Discussion
Discussion
In mice with fully established airway inflammation and remodelling, allergen cessation (four weeks) resulted in a rapid decrease in inflammatory cells such as eosinophils and neutrophils from the BALF. In contrast, macrophage numbers revealed a different kinetics initially increasing in numbers before returning to baseline levels. This temporary increase in macrophage numbers adds further support to the important role of this cell type in the resolution of inflammation (Leung et al. 2004, Porcheray et al. 2005, 2005).
Allergen cessation resulted in a rapid decrease in Goblet cell numbers, which is in line with observations made by other investigators (Blyth et al. 2000; Southam et al. 2008b;
Kumar et al. 2004). Our study expands on these investigations by performing comprehensive analysis of both inflammatory and remodelling parameters. It has been proposed that the cessation of allergen exposure does not completely attenuate airway remodelling (Henderson, JR et al. 2006; McMillan und Lloyd 2004; Kumar et al. 2004;
Leigh et al. 2002). In the studies by McMillan et al. and by Kumar et al. four weeks of allergen cessation was not sufficient to fully resolve airway remodelling (Kumar et al. 2004;
McMillan und Lloyd 2004). This observation was confirmed by the results of our study, however, prolongation of the resolution period to eight weeks completely attenuated lung tissue inflammation and fully reversed airway remodelling (Alrifai et al. 2014). Together this supports the notion that continued allergen exposure is required for the persistence of allergic airway inflammation and remodelling, and that avoidance of allergen exposure could ameliorate airway inflammation and remodelling at least in mice.
The extensive airway remodelling at twelve weeks of OVA challenge correlated with high levels of TGF- β in the BALF. TGF- β has important roles in mediating remodelling by inducing the production of extracellular matrix proteins and cell proliferation. It has been shown that TGF- β has a significant role in pulmonary fibrosis (Khalil et al. 1991).
Additionally increased TGF- β expression has been observed in asthmatic patients, which correlated with subepithelial fibrosis (Redington et al. 1997; Halwani et al. 2011; Vignola et al. 1997). Furthermore, in our study the decreasing level of TGF- β in BALF following allergen cessation also correlated with the resolution of airway remodelling, which further indicates the important role of this cytokine in remodelling and resolution. The increased IFN-Ƴ levels observed during resolution phases may also serve to further antagonise the profibrotic effects of TGF- β (Eickelberg et al. 2001).
ICS are the mainstay of asthma therapy in humans (Baran 1987). Studies in mice have predominately focused on the effects of ICS in acute asthma models (Chian et al. 2011;
Schmidt et al. 1994; Shen et al. 2002). We have here investigated the effects of ICS during the establishment of airway remodelling. The experimental protocol closely mimics the clinical situation, in which patients suffer from acute allergic asthma symptoms at the
Discussion
ICS treatment and is consistent with other studies (Chian et al. 2011; Schmidt et al. 1994;
Shen et al. 2002). Applying ICS during the transition from acute to chronic asthma, resulted in lower lung tissue inflammation, Goblet cell hyperplasia and collagen deposition.
ICS however did not alter allergen induced smooth muscle thickening. Together these results indicate that despite ICS OVA sensitization is retained and that ICS delay some but not all characteristics of chronic remodelling. Similar observations were reported in a chronic OVA-induced asthma model when budesonide was given for four weeks following allergen cessation, however in this case no differences in collagen deposition and smooth muscle mass were observed (Southam et al. 2008a).
Similar results have been obtained following the co-application of OVA and dexamethasone, which reduced Goblet cell hyperplasia but did not affect smooth muscle thickness (Karras et al. 2007; Miller et al. 2006). These observations again demonstrate that slowly progressing remodelling features are more resistant to therapeutic interventions. Our study also expands on works of Kumar and Herbert in which the authors showed that dexamethasone treatment resulted in reduced lung inflammation and collagen deposition (Herbert et al. 2008; Kumar et al. 2003), by investigating airway inflammation and remodelling over a longer treatment period and by maintaining allergen challenge after the cessation of ICS.
In a study by Southam et al. the simultaneous removal of both, the allergen and ICS, resulted in a marked rebound of Goblet cell hyperplasia, which was most apparent after prolonged co-application of budesonide and allergen (Southam et al. 2008b). Interestingly a minimum of six weeks of concurrent budesonide/ICS administration was required to confer this rebound effect. In our study the continuation of allergen challenge after the discontinuation of ICS resulted in slightly increased eosinophil counts but did not affect Goblet cell numbers or other remodelling characteristics. An important difference between these studies was that we maintained allergen challenge after cessation of ICS, a situation which reflects a non-compliant patient. The disparity between ICS effects in acute and chronic asthma supports the concept that there is a shift in immune responses throughout disease progression in allergic asthma (Wegmann et al. 2005). Therefore, the same therapy could confer different efficacy because of variability in the immune response pattern of different asthma patients. ICS are highly effective in reducing allergen induced eosinophilia and consequently in treating acute experimental asthma in which the eosinophils are the dominant cell type (Gauvreau et al. 2000). However, in chronic asthma phenotypes, which exhibit decreased eosinophils counts, other inflammatory cells have a more predominate role and are less responsive to corticosteroid therapy.
In conclusion, using a chronic model of experimental asthma we have shown that continuous allergen exposure in mice induces reversible airway remodelling. Treatment of
Discussion
established inflammation and remodeling can be partially accomplished with corticosteroids, however, most prominent beneficial effects are observed by allergen avoidance. This model offers new opportunities to further delineate the cellular and molecular signaling pathways that contribute to the transition from the acute to the chronic phenotype, and to elaborate the pathways of normal repair and structural reorganisation.
Summary
Summary
Asthma is associated with chronic airway inflammation and progressive airway remodelling. However, the dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly understood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes.
