Effects of 20,000 EU of Clinical Center Reference Endotoxin (CCRE) Versus Placebo(ENDOHEART)

To determine the systemic inflammatory effects of inhaled endotoxin and associated alterations in cardiovascular function. Subjects will undergo an exposure to inhaled endotoxin in a crossover fashion with normal saline inhalation. Blood samples and sputum samples will be taken before and after inhalation challenge to measure markers of systemic inflammation. Cardiovascular measures, including a heart rate variability monitor, flow mediated dilation of the brachial artery and left ventricular stain will also be measured.

The purpose of this study is to determine the systemic inflammatory effects of inhaled endotoxin and associated alterations in cardiovascular function. The investigators have previously found that inhalation of 20,000 Endotoxin Units (EU) of CCRE increases the neutrophil content of the blood; this dose can then be employed to screen populations for enhanced susceptibility to the systemic and cardiovascular inflammatory effect of inhaled endotoxin. Endotoxin is a commonly encountered bioaerosol and component of particulate matter (PM), a prevalent indoor and outdoor air pollutant \[1-3\]. For reasons that remain unclear, some individuals appear to be more susceptible to the inflammatory effects of inhaled endotoxin than are others, possibly owing to single nucleotide polymorphisms in the Toll-like receptor 4 (TLR4) gene that influence TLR4 signaling and function \[4-6\]. Exposure to PM is associated with increased cardiovascular morbidity and mortality \[7\]. PM exposure has been specifically linked with increases in blood pressure \[8,9\]. Susceptible individuals represent a population of particular interest for further mechanistic studies of the effects of endotoxin and for therapeutic trials. Systemic inflammatory response to inhaled endotoxin will be determined by measuring change in peripheral blood neutrophil counts, a biomarker of systemic inflammation, following inhaled CCRE vs placebo. Blood pressure, heart rate variability (HRV), vascular stiffness (by flow mediated dilation, or FMD) and left ventricular strain (LVS) will be measured before and after CCRE or placebo exposure to investigate the effect of endotoxin-induced systemic inflammation on cardiovascular function.

Eligibility Criteria:
Inclusion Criteria:

* Adult volunteers with no more than mild asthma
* Age 18-50 years, inclusive, of both sexes
* Demonstrate an increase in peripheral blood PMNs of 20% (compared to baseline values) following inhalation of 20,000 EU of CCRE.
* Negative pregnancy test for females who are not s/p hysterectomy with oophorectomy
* Normal lung function, defined as (NHanes III predicted set):

  1. Forced Vital Capacity (FVC) of \> 80 % of that predicted for gender, ethnicity, age and height
  2. Forced Expiratory Volume in the first second of the exhale (FEV1) of \> 80 % of that predicted for gender, ethnicity, age and height
  3. FEV1/FVC ratio of \> .75 of that predicted for gender, ethnicity, age and height
* Oxygen saturation of \> 93%, and blood pressure within the following limits: (Systolic between 150 - 90, Diastolic between 90-60 mm Hg)

Exclusion Criteria:

* Any chronic medical condition considered by the PI as a contraindication to the exposure study including significant cardiovascular disease, diabetes requiring medication, chronic renal disease, or chronic thyroid disease.
* Physician directed emergency treatment for asthma exacerbation within the preceding 3 months.
* Exacerbation of asthma more than 2x/week that would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma.
* Nighttime symptoms of cough or wheeze greater than 1x/week at baseline (not during a clearly recognized viral induced asthma exacerbation) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma
* Daily requirement for albuterol due to asthma symptoms (cough, wheeze, chest tightness) which would be characteristic of a person of moderate or severe persistent asthma as outlined in the current NHLBI guidelines for diagnosis and management of asthma. (Not to include prophylactic use of albuterol prior to exercise).
* History of intubation for asthma
* Daily use of NSAIDs, or inability to withhold NSAIDs for 4 days prior to dosing.
* Use of medications that may impact the results of the study to include, but not limited to, systemic corticosteroids, beta blockers.
* Cigarette smoking \> 1 pack per month.
* Body Mass Index \>35 kg/m2.
* Pregnant or breast feeding women
* Subjects who are employed within the past 6 months in an occupation with high risk for endotoxin exposure, such as grain storage sites or swine containment.
* Any acute, non-chronic medical condition requiring treatment, such as bronchitis, pneumonia or febrile illness within the prior 4 weeks.
* Participation in studies involving new molecular entities or an experimental environmental exposure in the past 4 weeks.