Smoking and Interstitial Lung Diseases: what s s new

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1 Smoking and Interstitial Lung Diseases: what s s new Katerina M. Antoniou, MD, PhD ERS 1.05 Group Chair As. Professor in Thoracic Medicine Head of the Molecular & Cellular Pneumonology Lab Medical School, University of Crete 6 th International Meeting on Pulmonary Rare diseases and orphan drugs Milan, Italy, February 27-28, 2015

2 The direct pathogenetic relationship between cigarette smoking respiratory diseases such as emphysema, (COPD), and lung cancer is well documented. Regarding interstitial lung damage there is strong evidence providing links with cigarette smoking. Pulm Med. 2011

3 Clin Chest Med. 2012

4 Respiratory Bronchiolitis RB represents a highly specific physiological response to smoking. RB is characterised by airway-centred accumulations of macrophages containing fine, granular yellow brown cytoplasmic pigments ( smoker s macrophages ) within distal bronchioles, alveolar ducts and adjacent alveolar spaces. Cytoplasmic pigmentation is variable and correlates with the numbers of pack years smoked. Caminati A, et al. ERR 2012

6 Pathogenetic insights

8 Autophagy is a highly conserved homeostatic mechanism It contributes to cellular homeostasis by: (a) providing an alternative source of metabolic fuel (b) removing damaged cellular components which are toxic to the cell (c) promoting cell death BioMed Research International 2013

9 Autophagy smoking- IPF In IPF is decreased possibly due to the action of TGF-β1. Smoking by inducing TGF-β1 production may suppresss autophagy

11 Alveolar type II cells (AECIIs) in the lungs of IPF patients exhibit marked accumulation of dysmorphic and dysfunctional mitochondria. Impaired mitochondria in IPF and aging lungs were associated with low expression of PTEN-induced putative kinase 1 (PINK1). Young PINK1-deficient mice developed similarly dysmorphic, dysfunctional mitochondria in the AECIIs and were vulnerable to apoptosis and development of lung fibrosis. PINK1 deficiency results in swollen, dysfunctional mitochondria and defective mitophagy, and promotes fibrosis in the aging lung. Bueno M, et al.j Clin Invest Fe

12 Bueno M, et al.j Clin Invest Fe

13 2012

16 PINK deficiency in UIP BALF macrophages PINK1 1.5 * * relative expression (GAPDH normalised) PINK1 C PINK1 IPF PINK1 RA-UIP n=23 n=55 n=20 Mann-Whitney test * : p<0.05 Varsamidi Irini, et al. ERS 2015 abstract submitted

17 AJRCCM 2012

18 No correlation of PINK1 expression and smoking status

19 Washko GR, NEJM 2011

20 Results (1) Interstitial lung abnormalities were present in 194/2416 (8%) of HRCTs These abnormalities were associated with: a. Reduced TLC (p<0.001) b. Lower % of emphysema (p<0.001) c. Restrictive lung deficit (TLC<80%) d. Not met the diagnostic criteria for COPD

21 The pathobiology of smoking can lead to two distinct patterns of injury emphysema (with destruction of the lung) or interstitial lung disease (with macrophage accumulation and fibrosis). NEJM 2011 relative lack of emphysema could be simply a reflection of the fact that the interstitial lung abnormalities mask emphysema or that more severe emphysema limits the extent of interstitial lung abnormalities.

22 Aim of the study To explore possible links between smoking; and a)ipf; b) NSIP; c) rheumatoid lung and d) SSc-ILD Antoniou K and Wells AU

23 to evaluate the functional consequences of smoking-related lung damage in CFA and to identify functional measures best reflecting the extent of fibrosing alveolitis on CT. 68 patients with CFA were studied. 14 patients with emphysema on CT were characterized by relative preservation of FVC and TLC (p < 0.005) and relative depression of dlco (p < 0.05) and Kco (p < ).

24 Wells AU, et al. AJRCCM 1997

28 Is smoking relevant to disease progression in IPF?

29 Our study addresses links between smoking and disease progression,, as judged by severity-adjusted survival.

30 * * * identical severity-adjusted survival

31 Does emphysema cluster with NSIP? Biopsy proven NSIP in smokers (n=18) Control cohort: Consecutive smokers in a smoking cessation clinic (n=137): Group A: A COPD on GOLD criteria (n=34) Group B: B Healthy smokers with normal FEV1 (n=103) HRCT evaluation

32 NSIP Findings Emphysema was present in 14/18 (77.8%) NSIP patients. Emphysema did not differ in prevalence between NSIP patients and control smokers with COPD (25/34, 73.5%) on univariate analysis and on multiple logistic regression. Emphysema was strikingly more prevalent in NSIP patients than in Group B control subjects (18/103, 17.5%), p< Marten K, Milne D, Antoniou KM, et al. Eur Radiol

33 Autoimmune rheumatic diseases Multifactorial in etiology Disease susceptibility: HLA, specific genes, sex Tobacco smoking has been linked to the development of SLE and RA. Interaction with genetic factors to create a significant risk of disease.

36 Results Antoniou KM, et al. Respirology 2013

37 Scleroderma lung and emphysema 1. Recent work has established that in suspected PAH, an elevated FVC/DLco ratio identifies an increased likelihood of PAH at right heart study. 2. In a recent large cohort of SSc patients with little or no lung disease, an elevated FVC/DLco ratio of over 1.60 was one of the three variables considered to justify the performance of a right heart study. However, an elevated FVC/DLco ratio is also seen when emphysema coexists with interstitial fibrosis.

38 We examined : 1. the prevalence of CPFE in SSc patients with interstitial lung disease (SSc-ILD) and 2. the effect of CPFE on PFTs used to evaluate the severity of SSc-ILD and the likelihood of PH. Antoniou KM, Margaritopoulos G, Goh N, et al. Arthritis Rheum submitted

39 Results Emphysema was present in : 41/336 cases overall (12.2%) in 26/132 smokers (19.7%) and in 15/201 life-long non smokers (7.5%)

40 CPFE in Scleroderma Lung After adjustment for the extent of ILD, emphysema: 1) reduced DLco by over 10% 2) had no effect on FVC 3) increased the FVC/DLco by over 40% In smokers and non-smokers

41 Antoniou KM, Margaritopoulos G, Goh N, et al. Arthritis Rheum submitted

42 Conclusions A predilection to emphysema in SSc-ILD: 1. its sporadic presence in non-smokers and 2. a low associated pack-year smoking history in smokers. The significance prevalence of emphysema in non-smokers with SSc-ILD provides indirect support for a pathogenetic basis for a syndrome of CPFE.

43 CPFE syndrome in Scleroderma lung: is associated with disproportionate impairment of measures of gas transfer and gas exchange a major confounding effect on the FVC/DLco ratio These findings have major implications for the construction of accurate screening algorithms for PH in SSc-ILD.

44 Collaborators Laboratory of Cellular and Molecular Pneumonology Katerina Antoniou Eliza Tsitoura, Post doc Researcher George Margaritopoulos, PhD Katerina Samara, PhD H Ismini Lasithiotaki Kostas Karagiannis Athanasia Proklou Eleni Bibaki Stella Sarantoulaki Stelios Michelakis Eirini Varsamidi Eirini Charalambous Hara Koutoulaki Royal Brompton Hospital and Harefield NHS Trust Athol Wells Elizabeth Renzoni Hiroe Sato Laboratory of Clinical Virology Giogros Sourvinos Evi Vlachava Melina Tseliou

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