Using BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and presence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of bronchoalveolar and peribronichal inflammatory cell infiltrate, Goblet cell hyperplasia, collagen deposition and smooth muscle thickening. Chronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and smooth muscle thickening).
After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and collagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only observed after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the development of lung Inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth muscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy was discontinued.
Utilising a model of experimental chronic asthma we have shown that repeated allergen exposure induces reversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in inhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective in preventing smooth muscle hypertrophy.
Zusammenfassung
Zusammenfassung
Asthma bronchiale ist eine chronisch-entzündliche Erkrankung der Atemwege mit progressiv ausgeprägten pathologischen Umbauprozessen in den Atemwegen (Remodelling). Die Dynamik der Entwicklung dieser Merkmale und ihre spontane und pharmakologische Reversibilität sind bisher nicht ganz verstanden. Wir haben daher in einem experimentellen Asthmamodell die Dynamik des Remodelling und der Reparatur der Atemwege sowie die Auswirkung pharmakologischer Interventionen auf diese Prozesse untersucht.
Unter Verwendung von BALB/c-Mäusen wurde die Kinetik der Entwicklung und des Rückgangs des chronischen Asthmas in Abwesenheit bzw. Anwesenheit einer inhalativen Corticosteroid (ICS)-Behandlung charakterisiert. Die Entzündung und das Remodelling der Atemwege wurden mittels der Analyse des entzündlichen Zellinfiltrats der Bronchoalveolar- und Peribronchialzellen, der Becherzell-Hyperplasie, der Kollagenablagerung und der Verdickung der glatten Muskulatur beurteilt. Chronische Allergenexposition führte zu frühem (Becherzell-Hyperplasie) bzw. zu spätem Remodelling (Kollagenablagerung und Verdickung der glatten Muskulatur). Vier Wochen nach dem Absetzen des Allergens waren eosinophile Infiltration, Becherzell-Hyperplasie und Kollagenablagerung wieder vollständig zurückgegangen; bis zum kompletten Rückgang der lymphozytären Infiltration und der Verdickung der glatten Muskulatur dauerte es 8 Wochen. Wurde die ICS-Therapie vor der vollständigen Etablierung eines chronischen Asthmas begonnen, reduzierte sie die Entwicklung von Lungenentzündung und verringerte Becherzell-Hyperplasie sowie Kollagenablagerung, beeinflusste jedoch nicht die Verdickung der glatten Muskulatur. Diese Effekte von ICS auf das Remodelling der Atemwege wurden für weitere vier Wochen aufrechterhalten, selbst wenn die Therapie unterbrochen wurde.
Unter Verwendung eines Modells von experimentellem chronischem Asthma haben wir gezeigt, dass wiederholte Allergenexposition bei Mäusen reversibel Remodelling und Entzündung der Atemwege induziert. Therapeutische Intervention mit ICS war teilweise wirksam bei der Hemmung des Übergangs von akutem zu chronischem Asthma durch die Verringerung der Entzündung der Atemwege und Remodelling, war aber unwirksam bei der Verhinderung der Hypertrophie der glatten Muskulatur.
References
6 References
Akinbami, Lara J.; Moorman, Jeanne E.; Liu, Xiang (2011): Asthma prevalence, health care use, and mortality: United States, 2005-2009. In: National health statistics reports (32), S. 1–14.
Alrifai, Mohammed; Marsh, Leigh M.; Dicke, Tanja; Kilic, Ayse; Conrad, Melanie L.; Renz, Harald; Garn, Holger (2014): Compartmental and temporal dynamics of chronic inflammation and airway remodelling in a chronic asthma mouse model. In: PloS one 9 (1), S. e85839. DOI: 10.1371/journal.pone.0085839.
Bara, I.; Ozier, A.; Tunon de Lara, J-M; Marthan, R.; Berger, P. (2010): Pathophysiology of bronchial smooth muscle remodelling in asthma. In: The European respiratory journal 36 (5), S. 1174–1184. DOI: 10.1183/09031936.00019810.
Baran, D. (1987): A comparison of inhaled budesonide and beclomethasone dipropionate in childhood asthma. In: British journal of diseases of the chest 81 (2), S. 170–175.
Bates, Jason H. T.; Rincon, Mercedes; Irvin, Charles G. (2009): Animal models of asthma.
In: American journal of physiology. Lung cellular and molecular physiology 297 (3), S. 10. DOI: 10.1152/ajplung.00027.2009.
Bergeron, Céline; Al-Ramli, Wisam; Hamid, Qutayba (2009): Remodeling in asthma. In:
Proceedings of the American Thoracic Society 6 (3), S. 301–305. DOI:
10.1513/pats.200808-089RM.
Blacquière, M. J.; Hylkema, M. N.; Postma, D. S.; Geerlings, M.; Timens, W.; Melgert, B.
N. (2010): Airway inflammation and remodeling in two mouse models of asthma:
comparison of males and females. In: International archives of allergy and immunology 153 (2), S. 173–181. DOI: 10.1159/000312635.
Blyth, D. I.; Wharton, T. F.; Pedrick, M. S.; Savage, T. J.; Sanjar, S. (2000): Airway subepithelial fibrosis in a murine model of atopic asthma: suppression by dexamethasone or anti-interleukin-5 antibody. In: American journal of respiratory cell and molecular biology 23 (2), S. 241–246. DOI: 10.1165/ajrcmb.23.2.3999.
Böcking, C.; Renz, H.; Pfefferle, P. I. (2012a): Prävalenz und sozioökonomische Bedeutung von Allergien in Deutschland. In: Bundesgesundheitsblatt, Gesundheitsforschung, Gesundheitsschutz 55 (3), S. 303–307. DOI:
10.1007/s00103-011-1427-6.
