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R Rodríguez-Roisin, MD Universitat de Barcelona INCREASED PERIPHERAL NEUTROPHIL STIFFNESS IN COPD: IS IT RELEVANT?

 Background  Approaches  Data  Implications AGENDA

GOLD DEFINITION, 2010 Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease with some significant extrapulmonary effects that may contribute to the severity in individual patients. Its pulmonary component is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lung to noxious particles or gases GOLD Update

Barnes, PJ. NEJM 2000;343: COPD & PULMONARY INFLAMMATION

WYE8N41 - Global Slide Kit Rytllä P et al. ERJ 2007:28: SPUTUM NEUTROPHILS IN STABLE COPD

7 NEUTROPHILS & BRONCHIAL GLANDS IN STABLE COPD Saetta M et al. AJRCCM 1997;156:1633-9

Hogg JC et al. NEJM 2004;350: NATURE OF SMALL AIRWAY OBSTRUCTION IN COPD

WYE8N41 - Global Slide Kit Hurst JR et al. NEJM 2010;363: SUSCEPTIBILITY TO FREQUENT COPD EXACERBATIONS

SYSTEMIC EFFECTS & COPD Agustí AGN et al. ERJ 2003;21:347-60

Noguera A et al. Thorax 2001;56:432-7 NEUTROPHIL RESPONSE IN COPD

 Background  Approaches  Data  Implications AGENDA

Induced Sputum Bronchoalveolar Lavage Bronchial Biopsy Lung Tissue Peripheral Blood APPROACHES

LUNG NEUTROPHIL RETENTION In the uninflamed lung, most neutrophils must become elongated to pass through the capillary bed into the venules. Inflammatoy stimuli induce neutrophils to become stiffer and less able to be deformable… Cell adhesion signalling Cell rheology Neutrophil sequestration within lungs Alveolar lumen Epithelium Endothelium Neutrophil 2-15 µm Capillary 6-8 µm Neutrophil Doerschuk CM. AJRCCM 1999;159:1693-5

…This retention is probably due to the process of deformation that neutrophils undergo when entering microcapillaries, which is dependent on neutrophil mechanical properties. The retention of neutrophils in microcapillaries is known to increase with neutrophil stiffness... LUNG NEUTROPHIL RETENTION Worthen, GS et al. Science 1989;245:183-6

…The stiffness of leukocytes could also regulate their adhesion to the endothelium in larger blood vessels by modulating the contact area between leukocytes and the endothelium. Neutrophil deformation and recovery during microvascular transit are dynamic processes... Wojcikiewicz EP et al. J Cell Sci 2003;116: LUNG NEUTROPHIL RETENTION

Extraction of 4 ml of peripheral venous blood Isolation of neutrophils Atomic Force Microscopy (AFM) 40 µm ATOMIC FORCE MICROSCOPE TECHNIQUE Laser beam Lens Cantilever Coverslip Neutrophil d Fotodiode AFM measurements Phase contrast image

 Background  Approaches  Data  Implications AGENDA

Peripheral blood neutrophil stiffness could be increased in parallel to the spirometric severity of COPD and the underlying structural derangement into the lungs This increased neutrophil stiffness could decrease after bilateral pulmonary transplantation HYPOTHESIS

PERIPHERAL NEUTROPHIL STIFFNESS & COPD

PERIPHERAL NEUTROPHIL STIFFNESS & COPD: AFTER LUNG TRANSPLANT (LT)

PERIPHERAL NEUTROPHIL STIFFNESS & COPD

1. Compared with healthy nonsmokers peripheral blood neutrophil stiffness is increased not only in COPD patients across the spectrum of all spirometric grades but also in smokers with normal lung function. SUMMARY (1)

2.Increased peripheral neutrophil stiffness is associated with the presence of symptoms and with lung function abnormalities (spirometry and gas exchange). 3.After lung transplantation increased peripheral neutrophil stiffness normalizes without differences with healthy nonsmokers. SUMMARY (2)

Increased peripheral neutrophil stiffness across the different COPD grades reflects both impact and severity of disease. Moreover, increased neutrophil stiffness precedes COPD development. Its reduction to normalcy after lung transplantation indicates that it is primarily modulated by underlying lung architectural pathology, without excluding a reduction of systemic inflammation CONCLUSIONS

Cell Stiffness, Pa AdmissionConvalescence p < 0.05 NON-RECURRENT EXACERBATIONS RECURRENT EXACERBATIONS NS AdmissionRecurrence PERIPHERAL NEUTROPHIL STIFFNESS & COPD EXACERBATIONS

Cell Stiffness, Pa ADO Index r = 0.60 p < 0.05 PERIPHERAL NEUTROPHIL STIFFNESS & COPD EXACERBATIONS

 Background  Approaches  Data  Implications AGENDA

Grootendorst DC et al. Thorax 2007;62: ROFLUMILAST & INFLAMMATORY CELLS IN STABLE COPD

Holz Y et al. ERJ 2010;35: NOVEL CXCR2 ANTAGONIST & NEUTROPHILIA INHIBITION

Universitat de Barcelona Almendros, Isaac (IDIBAPS) Hernández, Lisbeth (FCRB) Navajas, Daniel (UB) Roman, Antonio (HVH) ACKNOWLEDGEMENTS