Mesa 4. Nuevos abordajes y futuro de la EPOC Congreso A.R.C en EPOC

1. Mesa 4. Nuevos abordajes y futuro de la EPOC
Dra. Myriam
Calle Rubio
Hospital Clínico Universitario
San Carlos. Madrid

2. Mesa 4. Nuevos abordajes y futuro de la EPOC
[ATS] L-Carnitine
Supplementation
Attenuates Elastase-
Induced Emphysema
Progression
Conlon TM, Adamski J,
Eickelberg O, Yildirim AO

3. Mesa 4. Nuevos abordajes y futuro de la EPOC
Introduction
We have previously described a progressive emphysema following the
oropharyngeal application of porcine pancreatic elastase (PPE) into C57BL/6 mice,
characterized by a decline in lung function and progressive airspace enlargement.
Targeted metabolomic analysis of lung tissue from these mice revealed a reduction
in the concentration of a number of Acylcarnitines, with the greatest reduction in
free L-carnitine, a metabolite critical for transporting long chain fatty acids into the
mitochondria for their subsequent β-oxidation and a reported anti-oxidant.
We therefore hypothesized that supplementation with L-carnitine can impair the
development of PPEinduced emphysema.

4. Mesa 4. Nuevos abordajes y futuro de la EPOC
Methods
The progression of emphysema was examined in C57BL/6 mice that were
treated i.p. every other day with 500mg/kg L-carnitine following a single
oropharyngeal application of PPE, compared to mice that were not
supplemented with L-carnitine and PBS treated controls. Lung function and
histology were analyzed 28 days later. Alveolar epithelial type II-like murine LA-
4 cells were treated with L-carnitine and analyzed for apoptosis development
following PPE and H2O2 exposure, as well as wound healing ability.

5. Mesa 4. Nuevos abordajes y futuro de la EPOC
Resultados
PPE-treated mice demonstrated impaired lung function compared to PBS treated
controls (lung compliance of 0.067 ± 0.008 ml/cmH20 vs 0.035 ± 0.005 ml/cmH20,
respectively SD p<0.01), which improved following supplementation with L-carnitine
(lung compliance of 0.051 ± 0.006 ml/cmH20, p<0.01 compared to mice only treated
with PPE).
Lung histology also revealed that supplementation with L-carnitine reduced the
airspace enlargement caused by PPE-treatment.
Interestingly, L-carnitine significantly inhibited the development of both H2O2 and PPE
induced apoptosis in cultured LA-4 cells as determined by Annexin V staining.
However, culturing LA-4 cells in the presence of increasing concentrations of L-carnitine
did not improve the wound healing ability of these cells in a scratch assay.

6. Mesa 4. Nuevos abordajes y futuro de la EPOC
Conclusions
Our results indicate that supplementation of mice with L-carnitine
attenuates the severity of PPE-induced emphysema, and that this may
in part be due to reduced levels of apoptosis.
We therefore suggest that L-carnitine supplementation, which is used
clinically for the treatment of neonates with congenital metabolic diseases,
may be beneficial to COPD patients.

7. Mesa 4. Nuevos abordajes y futuro de la EPOC
[ATS] CFTR Potentiator
Ivacaftor, A Novel Mucus
Clearance Therapy In
COPD
Lin VY

8. Mesa 4. Nuevos abordajes y futuro de la EPOC
CFTR PotentiatorIvacaftor, a Novel Mucus Clearance
Therapy in COPD
COPD patients exhibit diminished Cystic Fibrosis Transmembrane Conductance
Regulator (CFTR)-dependent ion transport resembling that of cystic fibrosis (CF),
potentially causing mucus obstruction.
In healthy airways, CFTR conducts anions across the epithelium to drive airway hydration,
mucus maturation, and mucociliary clearance (MCC).
Titular tabla
We have previously shown that the CFTR potentiatorivacaftor (VX-770) can improve
CFTR anion transport in smoke-exposed epithelia, potentially ameliorating MCC in
COPD.
Am J RespirCrit Care Med 191;2015:A3871

9. Mesa 4. Nuevos abordajes y futuro de la EPOC
METHODS
Effects of ivacaftor on mucociliary properties were evaluated with micro-optical
coherence tomography (µOCT) imaging in primary human bronchial epithelial (HBE)
cells exposed to 2 % cigarette smoke extract (CSE), or human bronchial tissues exposed
to whole cigarette smoke (WCS) from one 3R4F cigarette for 10 minutes, and compared
to DMSO (Vehicle) or air controls.
Tomography (µOCT) simultaneously quantified airway surface liquid (ASL) depth, ciliary
beat frequency (CBF), and mucociliary transport (MCT). Changes in mucus viscosity were
determined using time of fluorescent recovery after photobleaching (FRAP).
Am J RespirCrit Care Med 191;2015:A3871

