PET Imaging of Endotoxin-induced iNOS Activation

PET Imaging of Endotoxin-induced iNOS Activation in Healthy Volunteers

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.

Study Overview

• Status: Completed
• Conditions: Pneumonia
• Intervention / Treatment: Drug: Endotoxin (E. coli O:113, Reference Endotoxin); Drug: [18F](+/-)NOS

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.

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University School of Medicne

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 44 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Endotoxin and [18F](+/-)NOS; 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); Other Names: Lipopolysaccharide; Drug: [18F](+/-)NOS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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.

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: Barnes-Jewish Hospital
• Investigators: Principal Investigator: Delphine L. Chen, MD, Washington University School of Medicine

Publications and helpful links

General Publications

• Huang HJ, Isakow W, Byers DE, Engle JT, Griffin EA, Kemp D, Brody SL, Gropler RJ, Miller JP, Chu W, Zhou D, Pierce RA, Castro M, Mach RH, Chen DL. Imaging pulmonary inducible nitric oxide synthase expression with PET. J Nucl Med. 2015 Jan;56(1):76-81. doi: 10.2967/jnumed.114.146381. Epub 2014 Dec 18.

Study record dates

Study Major Dates

• Study Start: December 1, 2010
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: July 28, 2011
• First Submitted That Met QC Criteria: July 29, 2011
• First Posted (Estimate): August 2, 2011

Study Record Updates

• Last Update Posted (Estimate): April 21, 2014
• Last Update Submitted That Met QC Criteria: April 17, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: positron emission tomography (PET); lung inflammation; lung anti-inflammatory therapy; fluorodeoxyglucose (FDG); inducible nitric oxide synthase (iNOS)
• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Pneumonia
• Other Study ID Numbers: BJHF/ICTS 7326-01