PET Imaging of Endotoxin-induced iNOS Activation

Study Overview
=================
Brief Summary
-----------------
The overall purpose of this research is to gain understanding of the basic responses of the lung to inflammation. Inflammation is the way our bodies react to irritation or injury, and involves red, warm, and often painful swelling of the affected tissue. Acute lung injury involves a generalized inflammation to the lung that is activated by any of several conditions: infection, trauma, inhalation of toxic substances, etc. When lung injury is severe, not enough oxygen can get into the body; this can lead to the need for mechanical support of breathing (mechanical ventilation), problems with brain, heart or other organ function, and in some cases, death. Inducible nitric oxide synthase (iNOS) contributes to the development of lung inflammation.

Detailed Description
-----------------
The investigators plan to use [18F](+/-)NOS (the F stands for fluorine and NOS stands for Nitric Oxide Synthase, the name for the investigational radioactive drug that targets iNOS) and positron emission tomography (PET) imaging as a measure of lung inflammation. PET is a machine that detects radiation and generates pictures using a donut shaped scanner similar in appearance to an x-ray CAT scan. 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 will not spread from one part of your body to another, and cannot spread to another person) and a small area in only one lung will be affected. In order to create this state of controlled lung inflammation, the investigators plan to put a small amount of endotoxin into a single small section of the lung using a bronchoscope (a long, flexible, narrow tube that is passed through the nose or the mouth into the airways of the lung). This use of endotoxin is considered investigational. The investigators have received permission from the FDA to use endotoxin in this research study.

Official Title
-----------------
PET Imaging of Endotoxin-induced iNOS Activation in Healthy Volunteers

Conditions
-----------------
Pneumonia

Intervention / Treatment
-----------------
* Drug: Endotoxin (E. coli O:113, Reference Endotoxin)
* Drug: [18F](+/-)NOS


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy man or woman, any race or ethnicity, age 19 - 44 years old Screening Pulmonary Function Test Screening oxygen saturation by pulse oximetry >97% on room air Capable of lying still and supine within the PET/CT scanner for 1.5 hours Capable of following instructions for breathing protocol during CT portion of PET/CT Able and willing to give informed consent BMI < 35 Exclusion Criteria: Pregnancy (confirmed by qualitative serum hCG pregnancy test) Lactation Active menstruation 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 Known allergy to drugs routinely used during bronchoscopy Inability lie flat for 1.5 hours for PET/CT scans or follow breathing protocol instructions for the CT portion of the PET/CT

Ages Eligible for Study
-----------------
Minimum Age: 19 Years
Maximum Age: 44 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Endotoxin and [18F](+/-)NOS<br>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 F-18 (+/-) NOS | Drug: Endotoxin (E. coli O:113, Reference Endotoxin)<br> <br> * Other names: Lipopolysaccharide;Drug: [18F](+/-)NOS<br> <br> |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution volume ratio (DVR), determined by Logan plot analysis, in the right middle lobe. |  | Change in DVR on post-endotoxin scan (Day 2) from baseline (Day 1). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Bronchoalveolar lavage (BAL) fluid cell counts. | Total nucleated and neutrophil cell counts obtained by BAL after endotoxin instillation. | 24 hours after endotoxin instillation. | 
| Number and percent of iNOS-stained BAL cells. |  | 24 hours after endotoxin instillation. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
lung inflammation, positron emission tomography (PET), fluorodeoxyglucose (FDG), inducible nitric oxide synthase (iNOS), lung anti-inflammatory therapy