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delle Guidelines 2011 libra.Le ricordiamo che questo materiale è

di proprietà dell’autore e fornito come supporto didattico per uso

personale.

R Rodríguez-Roisin, MD

Universitatde Barcelona

INCREASED PERIPHERAL NEUTROPHIL STIFFNESS IN

COPD: IS IT RELEVANT?

Background

Approaches

Data

Implications

AGENDA

Barnes, PJ. NEJM 2000;343:269-80

COPD & PULMONARY INFLAMMATION

WYE8N41 - Global Slide Kit

Rytllä P et al. ERJ 2007:28:1163-9

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;350:2645-53

NATURE OF SMALL AIRWAY OBSTRUCTION IN COPD

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 µmCapillary

6-8 µmNeutrophil

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

• 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 measurementsPhase 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

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

Cel

l S

tiff

nes

s, P

a

Admission Convalescence

p < 0.05

NON-RECURRENT EXACERBATIONS

RECURRENT EXACERBATIONS

NS

102

103

104

102

103

104

Admission Recurrence

PERIPHERAL NEUTROPHIL STIFFNESS& COPD EXACERBATIONS

102 103 104

5.5

6.0

5.0

6.5

7.0

7.5

8.0

8.5

Cell Stiffness, Pa

AD

O I

nd

ex

r = 0.60

p < 0.05

PERIPHERAL NEUTROPHIL STIFFNESS& COPD EXACERBATIONS

Background

Approaches

Data

Implications

AGENDA

Grootendorst DC et al. Thorax 2007;62:1081-7

ROFLUMILAST & INFLAMMATORYCELLS IN STABLE COPD

Holz Y et al. ERJ 2010;35:564-70

NOVEL CXCR2 ANTAGONIST & NEUTROPHILIA INHIBITION

Universitatde Barcelona

Almendros, Isaac (IDIBAPS)Hernández, Lisbeth (FCRB)

Navajas, Daniel (UB)Roman, Antonio (HVH)

ACKNOWLEDGEMENTS