- When bacteria enter the lungs, serious infections can occur. Researchers want to learn more
about the process of inflammation in the lungs by studying lung cells and the products that
they make. Lung cells are influenced by infections, smoking, and molecules made within the
body. Researchers also want to learn more about one of these molecules, called microRNA (or
micro ribonucleic acid).
- To better how the body responds to infection. Also, to understand which cells in the lung
secrete microRNA and how they may influence other lung cells.
- Healthy, non-smoking adults ages 18-45.
- Participants will be screened with a medical history and physical exam. They will have
blood and urine tests and an electrocardiogram.
- Participants will have blood drawn from an arm vein. They will have an intravenous
catheter (small plastic tube) placed in a vein.
- All participants will have bronchoscopy with bronchoalveolar lavage. They will be numbed
with medicine. A thin flexible tube will be placed through the nasal passages or the
mouth into the airways of the lung.
- Some participants will have bronchoscopy with bronchoalveolar lavage (rinsing the
airways with salt water) in order to obtain cells from lung. The water will then be
- Some participants will have two bronchoscopies; during the first procedure,
endotoxin, a molecule found in bacteria is squirted into a small portion of the
lung. Endotoxin is a molecule that acts like an infection but isn t one. After 6 to
48 hours, bronchoscopy with with bronchoalveolar lavage will be done to look at the
lung s response to endotoxin.
- Participants heart rhythm and rate, temperature and blood oxygen level will be monitored
during the procedures.
- Participants will be called the next day to see how they are feeling.
Defining the mechanisms that limit tissue injury during acute inflammation may provide the
basis for preventing secondary organ dysfunction during serious infections. We plan to use
the human endotoxin lung challenge model to study mechanisms associated with the initiation
and resolution of lung inflammation.
Endotoxin (LPS), an outer membrane component of Gram-negative bacteria, is a major microbial
factor that mediates inflammation associated with serious infections. For over fifty years,
endotoxin has been administered to humans as a challenge agent in order to understand basic
mechanisms of inflammation, to provide a proof of principle for pharmacologic interventions
(e.g., anti-cytokines, corticosteroids), or as an adjuvant for immunotherapy of malignancies.
We previously developed a human model to study the initiation and resolution of inflammation
in a lung segment following endotoxin bronchial instillation. The inflammatory response was
limited to the challenged segment and had minimal associated systemic responses. After direct
instillation into a lung segment, endotoxin elicits an inflammatory response characterized by
the local production of inflammatory mediators, proteins and increases in cellularity. The
predominate cell species found in the bronchoalveolar lavage (BAL) of the challenged segment
changes from a neutrophil influx at 2 - 6 hours to an influx of monocytes and lymphocytes at
24 and 48 hours following endotoxin challenge. At 6 hours, BAL pro-inflammatory activity
(i.e., tumor necrosis factor bioactivity and induction of intercellular adhesion molecule-1
on reporter cells) is present and absent at 24 and 48 hours post endotoxin. In addition,
unique subsets of lymphocytes are present in the lung during this inflammatory response.
We have recently shown that non-cellular microRNAs (miRNAs) are present in archived BAL from
normal healthy volunteer airways and are differentially expressed 6 hours after
endotoxin-induced acute lung inflammation. miRNA are single stranded non-coding RNA that
mediate posttranscriptional regulation of gene expression. Some extracellular miRNA species
may modulate local and distant cell processes. miRNA can activate Toll-like receptors (TLRs)
and have been described as blood biomarkers of different disease states. However, the
specific role of extracellular or secreted miRNAs in the lung is poorly defined. Our research
plan is designed to study the roles of miRNA in acute lung inflammation by investigating the
changes in miRNA signatures found in BAL and lung cells from healthy volunteers at baseline
and at 6, 24, or 48 hours after endotoxin segmental lung challenge. A panel of flow cytometry
cell surface markers will be performed on blood and BAL cells and intracellular and secreted
miRNA will be isolated from specific cell species (i.e., neutrophils, monocytes, macrophages,
and lymphocytes). We hypothesize that miRNA will have a role in modulating the initiation and
resolution of inflammation.
- INCLUSION CRITERIA:
1. Healthy 18 to 45 year old, nonsmoking subjects based on screening examination and
2. No significant active medical problems. This would include but not be limited to
any cardiac disorder (e.g. arrhythmia, valvular heart disease), pulmonary disease
(e.g. asthma requiring chronic medications, chronic bronchitis, emphysema),
neurologic disorder (e.g.
epilepsy), kidney disease (e.g. nephritis, nephrosis), rheumatologic disorder
(e.g. inflammatory arthritis), endocrine disorder (e.g. diabetes, thyroid
disease), liver disease (e.g. hepatitis), gastrointestinal disorder (e.g.
inflammatory bowel disease) or infectious
disease (e.g. human immunodeficiency virus).
3. No concurrent medications including aspirin or non-steroidal anti-inflammatory
drugs or have not taken these for at least 7 days prior to study participation.
4. Previous smokers would have to have abstained from cigarettes for at least one
year and have no greater than a 10-pack year smoking history. If you use a
hookah, e-cigarette, or vaping more than once a week, you must abstain for at
least 6 weeks prior to participating in the study.
5. Females must be practicing active method of birth control or abstinence of sexual
6. Must be willing to have samples stored
1. Any serious active medical problem as defined above
2. Pregnancy and/or lactation
3. BMI >30