Böcking, C.; Renz, H.; Pfefferle, P. I. (2012b): Prävalenz und sozioökonomische Bedeutung von Allergien in Deutschland. In: Bundesgesundheitsblatt
References
Gesundheitsforschung Gesundheitsschutz 55 (3), S. 303–307. DOI:
10.1007/s00103-011-1427-6.
Bos, I. S. T.; Gosens, R.; Zuidhof, A. B.; Schaafsma, D.; Halayko, A. J.; Meurs, H.;
Zaagsma, J. (2007): Inhibition of allergen-induced airway remodelling by tiotropium and budesonide: a comparison. In: The European respiratory journal 30 (4), S.
653–661. DOI: 10.1183/09031936.00004907.
Bousquet, J.; Jeffery, P. K.; Busse, W. W.; Johnson, M.; Vignola, A. M. (2000): Asthma.
From bronchoconstriction to airways inflammation and remodeling. In: American journal of respiratory and critical care medicine 161 (5), S. 1720–1745. DOI:
10.1164/ajrccm.161.5.9903102.
Bradding, Peter; Brightling, Chris (2007): Mast cell infiltration of airway smooth muscle in asthma. In: Respiratory medicine 101 (5), 1045; author reply 1046-7. DOI:
10.1016/j.rmed.2007.01.004.
Braman, Sidney S. (2006): The global burden of asthma. In: Chest 130 (1 Suppl), 4S-12S.
DOI: 10.1378/chest.130.1_suppl.4S.
Caramori, Gaetano; Groneberg, David; Ito, Kazuhiro; Casolari, Paolo; Adcock, Ian M.;
Papi, Alberto (2008): New drugs targeting Th2 lymphocytes in asthma. In: Journal of occupational medicine and toxicology (London, England) 3 Suppl 1, S. S6. DOI:
10.1186/1745-6673-3-S1-S6.
Chetta, A.; Foresi, A.; Del Donno, M.; Consigli, G. F.; Bertorelli, G.; Pesci, A. et al. (1996):
Bronchial responsiveness to distilled water and methacholine and its relationship to inflammation and remodeling of the airways in asthma. In: American journal of respiratory and critical care medicine 153 (3), S. 910–917. DOI:
10.1164/ajrccm.153.3.8630572.
Chian, Chih-Feng; Tsai, Chen-Liang; Wu, Chin-Pyng; Chiang, Chi-Huei; Su, Wen-Lin;
Chen, Chien-Wen; Perng, Wann-Cherng (2011): Five-day course of budesonide inhalation suspension is as effective as oral prednisolone in the treatment of mild to severe acute asthma exacerbations in adults. In: Pulmonary pharmacology &
therapeutics 24 (2), S. 256–260. DOI: 10.1016/j.pupt.2010.07.001.
Chu, H. W.; Martin, R. J. (2001): Are eosinophils still important in asthma? In: Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology 31 (4), S. 525–528.
Chu, Hong Wei; Breed, Rachel; Rino, John G.; Harbeck, Ronald J.; Sills, Michael R.;
Martin, Richard J. (2006): Repeated respiratory Mycoplasma pneumoniae
References
infections in mice: effect of host genetic background. In: Microbes and infection 8 (7), S. 1764–1772. DOI: 10.1016/j.micinf.2006.02.014.
Cohn, Lauren; Elias, Jack A.; Chupp, Geoffrey L. (2004): Asthma: mechanisms of disease persistence and progression. In: Annual review of immunology 22, S. 789–815.
DOI: 10.1146/annurev.immunol.22.012703.104716.
Conrad, Melanie L.; Ferstl, Ruth; Teich, René; Brand, Stephanie; Blümer, Nicole; Yildirim, Ali O. et al. (2009): Maternal TLR signaling is required for prenatal asthma protection by the nonpathogenic microbe Acinetobacter lwoffii F78. In: The Journal of experimental medicine 206 (13), S. 2869–2877. DOI: 10.1084/jem.20090845.
Cruz-Orive, L. M.; Weibel, E. R. (1990): Recent stereological methods for cell biology: a brief survey. In: The American journal of physiology 258 (4 Pt 1), S. 56.
Damera, Gautam; Panettieri, Reynold A. (2011): Does airway smooth muscle express an inflammatory phenotype in asthma? In: British journal of pharmacology 163 (1), S.
68–80. DOI: 10.1111/j.1476-5381.2010.01165.x.
Delmotte, Philippe; Ressmeyer, Anna-Rebekka; Bai, Yan; Sanderson, Michael J. (2010):
Mechanisms of airway smooth muscle relaxation induced by beta2-adrenergic agonists. In: Frontiers in bioscience (Landmark edition) 15, S. 750–764.
Douwes, J.; Gibson, P.; Pekkanen, J.; Pearce, N. (2002): Non-eosinophilic asthma:
importance and possible mechanisms. In: Thorax 57 (7), S. 643–648.
Eickelberg, O.; Pansky, A.; Koehler, E.; Bihl, M.; Tamm, M.; Hildebrand, P. et al. (2001):
Molecular mechanisms of TGF-(beta) antagonism by interferon (gamma) and cyclosporine A in lung fibroblasts. In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology 15 (3), S. 797–806.
DOI: 10.1096/fj.00-0233com.
Fahy, J. V. (2001): Remodeling of the airway epithelium in asthma. In: American journal of respiratory and critical care medicine 164 (10 Pt 2), S46-51. DOI:
10.1164/ajrccm.164.supplement_2.2106066.
Fang, Cailong; Corrigan, Chris J.; Ying, Sun (2008): The treatment targets of asthma:
from laboratory to clinic. In: Inflammation & allergy drug targets 7 (2), S. 119–128.
