholar
  • 57 Rush BR, Raub ES, Thomsen MM. et al. Pulmonary function and adrenal gland suppression with incremental doses of aerosolized beclomethasone dipropionate in horses with recurrent airway obstruction. J Am Vet Med Assoc 2000; 217 (03) 359-364
    CrossrefPubMedGoogle Scholar
  • 58 Rush BR, Worster AA, Flaminio MJ. et al. Alteration in adrenocortical function in horses with recurrent airway obstruction after aerosol and parenteral administration of beclomethasone dipropionate and dexamethasone, respectively. Am J Vet Res 1998; 59 (08) 1044-1047
    PubMedGoogle Scholar
  • 59 Munoz T, Leclere M, Jean D. et al. Serum cortisol concentration in horses with heaves treated with fluticasone proprionate over a 1 year period. Res Vet Sci 2015; 98: 112-114
    CrossrefPubMedGoogle Scholar
  • 60 Lavoie JP, Bullone M, Rodrigues N. et al. Effect of different doses of inhaled ciclesonide on lung function, clinical signs related to airflow limitation and serum cortisol levels in horses with experimentally induced mild to severe airway obstruction. Equine Vet J 2019; 51 (06) 779-786
    CrossrefPubMedGoogle Scholar
  • 61 Ammann VJ, Vrins AA, Lavoie JP. Effects of inhaled beclomethasone dipropionate on respiratory function in horses with chronic obstructive pulmonary disease (COPD). Equine Vet J 1998; 30 (02) 152-157
    CrossrefPubMedGoogle Scholar
  • 62 Kampmann C, Ohnesorge B, Venner M. et al. Budesonid-Aerosoltherapie und Lungenfunktion bei chronisch lungenkranken Pferden. Equine Med 2001; 17 (02) 155-160
    PubMedGoogle Scholar
  • 63 Couëtil LL, Art T, de Moffarts B. et al. Effect of beclomethasone dipropionate and dexamethasone isonicotinate on lung function, bronchoalveolar lavage fluid cytology and transcription factor expression in airways of horses with recurrent airway obstruction. J Vet Intern Med 2006; 20 (02) 399-406
    PubMedGoogle Scholar
  • 64 Couëtil LL, Chilcoat CD, DeNicola DB. et al. Randomized, controlled study of inhaled fluticasone propionate, oral administration of prednisone, and environmental management of horses with recurrent airway obstruction. Am J Vet Res 2005; 66 (10) 1665-1674
    CrossrefPubMedGoogle Scholar
  • 65 Laan TT, Bull S, van Nieuwstadt RA. et al. The effect of aerosolized and intravenously administered clenbuterol and aerosolized fluticasone propionate on horses challenged with Aspergillus fumigatus antigen. Vet Res Commun 2006; 30 (06) 623-635
    CrossrefPubMedGoogle Scholar
  • 66 Lavoie JP, Leclere M, Rodrigues N. et al. Efficacy of inhaled budesonide for the treatment of severe equine asthma. Equine Vet J 2019; 51 (03) 401-407
    CrossrefPubMedGoogle Scholar
  • 67 Léguillette R, Tohver T, Bond SL. et al. Effect of Dexamethasone and Fluticasone on Airway Hyperresponsiveness in Horses with Inflammatory Airway Disease. J Vet Intern Med 2017; 31 (04) 1193-1201
    PubMedGoogle Scholar
  • 68 Robinson NE, Berney C, Behan A. et al. Fluticasone propionate aerosol is more effective for prevention than treatment of recurrent airway obstruction. J Vet Intern Med 2009; 23 (06) 1247-1253
    PubMedGoogle Scholar
  • 69 Pirie RS, Mueller HW, Engel O. et al. Inhaled Ciclesonide in horses with severe equine asthma: Results of a large prospective European clinical trial. AAEP Proceedings 2020; 66: 298-299
    PubMedGoogle Scholar
  • 70 Lehmann B, Ladendorf I, Doherr MG. et al. Ten-day inhalation therapy with a combination preparation of Fluticason and Salmeterol – does it improve the clinical symptoms of horses suffering from equine asthma?. Equine Med 2019; 35 (02) 153-158
    CrossrefPubMedGoogle Scholar