Viral infections in airway remodeling

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1 Viral infections in airway remodeling Nikos Papadopoulos As. Proffesor,Head, Allergy Dpt, 2 nd Pediatric Clinic, University of Athens

2 Overview Acute events may have long term consequences Remodeling appears early in asthma Viral infections may initiate/perpetuate remodeling

3 Viral Infections trigger wheezing & asthma exacerbations

4 Respiratory viruses and asthma exacerbations 15% Children 85% Adults 60% 40% Johnston et al. BMJ (1995) 310:1225 Nicholson et al. BMJ (1993) 307:982 5% 24% Children 95% Adults 76% Ruuskanen et al. (2006) Wark et al. ERJ (2002) 19:68

5 Severe infections (with wheezing) early in life are associated with asthma later on

6 Rhinovirus infection at infancy Birth cohort of high risk infants (n=275) Severity, not frequency of RV infections predicts wheezing at 3 years Lemanske et al. J Allergy Clin Immunol 2005;116:571

7 Remodeling begins early in life

8 Elements of remodeling in asthma Inflammatory cell infiltration Fibroblast proliferation Angiogenesis Goblet cell hyperplasia Collagen deposition Smooth muscle hypertrophy Tissue destruction Hamid Q (ed). JACI 2003;111:1420

9 Biopsy study Remodeling in children 19 children with severe asthma (6-16y) 10 children without asthma (7-16y) adults (8 normal, 10 mild, 6 severe asthma) Payne et al. AJRCCM 2003;167:78

10 Virus-induced remodeling

11 Biology of airway remodelling A failure in the epithelial injury repair cycle Increased susceptibility to injury Impaired wound healing Vignola et al. Chest (2003) 123:417S

12 Possible interference Epithelial activation Th2 induction Cytotoxicity Vignola et al. Chest (2003) 123:417S

13 RV infection induces cytotoxicity Not extensive in-vivo Feasible in-vitro in sparsely seeded cultures Papadopoulos et al. J Inf Dis (2000) 181:1875

14 RV infection delays epithelial repair Baseline 24h-Control 24h-RV infected Bossios et al. Resp Res 2005;6:114

15 RV infection affects epithelial wound healing Sq pixels Unpopulated area (Square pixels) Control RV Hours Bossios et al. Resp Res 2005;6:114

16 Immune protection from viral cytotoxicity is hampered in an atopic environment Cytotoxicity Cytotoxicity (%) p= p= p< Control RV + atopic + normal Xatzipsalti et al. Clin Exp Allergy 2008

17 Angiogenesis as part of the remodeling process Hoshino et al. JACI 2001;107:295 Increased number of vessels and vessel area Tanaka et al. AJRCCM 2003;168:1

18 Rhinovirus infection upregulates VEGF expression & production Control RV1b VEGF (pg/ml) VEGF mrna time (hours) BEAS-2B cells exposed to 1MOI of RV1b Psarras, Papadopoulos et al. J Allergy Clin Immunol 2006; in press

19 RV induces angiogenesis in-vitro Medium RV VEGF Psarras, Papadopoulos et al. J Allergy Clin Immunol 2006;117:291

20 VEGF during RV-associated asthma exacerbations VEGF (pg/ml) baseline exacerbation Psarras, Papadopoulos et al. J Allergy Clin Immunol 2006; in press

21 RV-induced angiogenesis is increased in an atopic environment Psaras et al JAllergy Clin Immunol 2006;117:291

22 RV infection upregulates FGF-2 bfgf(pg/ml) ** ** * 0 0,1 0,2 0, C bfgf (pg/ml) *** ** *** * Time (hours) Control RV1b MOI 1000 R 2 =0.91 bfgf (pg/ml)= 9.16*CTX+4.96 Control RV1b F bfgf β-actin bfgf (pg/ml) Skevaki et al Cytotoxicity (%)

23 RV-infected epithelial cells stimulate fibroblast proliferation, through FGF-2 [ 3 H]-Thymidine incorporation (% of Control) anti-fgf-2 neutralizing Ab ** Control RV-CM FGF-2 Skevaki et al. submitted

24 TGF production by epithelial cells TGF-b1 log (pg/ml) p=0.07 p=0.02 Control RV + atopic + normal Xatzipsalti, Papadopoulos et al. Clin Exp Allergy 2008

25 Virus-induced remodeling: is it preventable?

26 Effect of Fluticasone + Salmeterol on VEGF production Volonaki et al Clin Exp Allergy 2006;36:1268

27 Effect on FGF-2 Volonaki et al Clin Exp Allergy 2006;36:1268

28 Effect of budesonide + formoterol RV B8 B9 F8 B8F8 B9F8 18S IL-6 CXCL8 CCL5 bfgf Fold-difference in gene expression compared to RV (normalised to 18S) ** # # * * ### ** ### IL-6 CXCL8 CCL5 bfgf ** B8 B9 F8 B8F8 B9F8 Skevaki et al 2009

29 Conclusions Viral infection may initiate and/or perpetuate the remodelling process disruption of the repair process Induction of remodeling-associated factors augmented in an atopic environment Some potential for prevention via steroids, combinations (?)

30 Acknowledgements

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