Furukawa, Toshiki; Sakagami, Takuro; Koya, Toshiyuki; Hasegawa, Takashi; Kawakami, Hidenori; Kimura, Yosuke et al. (2014): Characteristics of eosinophilic and non-eosinophilic asthma during treatment with inhaled corticosteroids. In: The Journal of asthma : official journal of the Association for the Care of Asthma, S. 1–6. DOI:
10.3109/02770903.2014.975357.
References
Galli, Stephen J.; Kalesnikoff, Janet; Grimbaldeston, Michele A.; Piliponsky, Adrian M.;
Williams, Cara M M; Tsai, Mindy (2005): Mast cells as "tunable" effector and immunoregulatory cells: recent advances. In: Annual review of immunology 23, S.
749–786. DOI: 10.1146/annurev.immunol.21.120601.141025.
Gauvreau, G. M.; Sulakvelidze, I.; Watson, R. M.; Inman, M. D.; Rerecich, T. J.; O'Byrne, P. M. (2000): Effects of once daily dosing with inhaled budesonide on airway hyperresponsiveness and airway inflammation following repeated low-dose allergen challenge in atopic asthmatics. In: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 30 (9), S. 1235 – 1243.
Ge, Xiao Na; Bahaie, Nooshin S.; Kang, Bit Na; Hosseinkhani, M. Reza; Ha, Sung Gil;
Frenzel, Elizabeth M. et al. (2010): Allergen-induced airway remodeling is impaired in galectin-3-deficient mice. In: Journal of immunology (Baltimore, Md. : 1950) 185 (2), S. 1205–1214. DOI: 10.4049/jimmunol.1000039.
Halwani, Rabih; Al-Muhsen, Saleh; Al-Jahdali, Hamdan; Hamid, Qutayba (2011): Role of transforming growth factor-beta in airway remodeling in asthma. In: American journal of respiratory cell and molecular biology 44 (2), S. 127–133. DOI:
10.1165/rcmb.2010-0027TR.
Harrington, Laurie E.; Hatton, Robin D.; Mangan, Paul R.; Turner, Henrietta; Murphy, Theresa L.; Murphy, Kenneth M.; Weaver, Casey T. (2005): Interleukin
17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. In: Nature immunology 6 (11), S. 1123–1132. DOI:
10.1038/ni1254.
Hassan, Muhannad; Jo, Taisuke; Risse, Paul-André; Tolloczko, Barbara; Lemière, Catherine; Olivenstein, Ronald et al. (2010): Airway smooth muscle remodeling is a dynamic process in severe long-standing asthma. In: The Journal of allergy and clinical immunology 125 (5), 1037-1045.e3. DOI: 10.1016/j.jaci.2010.02.031.
Henderson, William R., JR; Chiang, Gertrude K. S.; Tien, Ying-Tzang; Chi, Emil Y. (2006):
Reversal of allergen-induced airway remodeling by CysLT1 receptor blockade. In:
American journal of respiratory and critical care medicine 173 (7), S. 718–728. DOI:
10.1164/rccm.200501-088OC.
Herbert, C.; Hettiaratchi, A.; Webb, D. C.; Thomas, P. S.; Foster, P. S.; Kumar, R. K.
(2008): Suppression of cytokine expression by roflumilast and dexamethasone in a model of chronic asthma. In: Clinical and experimental allergy : journal of the
References
British Society for Allergy and Clinical Immunology 38 (5), S. 847–856. DOI:
10.1111/j.1365-2222.2008.02950.x.
Heusser, C. H.; Brinkmann, V. (1994): Immunantwort und Pathophysiologie der allergischen Reaktion. In: Therapeutische Umschau. Revue thérapeutique 51 (1), S. 14–18.
Hogan, Mary Beth; Piktel, Debra; Hubbs, Ann F.; McPherson, Leslie E.; Landreth, Kenneth S. (2008): Asthma progression to airway remodelling and bone marrow eosinophil responses in genetically distinct strains of mice. In: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 101 (6), S. 619–625. DOI: 10.1016/S1081-1206(10)60225-6.
Homer, R. J.; Elias, J. A. (2000): Consequences of long-term inflammation. Airway remodelling. In: Clinics in chest medicine 21 (2), 331-43, ix.
Hsia, Connie C. W.; Hyde, Dallas M.; Ochs, Matthias; Weibel, Ewald R. (2010): An official research policy statement of the American Thoracic Society/European Respiratory Society: standards for quantitative assessment of lung structure. In: American journal of respiratory and critical care medicine 181 (4), S. 394–418. DOI:
10.1164/rccm.200809-1522ST.
Hsieh, C. S.; Macatonia, S. E.; Tripp, C. S.; Wolf, S. F.; O'Garra, A.; Murphy, K. M. (1993):
Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. In: Science (New York, N.Y.) 260 (5107), S. 547–549.
Jeffery, P. K. (1992): Pathology of asthma. In: British medical bulletin 48 (1), S. 23–39.
Karagiannidis, Christian; Akdis, Mübeccel; Holopainen, Päivi; Woolley, Niina J.; Hense, Gabriele; Rückert, Beate et al. (2004): Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. In: The Journal of allergy and clinical immunology 114 (6), S. 1425–1433. DOI: 10.1016/j.jaci.2004.07.014.
Karras, James G.; Crosby, Jeffrey R.; Guha, Mausumee; Tung, David; Miller, Doreen A.;
Gaarde, William A. et al. (2007): Anti-inflammatory activity of inhaled IL-4 receptor-alpha antisense oligonucleotide in mice. In: American journal of respiratory cell and molecular biology 36 (3), S. 276–285. DOI: 10.1165/rcmb.2005-0456OC.
Kearley, Jennifer; Buckland, Karen F.; Mathie, Sara A.; Lloyd, Clare M. (2009): Resolution of allergic inflammation and airway hyperreactivity is dependent upon disruption of the T1/ST2-IL-33 pathway. In: American journal of respiratory and critical care medicine 179 (9), S. 772–781. DOI: 10.1164/rccm.200805-666OC.
