Mesa 4.5. myriam calle

Mesa 4. Nuevos abordajes y futuro de la EPOC

Dra. Myriam

Calle RubioHospital Clínico Universitario

San Carlos. Madrid


[ATS] L-Carnitine

Supplementation

Attenuates Elastase-

Induced Emphysema

Progression

Conlon TM, Adamski J,

Eickelberg O, Yildirim AO


IntroductionWe 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.


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.


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.


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.


[ATS] CFTR Potentiator

Ivacaftor, A Novel Mucus

Clearance Therapy In

COPD

Lin VY


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


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).



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).


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



[ERS] Increased

circulating alveolar

epithelial microparticles

in COPD patients

Takahashi T


• 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.


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.


Titular tabla



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).


Titular tabla



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.


Titular tabla



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.


Muchas gracias

por su atención

Mesa 4.5. myriam calle

Health & Medicine