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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