References
Kelly, Elizabeth A.; Jarjour, Nizar N. (2003): Role of matrix metalloproteinases in asthma.
In: Current opinion in pulmonary medicine 9 (1), S. 28–33.
Kelly, Margaret M.; O'Connor, Terence M.; Leigh, Richard; Otis, Joceline; Gwozd, Carol;
Gauvreau, Gail M. et al. (2010): Effects of budesonide and formoterol on allergen-induced airway responses, inflammation, and airway remodeling in asthma. In: The Journal of allergy and clinical immunology 125 (2), S. 349. DOI:
10.1016/j.jaci.2009.09.011.
Khalil, N.; O'Connor, R. N.; Unruh, H. W.; Warren, P. W.; Flanders, K. C.; Kemp, A. et al.
(1991): Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. In: American journal of respiratory cell and molecular biology 5 (2), S. 155–162.
Kim, Kevin K.; Wei, Ying; Szekeres, Charles; Kugler, Matthias C.; Wolters, Paul J.; Hill, Marla L. et al. (2009): Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. In: The Journal of clinical investigation 119 (1), S. 213–224. DOI: 10.1172/JCI36940.
Kinet, J. P. (1999): The high-affinity IgE receptor (Fc epsilon RI): from physiology to pathology. In: Annual review of immunology 17, S. 931–972. DOI: 10.11 46/annurev.immunol.17.1.931.
Kumar, R. K.; Herbert, C.; Kasper, M. (2004): Reversibility of airway inflammation and remodelling following cessation of antigenic challenge in a model of chronic asthma. In: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 34 (11), S. 1796–1802. DOI: 10.1111/j.1365-2222.2004.02097.x.
Kumar, Rakesh K.; Herbert, Cristan; Thomas, Paul S.; Wollin, Lutz; Beume, Rolf; Yang, Ming et al. (2003): Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma. In: The Journal of pharmacology and experimental therapeutics 307 (1), S. 349–355. DOI: 10.1124/jpet.103.053819.
Lachowicz-Scroggins, Marrah E.; Boushey, Homer A.; Finkbeiner, Walter E.; Widdicombe, Jonathan H. (2010): Interleukin-13-induced mucous metaplasia increases susceptibility of human airway epithelium to rhinovirus infection. In: American journal of respiratory cell and molecular biology 43 (6), S. 652–661. DOI:
10.1165/rcmb.2009-0244OC.
Lederlin, Mathieu; Ozier, Annaig; Montaudon, Michel; Begueret, Hugues; Ousova, Olga;
Marthan, Roger et al. (2010): Airway remodeling in a mouse asthma model
References
assessed by in-vivo respiratory-gated micro-computed tomography. In: European radiology 20 (1), S. 128–137. DOI: 10.1007/s00330-009-1541-0.
Leigh, Richard; Ellis, Russ; Wattie, Jennifer; Southam, David S.; Hoogh, Meta de; Gauldie, Jack et al. (2002): Dysfunction and remodeling of the mouse airway persist after resolution of acute allergen-induced airway inflammation. In: American journal of respiratory cell and molecular biology 27 (5), S. 526–535. DOI:
10.1165/rcmb.2002-0048OC.
Leung, S-Y; Eynott, P.; Noble, A.; Nath, P.; Chung, K. F. (2004): Resolution of allergic airways inflammation but persistence of airway smooth muscle proliferation after repeated allergen exposures. In: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 34 (2), S. 213–220.
Liang, Spencer C.; Tan, Xiang-Yang; Luxenberg, Deborah P.; Karim, Riyez; Dunussi-Joannopoulos, Kyriaki; Collins, Mary; Fouser, Lynette A. (2006): Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. In: The Journal of experimental medicine 203 (10), S.
2271–2279. DOI: 10.1084/jem.20061308.
Macdowell, Ana L.; Peters, Stephen P. (2007): Neutrophils in asthma. In: Current allergy and asthma reports 7 (6), S. 464–468.
Masoli, Matthew; Fabian, Denise; Holt, Shaun; Beasley, Richard (2004): The global burden of asthma: executive summary of the GINA Dissemination Committee report. In: Allergy 59 (5), S. 469–478. DOI: 10.1111/j.1398-9995.2004.00526.x.
McMillan, S. J.; Lloyd, C. M. (2004): Prolonged allergen challenge in mice leads to persistent airway remodelling. In: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 34 (3), S. 497–507.
Miller, Marina; Cho, Jae Youn; McElwain, Kirsti; McElwain, Shauna; Shim, Jung Yeon;
Manni, Michael et al. (2006): Corticosteroids prevent myofibroblast accumulation and airway remodeling in mice. In: American journal of physiology. Lung cellular and molecular physiology 290 (1), S. L162-9. DOI: 10.1152/ajplung.00252.2005.
Monteseirín, J. (2009): Neutrophils and asthma. In: Journal of investigational allergology &
clinical immunology 19 (5), S. 340–354.
Murdoch, Jenna R.; Lloyd, Clare M. (2010): Chronic inflammation and asthma. In:
Mutation research 690 (1-2), S. 24–39. DOI: 10.1016/j.mrfmmm.2009.09.005.
References
Nials, Anthony T.; Uddin, Sorif (2008): Mouse models of allergic asthma: acute and chronic allergen challenge. In: Disease models & mechanisms 1 (4-5), S. 213–220.
DOI: 10.1242/dmm.000323.
Nygaard, Unni Cecilie; Aase, Audun; Lovik, Martinus (2005): The allergy adjuvant effect of particles - genetic factors influence antibody and cytokine responses. In: BMC immunology 6, S. 11. DOI: 10.1186/1471-2172-6-11.
