Epigenetic Effects of Diesel Exhaust and Ozone Exposure
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 42
- 试验地点
- 2
- 主要终点
- Airway responses
研究概览
简要总结
Purpose: The purpose of this protocol is to compare the genetic and epigenetic effects between diesel exhaust and ozone exposure in healthy individuals and in mild/moderate asthmatics.
Participants: The investigators will recruit up to 30 mild to moderate asthmatics and up to 50 healthy adults to participate in this study.
Procedures (methods): Subjects will be exposed to clean air, to 300 µg/m3 of diesel exhaust for 2 hours and to 0.3 ppm of ozone for 2 hours with intermittent exercise in a controlled environment chamber. Primary endpoints will include spirometry and lung cell changes post-exposure. Secondary endpoints will include analysis of blood clotting/coagulation factors, Holter monitoring of cardiac parameters, analysis of soluble factors present in plasma and bronchial lavage and analysis of intracellular factors present in lung tissue obtained from a brush biopsy.
详细描述
This study will compare the epigenetic responses of healthy adults and adults with mild asthma to diesel exhaust and ozone exposures. Up to fifty subjects will be recruited into the healthy adult group and up to thirty subjects into the mild to moderate asthmatic group. Both the normal healthy group and the asthmatic group will be randomly exposed to clean air, diesel exhaust and ozone with exposures separated by a minimum of two weeks followed by a bronchoscopy procedure 18-24 h post-exposure. Additionally, the healthy group will participate in a second arm of the study in which they will be randomly exposed to clean air and ozone only separated by a minimum of 2 weeks followed by a bronchoscopy procedure 1 h post-exposure. Responses of primary interest will include: 1) genetic and epigenetic changes 2) FEV1 as measured by spirometry, and 3) lung inflammation and cell changes as evaluated by bronchoalveolar lavage. The performance of these tests and procedures are considered essential to conducting the study. Exploratory endpoints will include: blood CBC and differential, fibrinogen and platelets, changes in IL 6 and IL 8 comparing pre-exposure with post-exposure values. Safety endpoints will include comparison of temperature, telemetry, respiratory rate, O2 saturation and symptoms scores for pre- and post-exposure, and at 18-24 hours post-exposure. All medical procedures will be performed by study personnel.
Up to an additional 15 healthy subjects will be recruited specifically to be exposed to ozone generated using the heavy non-radioactive isotope of oxygen (18O). There is no risk to the subject of inhaling this isotope, which is naturally occurring in small concentrations. We have previously used 18Ozone in a study approved by the UNC IRB in 1993. The purpose of these exposures is to measure the amount of 18O label attached to airway epithelial cells removed during bronchoscopy and thus calculate the dose of ozone these cells received. We will draw a small blood sample but no other tests will be performed on these subjects other than routine spirometry to ensure they are not at risk for bronchoscopy.
Physical Examination Day:
Prior to recruitment into the study, subjects will undergo a physical exam. During this visit, a short review of the subject's history will be performed and vital signs, height and weight will be assessed (temperature, pulse, respiratory rate, and blood pressure), to determine whether the individual meets any major exclusion criteria for the study. Up to 50 ml of blood may be collected for a CBC/ differential, chemistry and lipid panels. At this time the subject may undergo a physical examination for bronchoscopy or may be scheduled for one at another time.
In order to participate in this study, subjects will be asked to:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy Individuals Specific Inclusion Criteria
- •Physical exams will be performed by study physicians during the screening visit (IRB approved EPA protocol 95-EPA-66).
- •Normal lung function (pre or post albuterol), defined by Knudson 1976/1984 as:
- •- FVC of > 75 % of that predicted for gender, ethnicity, age and height.
- •- FEV1 of > 75 % of that predicted for gender, ethnicity, age and height.
- •- FEV1/FVC ratio of > 75 % of predicted values.
- •Oxygen saturation of > 96 %.
- •Ability to tolerate intervals of moderate exercise
- •Mild to Moderate Asthmatics
- •Inclusion Criteria:
- •Physical exams will be performed by study physicians during the screening visit (IRB approved EPA protocol 95-EPA-66) where diagnosis will be judged by EPA physicians.
- •Mild/Moderate asthmatics as defined by NHLBI guidelines.
- •Positive history of asthma (wheezing, chest tightness, and reversible airway obstruction);
- •Baseline FEV1/FVC ≥ 60%;
- •Oxygen saturation of ≥ 94%
- •Ability to tolerate moderate exercise
排除标准
- •Healthy Individuals
- •A history of chronic illnesses such as diabetes, rheumatological diseases, immunodeficiency state, known clinically significant cardiac disease (including myocardial infarction, congestive heart failure and angina), chronic respiratory diseases such as chronic obstructive pulmonary disease, and lung cancer.
- •If the subject is pregnant, attempting to become pregnant or breastfeeding.
- •Allergy to any medications which may be used or prescribed in the course of this study.
- •Subjects currently taking mega doses of vitamins and supplements, homeopathic/naturopathic medicines or medications which may impact the results of the PM and/or ozone challenge or interfere with any other medications potentially used in the study (to include systemic steroids and beta blockers). Subjects must refrain from all over the counter anti-inflammatory agents including those for allergies, and naproxen, and anti-oxidants for a period of one week prior to exposure. Medications not specifically mentioned here may be reviewed by the investigators prior to a subject's inclusion in the study.
- •Smoking history within 2 years of the study.
- •Use of inhaled steroids, cromolyn, or leukotriene inhibitors (Montelukast, Zafirkulast, etc) initiated within the past month (except for use of cromolyn exclusively prior to exercise). Patients must be on a stable regimen of therapy.
