Assessing NOS Uptake With PET Imaging in Lung Inflammation

The purpose of this study is to learn more about the basic responses of the lungs to inflammation using positron emission tomography, or PET, imaging scans of the lungs. PET is a machine that detects radiation and generates pictures using a donut-shaped scanner similar in appearance to an x-ray "CAT" or computed tomography (CT) scan or an MRI. Inflammation is the way our bodies react to irritation or injury, and involves red, warm, and often painful swelling of the affected tissue. An enzyme called inducible nitric oxide synthase (iNOS) contributes to the development of lung inflammation.

The investigators plan to use three radioactive tracers to produce the PET images for measuring lung inflammation: [18F](+/-)NOS (the F stands for fluorine and NOS stands for Nitric Oxide Synthase, which targets iNOS), O-15 carbon monoxide ([15O]CO), and O-15 water ([15O]H2O). The NOS tracer gives information specifically about lung inflammation, while the carbon monoxide and water tracers give information about whether the lung inflammation causes more blood or water to be retained in the area of lung inflammation. In order to show that [18F](+/-)NOS-PET is related to the amount of inflammation, the investigators first need to create a state of controlled lung inflammation that can be measured and quantified. "Controlled lung inflammation" means a reaction in the lungs that is similar to that which occurs during lung infection (increased respiratory secretions and cough). It is "controlled" because the investigators will not be using anything alive or contagious (it does not spread from one part of the body to another, and cannot spread to another person), and a small area in only one lung will be affected. In order to created this state of controlled lung inflammation, the investigators plan to place a small amount of a purified bacterial substance called endotoxin into a single small section of the lung using a bronchoscope (a long, flexible narrow tube that is passed through the mouth into the airways of the lung). This use of endotoxin is considered investigational, and the investigators have received permission from the FDA to use endotoxin in this research study.

All volunteers in this study will receive endotoxin in a single segment of the lung to induce mild, self-limited inflammation. They will also be imaged before and after endotoxin instillation with the novel PET tracer [18F](+/-)NOS.

The endotoxin will be reconstituted with sterile water to a final concentration of 2,000 endotoxin units/ml. The dose of 4 ng/kg will be prepared to a final volume of 2 ml and will be administered using a 5F balloon-tipped monitoring catheter inserted via a fiberoptic bronchoscope into the lateral segment of the right middle lobe of the lung on the morning of Day 2.

7 mCi of [18F](+/-)NOS will be injected intravenously at the start of a 60-minute dynamic PET scan acquisition

Comparison of DVR by Logan plot for [18F](+/-)NOS uptake, pulmonary blood flow (PBF) and extravascular lung water (EVLW) in the regions of interest generated from scans obtained before and after endotoxin instillation and in the right and left lungs will be compared using a repeated-measures t-test, with statistical significance set at p<0.05. The DVR determined for [18F](+/-)NOS normalized for either PBF or EVLW will also be compared using a repeated-measures t-test before and after endotoxin as well as in the right and left lungs to determine whether differences in [18F](+/-)NOS uptake depend on either PBF or EVLW.

Inclusion Criteria: Healthy man or woman, any race or ethnicity, age 19-44 years old Screening FEV1 and FVC greater than or equal to 90% of predicted Screening oxygen saturation by pulse oximetry greater than or equal to 97% on room air Capable of lying still and supine with arms raised above the head within PET/CT scanner for 2-2.5 hours Capable of following instructions for breathing protocol during CT portion of PET/CT scans Able and willing to give informed consent Body Mass Index (BMI) < 35 Exclusion Criteria: Pregnancy (confirmed by qualitative serum hCG pregnancy test) Lactation History of cardiopulmonary disease Currently taking any prescription medications History of tobacco use or illicit drug use within the past year Presence of implanted electronic medical device Enrollment in another research study of an investigational drug Known allergy to both trimethoprim/sulfamethoxazole and amoxicillin, Penicillin, Lidocaine, Demerol, Versed, and/or Fentanyl Inability to lie flat for 2-2.5 hours for PET/CT scans or follow breathing protocol instructions for the CT portion of the PET/CT Prior research-related radiation exposure within the past year such that participation in this study would result in exposures that exceed the limits as defined by the FDA RDRC regulations (21 CFR 361.1)