Ohno, I.; Nitta, Y.; Yamauchi, K.; Hoshi, H.; Honma, M.; Woolley, K. et al. (1996):
Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation. In: American journal of respiratory cell and molecular biology 15 (3), S. 404–409. DOI: 10.1165/ajrcmb.15.3.8810646.
Olin, J. Tod; Wechsler, Michael E. (2014): Asthma: pathogenesis and novel drugs for treatment. In: BMJ (Clinical research ed.) 349, g5517.
Paul, W. E.; Seder, R. A. (1994): Lymphocyte responses and cytokines. In: Cell 76 (2), S.
241–251.
Pawankar, Ruby; Hayashi, Miyuki; Yamanishi, Shingo; Igarashi, Toru (2015): The paradigm of cytokine networks in allergic airway inflammation. In: Current opinion in allergy and clinical immunology 15 (1), S. 41–48. DOI:
10.1097/ACI.0000000000000129.
Pepper, Amber N.; Renz, Harald; Casale, Thomas B.; Garn, Holger (2017): Biologic Therapy and Novel Molecular Targets of Severe Asthma. In: The journal of allergy and clinical immunology. In practice 5 (4), S. 909–916. DOI:
10.1016/j.jaip.2017.04.038.
Pereira, R. F.; Halford, K. W.; O'Hara, M. D.; Leeper, D. B.; Sokolov, B. P.; Pollard, M. D.
et al. (1995): Cultured adherent cells from marrow can serve as long-lasting precursor cells for bone, cartilage, and lung in irradiated mice. In: Proceedings of the National Academy of Sciences of the United States of America 92 (11), S.
4857–4861.
Persson, Carl; Uller, Lena (2010): Transepithelial exit of leucocytes: inflicting, reflecting or resolving airway inflammation? In: Thorax 65 (12), S. 1111–1115. DOI:
10.1136/thx.2009.133363.
Porcheray, F.; Viaud, S.; Rimaniol, A-C; Leone, C.; Samah, B.; Dereuddre-Bosquet, N. et al. (2005): Macrophage activation switching: an asset for the resolution of inflammation. In: Clinical and experimental immunology 142 (3), S. 481–489. DOI:
10.1111/j.1365-2249.2005.02934.x.
References
Pouliot, Philippe; Willart, Monique A.; Hammad, Hamida; Lambrecht, Bart N. (2010):
Studying the function of dendritic cells in mouse models of asthma. In: Methods in molecular biology (Clifton, N.J.) 595, S. 331–349. DOI: 10.1007/978-1-60761-421-0_22.
Prussin, Calman; Metcalfe, Dean D. (2003): 4. IgE, mast cells, basophils, and eosinophils.
In: The Journal of allergy and clinical immunology 111 (2 Suppl), S486-94.
Ray, A.; Khare, A.; Krishnamoorthy, N.; Qi, Z.; Ray, P. (2010): Regulatory T cells in many flavors control asthma. In: Mucosal immunology 3 (3), S. 216–229. DOI:
10.1038/mi.2010.4.
Redington, A. E.; Madden, J.; Frew, A. J.; Djukanovic, R.; Roche, W. R.; Holgate, S. T.;
Howarth, P. H. (1997): Transforming growth factor-beta 1 in asthma. Measurement in bronchoalveolar lavage fluid. In: American journal of respiratory and critical care medicine 156 (2 Pt 1), S. 642–647. DOI: 10.1164/ajrccm.156.2.9605065.
Robinson, D. S.; Hamid, Q.; Jacobson, M.; Ying, S.; Kay, A. B.; Durham, S. R. (1993):
Evidence for Th2-type T helper cell control of allergic disease in vivo. In: Springer seminars in immunopathology 15 (1), S. 17–27.
Romagnani, S. (2006): Regulation of the T cell response. In: Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 36 (11), S. 1357–1366. DOI: 10.1111/j.1365-2222.2006.02606.x.
Rose, M. C.; Piazza, F. M.; Chen, Y. A.; Alimam, M. Z.; Bautista, M. V.; Letwin, N.; Rajput, B. (2000): Model systems for investigating mucin gene expression in airway diseases. In: Journal of aerosol medicine : the official journal of the International Society for Aerosols in Medicine 13 (3), S. 245–261.
Roth, Michael; Tamm, Michael (2010): The effects of omalizumab on IgE-induced cytokine synthesis by asthmatic airway smooth muscle cells. In: Annals of allergy, asthma &
immunology : official publication of the American College of Allergy, Asthma, &
Immunology 104 (2), S. 152–160. DOI: 10.1016/j.anai.2009.11.022.
Rothenberg, Marc E.; Hogan, Simon P. (2006): The eosinophil. In: Annual review of immunology 24, S. 147–174. DOI: 10.1146/annurev.immunol.24.021605.090720.
Sakai, K.; Yokoyama, A.; Kohno, N.; Hamada, H.; Hiwada, K. (2001): Prolonged antigen exposure ameliorates airway inflammation but not remodeling in a mouse model of bronchial asthma. In: International archives of allergy and immunology 126 (2), S.
126–134.
References
Sampson, A. P. (2000): The role of eosinophils and neutrophils in inflammation. In:
Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology 30 Suppl 1, S. 22–27.
Schmid, Daphné A.; Irving, Melita B.; Posevitz, Vilmos; Hebeisen, Michael; Posevitz-Fejfar, Anita; Sarria, J-C Floyd et al. (2010): Evidence for a TCR affinity threshold delimiting maximal CD8 T cell function. In: Journal of immunology (Baltimore, Md. : 1950) 184 (9), S. 4936–4946. DOI: 10.4049/jimmunol.1000173.
