Résumé
Chronic obstructive pulmonary disease (COPD) is currently the third cause of death worldwide. Emphysema is an abnormal enlargement of air spaces in the lungs, with destruction of alveolar parishes. Cardiovascular disorders are the most frequent and serious comorbidities of COPD. Their interconnection is poorly understood but several hypotheses have been proposed, including hyperinflation, oxidative stress, and inflammation.
In a rat model with exacerbated elastase (ELA)-induced emphysema that develops heart failure with preserved ejection fraction, our goal is to (1) describe the relationship between exacerbated emphysema and cardiovascular hemodynamic disorders, (2) characterize the inflammation status 24h and 5 weeks after an exacerbation.
The model includes a weekly intra-tracheal instillation of ELA, during four weeks with doses of 4, 6 or 10UI. At week 4, lipopolysaccharide (LPS) was instillated with ELA to mimic an exacerbation and approximate clinical conditions. Experiments were performed 24hours after the last intra-tracheal instillation (ELA+LPS) and at week 9 just before sacrifice. In vivo, we did a cardiac stress test on metabolic treadmill, whole body plethysmography, echocardiography, arterial pressure, and collected blood samples. Ex vivo, we explanted the heart/lung block to assess pulmonary compliance and histology analyses.
We identified a respiratory functional impairment proportional to the dose of elastase instilled. An exercise intolerance appeared after the exacerbation and persisted 5 weeks later. We observed a diastolic dysfunction after the exacerbation and at week 9, with a significantly dose dependent increased E/E’ ratio, correlated with the extent of emphysema. A systolic and diastolic arterial hypertension appeared at week 9, especially in the 10UI elastase group. There was an increased lung compliance and decreased elastance. The characterization of inflammation is under investigation.
This ELA-LPS animal model presents a chronic profile of heart failure with preserved ejection fraction linked in a dose-dependent manner to the intensity of the emphysema. Cardiopulmonary changes are accompanied by a reduction in exercise tolerance as well as arterial hypertension. This model seems useful to better understand the mechanisms of cardiac changes induced by emphysema. At length, we aim to develop an inhibition of T1 or T2 inflammation pathway, to determine the part played by this inflammation.