- •Untreated hypertension (> 150 systolic, > 90 diastolic)
- •Unspecified illnesses, which in the judgment of the investigator might increase the risk associated with PM inhalation challenge or exercise, will be a basis for exclusion.
- •History of skin allergy to tape or electrodes.
- •Subjects who do not understand or speak English
- •Subjects who are unable to perform moderate exercise
- •Exclusion criteria for bronchoscopy:
- •Any food or fluids after midnight prior to bronchoscopy
- •FEV1/FVC ratio less than 60% predicted on AM of bronchoscopy.
- •Regular use of aspirin or other nonsteroidal anti-inflammatory drugs (which inhibit platelet function).
- •Mild to Moderate Asthmatics
- •Use of oral steroid therapy within the past month
- •2. Physician directed emergency treatment for asthma exacerbation within the preceding 6 months.
- •3. Abnormal EKG that precludes evaluating heart rate variability.
- •Aside from mild/moderate asthma, a history of chronic illnesses such as diabetes, rheumatological diseases, immunodeficiency state, known clinically significant cardiac disease (including myocardial infarction, congestive heart failure and angina), chronic respiratory diseases such as chronic obstructive pulmonary disease or severe asthma, and cancer (possible exception for history of nonmelanoma skin cancer).
- •5. If the subject is pregnant, attempting to become pregnant or breastfeeding.
- •Allergy to any medications which may be used or prescribed in the course of this study
- •Subjects currently taking mega doses of vitamins and supplements, homeopathic/naturopathic medicines or medications which may impact the results of the PM challenge or interfere with any other medications potentially used in the study (to include systemic steroids and beta blockers). Subjects must refrain from all over the counter anti-inflammatory agents including those for allergies, and naproxen, and anti-oxidants for a period of one week prior to exposure. Medications not specifically mentioned here may be reviewed by the investigators prior to a subject's inclusion in the study.
- •8. Dosing level of an inhaled steroid must be consistent with mild asthma as outlined by the NHLBI NAEPP guidelines. Regular use of oral corticosteroids, or use of inhaled steroid at doses typically used for severe asthma, will result in exclusion of that individual from the protocol.
- •9. Severe asthmatics as defined by: nighttime symptoms of cough or wheeze greater than 1 time per week at baseline, daily exacerbation of asthma or requirement for albuterol due to asthma symptoms (cough, wheeze, chest tightness, but not to include prophylactic use of albuterol prior to exercise), more than mild interference with normal activity, any episode of physician directed emergency treatment for asthma requiring oral corticosteroid therapy within the past twelve months.
- •10. Smoking history within 2 years of study.
- •Use of inhaled steroids, cromolyn, or leukotriene inhibitors (Montelukast, Zafirkulast, etc) initiated within the past month (except for use of cromolyn exclusively prior to exercise). Patients must be on a stable regimen of therapy.
- •12. History of skin allergy to tape or electrodes.
- •History of respiratory diseases other than allergic rhinitis and asthma
- •Untreated hypertension (> 150 systolic, > 90 diastolic)
- •Unspecified illnesses, which in the judgment of the investigator might increase the risk associated with PM inhalation challenge or exercise, will be a basis for exclusion.
- •17. Subjects who do not understand or speak English
- •Subjects who are unable to perform moderate exercise
- •Exclusion criteria for bronchoscopy:
- •Any food or fluids after midnight prior to bronchoscopy
- •FEV1/FVC ratio less than 60% predicted on AM of bronchoscopy.
- •Regular use of aspirin or other nonsteroidal anti-inflammatory drugs (which inhibit platelet function).
研究组 & 干预措施
Clean air exposure
Exposure to clean air will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed to clean air for 2 hours. Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC.
干预措施: Clean Air (Other)
Diesel exhaust exposure
Exposure to diesel exhaust will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed to diesel exhaust (up to 300 ug/m3). Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC. The DE will be generated from a diesel generator used to power a load bank that is located outside the Human Studies Facility, and subsequently introduced into the exposure chamber after different dilutions with clean HEPA and charcoal filtered and humidified air to give a chamber concentration of up to 300 μg/m3.
干预措施: Diesel exhaust (Other)
18Ozone
Exposure to ozone generated using the heavy non-radioactive isotope of oxygen (18O). Exposure to 0.3ppm 18O will be conducted in an exposure chamber at the EPA Human Studies Facility on the UNC campus. Each subject will be exposed for 2 hours. Subjects will begin exercising on an exercise bike. Each exercise session will consist of a 15 minute exercise interval at a level of up to 25 L/m2/BSA followed by a 15 minute rest period. The exposure atmosphere will be at approximately 40 + 10% RH and approximately 22 + 2 oC. Ozone exposures will be conducted in a (6 ft x 6 ft x 8 ft) stainless steel chamber with a continuous supply of exposure medium. Ozone will be monitored continuously.
干预措施: Ozone18 (Other)
结局指标
主要结局
Airway responses
时间窗: Pre exposure to 24hours post exposure
Airway responses include spirometry and lung cell changes following exposure to either clean air, ozone or diesel exhaust Lung cell changes include change in number and type of cells, changes in genetic (gene expression) and epigenetic responses (primarily changes in DNA methylation, microRNA expression and chromatin modification.
次要结局
- Cardiovascular responses(Pre exposure to 24hours post exposure)
- Soluble factors(Pre exposure to 24hours post exposure)
研究者
David Diaz-Sanchez
Chief, Clinical Research Branch
Environmental Protection Agency (EPA)