Schmidt, Matthias; Sun, Guo; Stacey, Martin A.; Mori, Luca; Mattoli, Sabrina (2003):
Identification of circulating fibrocytes as precursors of bronchial myofibroblasts in asthma. In: Journal of immunology (Baltimore, Md. : 1950) 171 (1), S. 380–389.
Schmidt, J.; Fleissner, S.; Heimann-Weitschat, I.; Lindstaedt, R.; Szelenyi, I. (1994): The effect of different corticosteroids and cyclosporin A on 4 and interleukin-5 release from murine TH2-type T cells. In: European journal of pharmacology 260 (2-3), S. 247–250.
Schroeder, John T. (2009): Basophils beyond effector cells of allergic inflammation. In:
Advances in immunology 101, S. 123–161. DOI: 10.1016/S0065-2776(08)01004-3.
Selmi, Carlo (2010): Autoimmunity in 2009. In: Autoimmunity reviews 9 (12), S. 795–800.
DOI: 10.1016/j.autrev.2010.08.008.
Shen, Huahao; O'Byrne, Paul M.; Ellis, Russ; Wattie, Jennifer; Tang, Chibing; Inman, Mark D. (2002): The effects of intranasal budesonide on allergen-induced production of interleukin-5 and eotaxin, airways, blood, and bone marrow eosinophilia, and eosinophil progenitor expansion in sensitized mice. In: American journal of respiratory and critical care medicine 166 (2), S. 146–153. DOI:
10.1164/rccm.2008161.
Shim, J. J.; Dabbagh, K.; Ueki, I. F.; Dao-Pick, T.; Burgel, P. R.; Takeyama, K. et al.
(2001): IL-13 induces mucin production by stimulating epidermal growth factor receptors and by activating neutrophils. In: American journal of physiology. Lung cellular and molecular physiology 280 (1), L134-40.
Solway, Julian; Irvin, Charles G. (2007): Airway smooth muscle as a target for asthma therapy. In: The New England journal of medicine 356 (13), S. 1367–1369. DOI:
10.1056/NEJMe078005.
Southam, D. S.; Ellis, R.; Wattie, J.; Young, S.; Inman, M. D. (2008a): Budesonide prevents but does not reverse sustained airway hyperresponsiveness in mice. In:
References
The European respiratory journal 32 (4), S. 970–978. DOI:
10.1183/09031936.00125307.
Southam, David S.; Ellis, Russ; Wattie, Jennifer; Glass, William; Inman, Mark D. (2008b):
Goblet cell rebound and airway dysfunction with corticosteroid withdrawal in a mouse model of asthma. In: American journal of respiratory and critical care medicine 178 (11), S. 1115–1122. DOI: 10.1164/rccm.200801-084OC.
Stewart, A. G.; Grigoriadis, G.; Harris, T. (1994): Mitogenic actions of endothelin-1 and epidermal growth factor in cultured airway smooth muscle. In: Clinical and experimental pharmacology & physiology 21 (4), S. 277–285.
Stockinger, Brigitta; Veldhoen, Marc (2007): Differentiation and function of Th17 T cells. In:
Current opinion in immunology 19 (3), S. 281–286. DOI: 10.1016/j.coi.2007.04.005.
Suissa, S.; Ernst, P.; Kezouh, A. (2002): Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma. In: Thorax 57 (10), S. 880–884.
Temelkovski, J.; Hogan, S. P.; Shepherd, D. P.; Foster, P. S.; Kumar, R. K. (1998): An improved murine model of asthma: selective airway inflammation, epithelial lesions and increased methacholine responsiveness following chronic exposure to aerosolised allergen. In: Thorax 53 (10), S. 849–856.
Ting, C. N.; Olson, M. C.; Barton, K. P.; Leiden, J. M. (1996): Transcription factor GATA-3 is required for development of the T-cell lineage. In: Nature 384 (6608), S. 474–
478. DOI: 10.1038/384474a0.
Tliba, Omar; Panettieri, Reynold A. (2009): Noncontractile functions of airway smooth muscle cells in asthma. In: Annual review of physiology 71, S. 509–535. DOI:
10.1146/annurev.physiol.010908.163227.
Townsend, Michael J.; Monroe, John G.; Chan, Andrew C. (2010): B-cell targeted therapies in human autoimmune diseases: an updated perspective. In: Immunol.
Rev. 237 (1), S. 264–283. DOI: 10.1111/j.1600-065X.2010.00945.x.
Van Hove, C L; Maes, T.; Joos, G. F.; Tournoy, K. G. (2008): Chronic inflammation in asthma: a contest of persistence vs resolution. In: Allergy 63 (9), S. 1095–1109.
DOI: 10.1111/j.1398-9995.2008.01772.x.
Van Hove, Chris L.; Maes, Tania; Joos, Guy F.; Tournoy, Kurt G. (2007): Prolonged inhaled allergen exposure can induce persistent tolerance. In: American journal of respiratory cell and molecular biology 36 (5), S. 573–584. DOI:
10.1165/rcmb.2006-0385OC.
References
Vercelli, Donata (2008): Discovering susceptibility genes for asthma and allergy. In:
Nature reviews. Immunology 8 (3), S. 169–182. DOI: 10.1038/nri2257.
Vernal, Rolando; Garcia-Sanz, Jose (2008): Th17 and Treg Cells, Two New Lymphocyte Subpopulations with a Key Role in the Immune Response Against Infection. In:
IDDT 8 (4), S. 207–220. DOI: 10.2174/187152608786734197.
Vicario, M.; Blanchard, C.; Stringer, K. F.; Collins, M. H.; Mingler, M. K.; Ahrens, A. et al.
(2010): Local B cells and IgE production in the oesophageal mucosa in eosinophilic oesophagitis. In: Gut 59 (1), S. 12–20. DOI: 10.1136/gut.2009.178020.
