Grantee Research Project Results

2010 Progress Report: Endotoxin Exposure and Asthma in Children

EPA Grant Number: R834515C001
Subproject: this is subproject number 001 , established and managed by the Center Director under grant R834515
(EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
Center: Denver Childrens Environmental Health Center - Environmental Determinants of Airway Disease in Children
Center Director: Guo, Yanbing
Title: Endotoxin Exposure and Asthma in Children
Investigators: Schwartz, David A.
Current Investigators: Schwartz, David A. , Covar, Ronina A , Litonjua, Augusto A. , Liu, Andrew H. , Crooks, James L , Van Dyke, Michael V. , Forssen, Anna , Sordillo, Joanne , Rabinovitch, Nathan , Szefler, Stanley , Fingerlin, Tasha
Institution: National Jewish Health
Current Institution: National Jewish Health , Harvard University , National Jewish Medical and Research Center
EPA Project Officer: Hahn, Intaek
Project Period: June 22, 2010 through June 21, 2015 (Extended to June 21, 2017)
Project Period Covered by this Report: June 22, 2010 through June 21,2011
RFA: Children's Environmental Health and Disease Prevention Research Centers (with NIEHS) (2009) RFA Text | Recipients Lists
Research Category: Children's Health , Human Health

Objective:

We hypothesize that higher levels of endotoxin exposure cause persistent, problematic asthma and that key environmental (ozone and allergens) and genetic modifiers (endotoxin receptor polymorphisms) contribute to endotoxin susceptibility and pathological asthmatic responses. We are studying these endotoxin-induced airway conditions in children through three complementary clinical investigations.

First, we are capitalizing on an ancillary study of an NIH-sponsored multi-center cohort of children with asthma (Childhood Asthma Management Program), which has tracked asthma severity for more than a decade, to determine if endotoxin exposure, modified by genetics and environment, is associated with greater disease severity and persistence.

Second, we are planning a panel study of children with asthma to investigate whether endotoxin exposure, modified by environment, is associated with inflamed airways and elevated TLR expression on airway macrophages. Clinically, these inflammatory responses could drive poor asthma control and exacerbations.

Finally, we are taking advantage of a HUD-sponsored inner-city home intervention study to determine if a home environment intervention will reduce home endotoxin levels and improve asthma. This combination of studies is expected to provide an understanding of how endotoxin interacts with other potentially toxic exposures in the susceptible host to cause persistent, problematic asthma. These studies will help us to determine the levels of endotoxin exposure that are likely to be problematic for children with asthma, and to develop environmental educational and intervention programs to improve health outcomes.

Progress Summary:

As proposed, three complementary studies address the aims and hypotheses of Project 1: (1) Childhood Asthma Management Program (CAMP) ancillary study; (2) Denver Panel Study (DPS); and (3) Housing & Urban Development (HUD) ancillary study. For the CAMP study, house dust samples from 980 CAMP study participants were shipped to the Denver site for endotoxin measurement. An important decision was made to change the lab assay for dust endotoxin from one based on the limulus amebocyte lysate (LAL) to recombinant Factor C (rFC) derived from the Limulus amebocyte. rFC has significant technical advantages compared to LAL. In lab pilot studies to validate rFC measures, a high correlation was observed between rFC and LAL (19 dust samples, correlation r = 0.92). Other rFC lab method refinements were made, based on additional lab pilots. These rFC methods will be used to measure dust endotoxin in all of our Children's Environmental Health Center studies. In Aim 2, for the DPS study, we completed a lab pilot to determine the induced sputum yield for airway macrophages from people with asthma via bead separation methods. There was high variability in the proportion and number of airway macrophages from different samples (10 participant samples: median 75,000 airway macrophages/sample; range 5,000-510,000). Accordingly, we plan a screening visit for potential study participants to assess their induced sputum yield prior to enrollment in the DPS study. For Aim 4, the original investigation of seven functional polymorphisms and 31 SNPs in three endotoxin receptor complex genes has been expanded due to the availability of extensive genotyping of CAMP study participants in a separate effort via Illumina 550K SNP genotyping methods. With this expanded scope of envirogenomic investigation, innovative observations in this study will benefit from validation in replication cohort investigations. Therefore, we have identified potential race-matched cohorts for such validation studies, in case they become necessary.

Future Activities:

For the CAMP study, we will complete EPA, GCP, and IRB approval processes. We plan to complete house dust endotoxin measures and expand genotyping of CAMP participants, analyze endotoxin exposure and genetic modifiers of asthma outcomes, and submit results for presentation and publication. For the HUD study, study participant enrollment and house dust sample collection will be completed, allergen and endotoxin levels in dust samples will be measured, and the effect of the home intervention on dust endotoxin levels and asthma outcomes will be analyzed. Over the course of the coming year, we aim to complete the endotoxin measures and analyses for the CAMP and HUD studies, while planning and organizing for the DPS asthma study.

Journal Articles:

No journal articles submitted with this report: View all 23 publications for this subproject

Supplemental Keywords:

Endotoxin, exposure, children, asthma, risk, health effects, susceptibility, sensitive populations, genetic pre-disposition, genetic polymorphism, indoor air, dose-response, ozone, remediation, human health, health, health effects, biology, health risk assessment, children's health, allergens/asthma, asthma indices, intervention, Health, Scientific Discipline, HUMAN HEALTH, Health Risk Assessment, Physiology, Biology, Allergens/Asthma, Health Effects, sensitive populations, airway inflammation, asthma, asthma indices, asthma triggers, children, endotoxin, allergic response

Relevant Websites:

Children's Environmental Health Center (CEHC) - National Jewish Health

Progress and Final Reports:

Original Abstract

Main Center Abstract and Reports:

R834515 Denver Childrens Environmental Health Center - Environmental Determinants of Airway Disease in Children

Subprojects under this Center: (EPA does not fund or establish subprojects; EPA awards and manages the overall grant for this center).
R834515C001 Endotoxin Exposure and Asthma in Children
R834515C002 Environmental Determinants of Early Host Response to RSV
R834515C003 Environmental Determinants of Host Defense

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The perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.