The goal of this clinical trial is to evaluate whether inhaled Treprostinil (Tyvaso) can improve oxygen delivery and blood flow in the lungs in adults (age ≥40) with chronic obstructive pulmonary disease (COPD) and hypoxemia who have less severe reduction in lung blood volume (diffusing capacity of the lungs for carbon monoxide [DLCO] ≥45%).

The main questions it aims to answer are:

1. Does inhaled Treprostinil increase pulmonary capillary blood volume in ventilated lung regions, as measured by hyperpolarized xenon-129 magnetic resonance imaging (HP129Xe MRI)?
2. Does inhaled Treprostinil improve oxygen delivery (measured as red blood cell [RBC] chemical shift) and maintain or only slightly change pulmonary vascular resistance (measured by RBC oscillation amplitude)?
3. Can pre-treatment MRI parameters (RBC transfer and RBC oscillation amplitude) predict who will respond to inhaled Treprostinil?

Participants will:

• Use the Tyvaso nebulizer (inhaled Treprostinil) 4 times daily for 4 weeks, starting at 3 breaths per session and increasing to a maximum of 6 breaths per session as tolerated.
• Undergo HP129Xe MRI before and after treatment to assess regional lung function and oxygen exchange.
• Complete pulmonary function tests (PFTs), 6-minute walk tests (6MWT), and echocardiograms at the beginning and end of the study.
• Be monitored for adverse events, with a phone check-in midway through and after the treatment period.

This is a single-arm, proof-of-concept study evaluating the effects of inhaled Treprostinil (Tyvaso nebulizer) on regional gas exchange and capillary blood oxygenation in patients with chronic obstructive pulmonary disease (COPD) and hypoxemia. The study will enroll 10 outpatient subjects aged ≥40 with a chronic bronchitis phenotype, confirmed COPD diagnosis, and a diffusing capacity of the lungs for carbon monoxide (DLCO) ≥45% predicted. All participants will receive inhaled Treprostinil via a 4-week dose titration protocol (starting at 3 breaths four times daily and increasing to 6 breaths as tolerated).

The primary objectives are to "determine the effects of inhaled Treprostinil on regional gas exchange and capillary blood oxygenation as measured by hyperpolarized xenon-129 magnetic resonance imaging (HP129Xe MRI), including ventilation defect percentage (VDP), membrane defect percentage, red blood cell (RBC) transfer defect percentage and normalized RBC oscillation amplitude and RBC frequency shift," and to "determine whether pre-treatment VDP, membrane defect percentage, RBC transfer defect percentage, RBC chemical shift and normalized RBC oscillation amplitude predict a positive response to inhaled Treprostinil."

Assessments will include HP129Xe MRI, spirometry with DLCO, 6-minute walk testing (6MWT), and echocardiography at baseline and after 4 weeks. Data will be analyzed for changes in regional lung function and oxygenation. Safety monitoring will focus on known adverse effects of inhaled Treprostinil including "cough, headache, hypotension, oropharyngeal pain, throat irritation and nausea," and will address more serious risks observed in the PERFECT trial (COPD exacerbation, respiratory failure, myocardial infarction, and death). By selecting subjects with DLCO ≥45% predicted and using a shorter 4-week treatment duration with titrated dosing, the study aims to mitigate these risks.

Inclusion Criteria

• Outpatients of either gender, age ≥ 40.
• Clinical evidence of chronic bronchitis (a productive cough lasting more than 3 months within a 2-year period).
• Current or former cigarette smokers with a smoking history of 20 or more pack-years.
• Clinical diagnosis of chronic obstructive pulmonary disease (COPD) confirmed by spirometry demonstrating forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) ratio < 0.70, pre-bronchodilator FEV1 ≥ 30% predicted, and diffusing capacity of the lungs for carbon monoxide (DLCO) ≥ 45% predicted.
• On stable maintenance COPD medications including inhaled corticosteroids (ICS), long-acting beta agonists (LABA), long-acting muscarinic antagonists (LAMA), combination inhalers, azithromycin, or roflumilast (with no changes over the past 3 months).
• Patients with hypoxemia, evidenced by the use of supplemental oxygen at rest or during exercise (≤ 4 liters/minute).
• Willing and able to give informed consent and adhere to visit and protocol schedules (consent must be obtained prior to any study procedures).
• Women of childbearing potential must have a negative serum pregnancy test, confirmed prior to participation in this investigational protocol.

Exclusion Criteria

• Upper respiratory tract infection within 6 weeks (participants may be rescreened after this period).
• History of lung resection surgery or pleural decortication.
• Previous history of pneumothorax.
• Imaging evidence of interstitial lung disease, occupational lung disease, or chronic infectious lung disease.
• History of asthma.
• History of exposure to occupational or environmental hazards known to cause lung disease.
• Positive pregnancy test for women of childbearing potential.
• Major chronic illness that, in the judgment of the study physician, would interfere with participation in the study.

For Magnetic Resonance Imaging (MRI):

• Contraindications to MRI based on screening questionnaire responses.
• Participant is pregnant or lactating.
• Respiratory illness of bacterial or viral etiology within 6 weeks prior to MRI.
• Known cardiac arrhythmia.
• Participant does not fit into the hyperpolarized xenon-129 (^129Xe) vest coil used for MRI.
• Participant cannot hold their breath for 10 seconds.
• Participant is unlikely to comply with instructions during imaging.

Individual participant data (IPD) will not be shared for this study. The consent form limits future data use to internal research on lung disease and COPD and does not authorize sharing of de-identified IPD with external investigators. Therefore, data cannot be made available to other researchers outside of the study team.