ATMOS: Noninvasive Treatment for Emphysema

Date: October 8, 2021 | View Publication

Abstract

Emphysema is a common phenotype of chronic obstructive pulmonary disease (COPD). Although resection of emphysematous tissue can improve lung mechanics, it is invasive and fraught with adverse effects. Meanwhile, radiofrequency (RF) treatment is an extracorporeal method that leads to tissue destruction and remodeling, resulting in “volume reduction” and overall improvement in lung compliance of emphysematous lungs. Whether these changes lead to improved exercise tolerance is unknown. Here, we investigated the effectiveness of RF treatment to improve the exercise capacity of mice with emphysema. Fifty-two mice (7 weeks of age) were used in this experiment. A bilateral emphysema model was created by intratracheally instilling porcine pancreatic elastase (PPE) (1.5U/100 g body weight). RF treatment (0.5 W/ g body weight) was administered extracorporeally 14 days later and mice were sacrificed after another 21 days. The exercise capacity of mice was measured using a treadmill. Treadmill runs were performed just before PPE instillation (baseline), before RF treatment and before sacrifice. Following sacrifice, lung compliance and mean linear intercept (Lm) were measured and fibrosis was assessed using a modified Ashcroft score. There were 3 experimental groups: controls (instilled with saline, n = 12), emphysema (instilled with porcine pancreatic elastase, PPE, n = 11) and emphysema + treatment (instilled with PPE and given RF, n = 9). At endpoint, the maximum velocity of the emphysema + treatment group was significantly higher than that of the emphysema group, indicating improved exercise tolerance (86.29% of baseline vs 61.69% of baseline, p = 0.01). Histological analysis revealed a significant reduction in emphysema as denoted by Lm between the two groups (median 29.60 µm vs 35.68 µm, p = 0.03). The emphysema + treatment group also demonstrated a higher prevalence of lung fibrosis (≧Grade 3) compared with the emphysema group (11.7% vs 5.4%, p < 0.01). No severe adverse events from RF were observed. RF treatment improved the exercise capacity of mice with emphysema. These data highlight the therapeutic potential of RF treatment in improving the functional status of patients with COPD.

Chronic Obstructive Pulmonary Disease (COPD) is a common inflammatory disorder of the lung, characterized by persistent airflow limitation. In COPD, the airways become progressively narrowed, resulting in impaired lung function, increased work of breathing, and shortness of breath. Currently, COPD affects over 300 million people worldwide and is the leading cause of hospitalizations in many industrialized countries such as the United States (US) and Canada. COPD is responsible for over 4.5 million deaths annually and is one of the major causes of mortality worldwide^1,2. Typically, smoking-related COPD is accompanied by emphysema, which is characterized by the destruction of lung tissue resulting in the loss of alveolar integrity, enlargement of the alveolar spaces, poor gas exchange, and airway collapse due to the loss of elastic recoil³. This remodeling results in impairment in airflow and hypoxemia.

Lung volume reduction surgery (LVRS) is a potential treatment for COPD, but it is limited to a subpopulation of patients with severe emphysema involving the upper lobes and with low exercise capacity. LVRS has been demonstrated to reduce breathlessness, improve exercise capacity and lung function, and prolong survival^4,5. The physiologic basis for this treatment is that by selectively removing the most diseased segments of the lung, the lung deflates and there is better matching of ventilation and (blood) perfusion, leading to less gas trapping and improved gas exchange, respectively, during exercise⁶. However, LVRS is invasive and fraught with considerable perioperative morbidity and mortality related to the procedure. As such, very few sites currently perform LVRS^2,3,7. To overcome the high invasiveness and the cost of LVRS, endoscopic lung volume reduction (ELVR) including bronchoscopic lung volume reduction (BLVR) has been developed using one-way valves, coil implants (LVR coil, LVR-C), sealants/hydrogels (BioLVR), airway bypass stents, and bronchial thermal vapor ablation (BTVA) therapy. However, these methods are still invasive and expensive and fraught with certain adverse effects including hemoptysis and pneumothorax^8,9,10,11,12. According to a multicenter randomized controlled trial to evaluate endobronchial valves (EBV), 26.6% (34/128) of EBV subjects developed pneumothorax and four deaths occurred (4/128)⁸. Moreover, it is still difficult to determine the patients who benefit from ELVR^9,10.Thus, minimally-invasive (or ideally completely non-invasive) modalities to deliver the benefits of LVRS are still clinically needed.

Radiofrequency (RF) is commonly used to treat solid tumors and atrial fibrillation in a procedure called RF ablation (RFA)^12,13. The principle of RFA is that RF waves agitate water molecules in the surrounding tissue, producing friction and heat, which in turn induce cellular death via coagulation and necrosis¹². Healthy regions with good blood supply are relatively spared from thermal damage because the circulating blood can absorb the external heat and carry it away via a process known as a “heat sink effect”¹⁴. A well-known pathologic feature of emphysema is pulmonary vascular remodeling, which causes diminution of blood flow to the emphysematous regions¹⁵, making these areas susceptible to thermal injury. Based on these concepts, we applied RF therapy extracorporeally to destroy emphysematous regions of the COPD lung in a rodent model of emphysema. Previously, we showed that the application, using external electrodes, of RF energy in the form of electromagnetic waves improved lung compliance by selectively heating pulmonary emphysematous tissue and inducing mild fibrosis in the affected lung while sparing normal lung regions¹⁶. However, in that study, we did not determine whether the physiological changes led to improvements in the functional status of animals with emphysema which would a critical indicator of a beneficial therapeutic effect. Here, we investigated the effectiveness of extracorporeal RF treatment in improving the exercise capacity of mice with emphysema.