The purpose of this study is to demonstrate the safety and efficacy of AeriSeal System treatment plus optimal medical therapy compared in patients with advanced upper lobe predominant (ULP) heterogeneous emphysema.

Inclusion Criteria:

1. Willing and able to provide informed consent

2. Age ≥ 40 years

3. On optimal medical therapy* for more than 1 month

4. Advanced upper lobe predominant emphysema confirmed by CT scan

5. Two (2) subsegments appropriate for treatment in 2 different upper lobe segments in each lung based upon CT scan (total 4 available subsegments)

6. MRCD score of ≥ 2 post pulmonary rehab (using modified MRCD scale of 0-4)

7. 6MWT distance ≥ 150 m post pulmonary rehab

8. Spirometry 15 minutes after administration of a bronchodilator showing BOTH:

   1. FEV1 < 50% predicted
   2. FEV1/FVC ratio < 70%

9. Plethysmographic lung volumes showing BOTH:

   1. TLC > 100% predicted
   2. RV > 150% predicted

10. DLco ≥ 20% and ≤ 60% predicted

11. Blood gases and oxygen saturation showing BOTH:

    1. SpO2 ≥ 90% on ≤ 4 L/min supplemental O2
    2. PaCO2 < 65 torr

12. Smoking history of ≥ 20 pack-years with abstinence for 16 weeks

Exclusion Criteria:

1. Prior lung volume reduction surgery, lobectomy or pneumonectomy, or lung transplantation

2. Requirement for ventilator support (other than CPAP or BPAP for sleep apnea)

3. Three (3) or more COPD exacerbations requiring hospitalization within 1 year of Screening visit or a COPD exacerbation requiring hospitalization within 8 weeks

4. Use of systemic steroids > 20 mg/day or equivalent immunosuppressive agents, heparins, oral anticoagulants or investigational medications

   Exclusion Criteria (continued):

5. a-1 antitrypsin serum level of < 80 mg/dL (immunodiffusion) or < 11 µmol/L (nephelometry)

6. CT scan: Presence of any of the following radiologic abnormalities:

   1. Pulmonary nodule on CT scan greater than 1.0 cm in diameter
   2. Radiologic picture consistent with active pulmonary infection
   3. Significant interstitial lung disease
   4. Significant pleural disease
   5. Giant bullous disease

7. Clinically significant asthma

8. Clinically significant bronchiectasis

9. Pulmonary hypertension

10. Allergy or sensitivity to medications required to safely perform AeriSeal System treatment under general anesthesia or conscious (moderate procedural) sedation

11. Participation in an investigational study of a drug, biologic, or device not currently approved for marketing

12. Body mass index < 15 kg/m2 or > 35 kg/m2

13. Female patient pregnant or breast-feeding or planning to be pregnant in the next year

14. Any abnormal screening laboratory test result

15. Significant comorbidity including any of the following:

    1. HIV/AIDs
    2. Active malignancy
    3. Stroke or TIA within 12 months
    4. Myocardial infarction within 12 months
    5. Congestive heart failure within 12 months

16. Any condition that would interfere with the intent of the study or would make participation not in the best interest of the patient such as alcoholism, high risk for drug abuse or noncompliance in returning for follow-up visits