10. Mesa 4. Nuevos abordajes y futuro de la EPOC
RESULTS
In HBE cells, cigarette smoke reduced ASL height by 36 % (Veh 13.3 ± 0.7, CSE 8.4 ± 0.6 µm),
CBF by 15 % (Veh 5.9 ± 0.2, CSE 5.0 ± 0.1 Hz), and MCT by 98 % (Veh 0.25 ± 0.03, CSE 0.004 ±
0.002 mm/min). Ivacaftor rescued these smoke-induced effects on ASL (18.8 ± 1.3 µm, p <
0.001), CBF (6.62 ± 0.2 Hz, p < 0.001), and MCT (0.25 ± 0.03 mm/min, p < 0.001).
FRAP indicated ivacaftor reduced mucus viscosity in airway tissues from non-smokers and
healthy smokers by 56 % (Veh 14.9 ± 0.3, ivacaftor 6.4 ± 0.6 s, p < 0.0001).

11. Mesa 4. Nuevos abordajes y futuro de la EPOC
CONCLUSIONS:
CFTR activation by ivacaftor overcomes cigarette smoke-induced mucus clearance
abnormalities.
Ivacaftor conferred marked improvements in MCT in smoke-exposed bronchial
tissue by reducing mucus viscosity, indicating its potential as a novel COPD
therapy.
CFTR PotentiatorIvacaftor, a Novel Mucus Clearance Therapy in COPD
Am J RespirCrit Care Med 191;2015:A3871

12. Mesa 4. Nuevos abordajes y futuro de la EPOC
[ERS] Increased
circulating alveolar
epithelial microparticles
in COPD patients
Takahashi T

13. Mesa 4. Nuevos abordajes y futuro de la EPOC
• El aumento de la circulación de MPs refleja
daño endotelial.
• La circulación MPs esta aumentada en estres
oxidativo, infección, ECV…
• En la EPOC están ↑ VE-cadherin, PECAM,
E-selectin.
• Existen datos que sugieren su papel en la
patogénesis de enfisema.
• Es necesario estudiar su papel en la
progresión de la EPOC y la incidencia de
ECV.

14. Mesa 4. Nuevos abordajes y futuro de la EPOC
Titular tabla
Increased circulating alveolar epithelial
microparticles in COPD patients
We hypothesized that circulating alveolar epithelium-derived MPs
(Alveolar Epithelial MPs) increased in COPD patients.
Aims: To compare Alveolar Epithelial MP levels between stable
COPD patients and healthy non-COPD volunteers.

15. Mesa 4. Nuevos abordajes y futuro de la EPOC
Titular tabla
Increased circulating alveolar epithelial
microparticles in COPD patients
Methods: 46 stable COPD patients and 16 healthy volunteers
matched with age and smoking history were enrolled. Blood samples
were collected, and plasma was stained with antibodies and analyzed
using FACS. Ep-CAM and E-cadherin are specific markers for epithelial
cells. RAGE is highly expressed in alveolar type I cells. We defined
Alveolar Epithelial MPs as follow; RAGE+/Ep-CAM+ MPs (Alveolar Ep-
CAM MPs) and RAGE+/E-cadherin+ MPs (Alveolar E-cad MPs).

16. Mesa 4. Nuevos abordajes y futuro de la EPOC
Titular tabla
Increased circulating alveolar epithelial
microparticles in COPD patients
Results:
• Both Alveolar Ep-CAM and E-cad MPs were significantly higher
in the stable COPD patients than in the healthy volunteers
(Alveolar Ep-CAM MPs: p= 0.001, Alveolar E-cad MPs: p< 0.001).
• There was no significant difference in the two Alveolar Epithelial
MP levels among the GOLD stages although their levels in each
stage were significantly higher than those in healthy volunteers.

17. Mesa 4. Nuevos abordajes y futuro de la EPOC
Titular tabla
Increased circulating alveolar epithelial
microparticles in COPD patients
Conclusions: Alveolar epithelial MPs are released into the circulation
in COPD patients, indicating the presence of epithelial injury and
disruption of the alveolar epithelial-endothelial barrier function.

18. Mesa 4. Nuevos abordajes y futuro de la EPOC
Muchas gracias
por su atención