Vignola, A. M.; Chanez, P.; Chiappara, G.; Merendino, A.; Pace, E.; Rizzo, A. et al. (1997):
Transforming growth factor-beta expression in mucosal biopsies in asthma and chronic bronchitis. In: American journal of respiratory and critical care medicine 156 (2 Pt 1), S. 591–599. DOI: 10.1164/ajrccm.156.2.9609066.
Wasserman, S. I. (1984): The human lung mast cell. In: Environ. Health Perspect. 55, S.
259–269.
Wegmann, M.; Fehrenbach, H.; Fehrenbach, A.; Held, T.; Schramm, C.; Garn, H.; Renz, H. (2005): Involvement of distal airways in a chronic model of experimental asthma.
In: Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology 35 (10), S. 1263–1271. DOI:
Witko-Sarsat, V.; Rieu, P.; Descamps-Latscha, B.; Lesavre, P.; Halbwachs-Mecarelli, L.
(2000): Neutrophils: molecules, functions and pathophysiological aspects. In:
Laboratory investigation; a journal of technical methods and pathology 80 (5), S.
617–653.
Yang, Ivana V.; Schwartz, David A. (2012): Epigenetic mechanisms and the development of asthma. In: The Journal of allergy and clinical immunology 130 (6), S. 1243–
1255. DOI: 10.1016/j.jaci.2012.07.052.
Zosky, G. R.; Sly, P. D. (2007): Animal models of asthma. In: Clinical and experimental allergy: journal of the British Society for Allergy and Clinical Immunology 37 (7), S.
973–988. DOI: 10.1111/j.1365-2222.2007.02740.x.
Zuhdi Alimam, M.; Piazza, F. M.; Selby, D. M.; Letwin, N.; Huang, L.; Rose, M. C. (2000):
Muc-5/5ac mucin messenger RNA and protein expression is a marker of goblet cell metaplasia in murine airways. In: American journal of respiratory cell and molecular biology 22 (3), S. 253–260. DOI: 10.1165/ajrcmb.22.3.3768.
LIST OF ACADEMIC TEACHERS
LIST OF ACADEMIC TEACHERS
My academic teachers include the Professors and Privatdozents from:
Philipps University Marburg: Garn, Renz
Damascus University: Abu-Asali, abu-Samra, Al-Haffar, Ali, Al-Jokhadar, Abbas, Bukdash, Hajar, Kabani, Katan, Jairoudi, Makhlof, Mansour, Mourad, Nahas, Othman, Reehawi, Sabah, Shaikha
Curriculum Vitae
Curriculum Vitae
Mohammed Alrifai M.D.
1993-1999 Study of human medicine, Damascus University, Syria.
1999 Sate examination and licence to practise medicine, 1999 Master degree on medicine. Title (Role of old and
New laboratory diagnostics to investigate causes of liver . Cirrhosis in Syria)
Professional Career
1999-2003 Resident physician at the department of laboratory medicine, Al Mouassat university hospital, Damascus University, Syria.
2003 Specialist in the field of laboratory medicine 11/2003 – 06/2006 Head of private Laboratory, Damascus, Syria.
06/2006 – 02/2008 Specialist in the central laboratory, Al Mouassat university hospital, Damascus University, Syria.
02/2008 – 10/2011 Doktorand in the field of immunology and haematology, biomedical research centre, Philipps University, Marburg, Germany (Head: Prof.
Dr. H. Renz)
02/2008 – 10/2011 Resident in the institute of laboratory medicine and pathochemistry and molecular diagnostics, University hospital Giessen and Marburg GmbH, Marburg, Germany (Head: Prof. Dr. H. Renz)
Since 10/2011 Physician in the Department of Hemostaseology (Head:
Prof. Dr. B. Kemkes-Matthes), University Hospital Giessen
and Marburg GmbH, Giessen, since 01.08.2018 (partial time 51%) 28.09.2016 Recognition of the specialist title for Laboratory Medicine
01.08.2017 Specialist (partial time 49%) in the institute of laboratory medicine and pathochemistry and molecular diagnostics, University hospital Giessen and Marburg GmbH, Giessen, Germany (Head: Prof. Dr. H.
Renz)
20.10.2017 Specialist in the field of Hemostaseology Languages Arabic, German and English
Publications
Publications:
-
Compartmental and temporal dynamics of chronic inflammation and airway remodelling in a chronic asthma mouse model. Mohammed Alrifai, Leigh M.Marsh, Tanja Dicke, Ayse Kılıç, Melanie L. Conrad, Harald Renz, and Holger Garn. PLoS One. 2014 Jan 21;9(1):e85839. doi: 0.1371/journal.pone. 0085839.
eCollection 2014.
-
Suppression of adrenomedullin contributes to vascular leakage and altered epithelial repair during asthma.Hagner S, Welz H, Kicic A, Alrifai M, MarshLM, Sutanto EN,Ling KM, Stick SM, Müller B, Weissmann N, Renz H. Allergy.
2012 Aug;67(8):998-1006. doi: 10.1111/j.1398-9995.2012.02851.x. Epub 2012 Jun 12.
-
Neonatal supplementation of processed supernatant from Lactobacillusrhamnosus GG improves allergic airway inflammation in mice later in life. Harb H, van Tol EA, Heine H, Braaksma M, Gross G, Overkamp K, Hennen M, Alrifai M, Conrad ML, Renz H, Garn H. Clin Exp Allergy. 2013 Mar;43(3):353-64. doi:
10.1111/cea.12047.
-
A highly specialised self-made computer program enhances efficiency and safety of immunohaematology reports. Slonka J, Alrifai M, Bein G, Sachs UJ.Transfus Med. 2013 Jun;23(3):207-14. doi: 10.1111/tme.12024. Epub 2013 Mar 21.