![[logo] US EPA](http://www.epa.gov/epafiles/images/logo_epaseal.gif){kind=logo}
University of Iowa Children's Environmental Airway Disease Center (1998-2003)
Principal Investigator: Gary Hunninghake, MD
| Overview | Community Partners |
| Exposures and Outcomes | Selected Publications |
| Research Projects |
Research at the the Iowa Children’s Center focused on the etiology and pathogenesis of airway disease in children from rural communities. Iowa researchers found that the incidence and severity of asthma in rural children is similar to that of children raised in urban environments – the Iowa children do not appear to be protected. Another finding is that viral infections appear to increase sensitivity to other environmental exposures. Products of bacteria and fungi are prevalent in the rural environment and may be specific triggers but are often non-specific for asthma. However, Iowa researchers found that exposure to endotoxin can trigger asthma, including fixed airways disease in an animal model. Center research has also described mechanisms by which respiratory syncytial virus (RSV), a virus that triggers asthma, can escape antiviral mechanisms in the airway and pathways that the virus uses to trigger inflammation. The Center also found that a structured intervention program can lessen the severity of asthma symptoms. In many rural areas, the unit of community is often the school district, which may encompass more than one small town. University of Iowa researchers developed a community coalition (CARE-Net) to address issues of science, education and health care delivery appropriate for a rural setting.
Primary Exposures: Grain dust, endotoxin, bacteria and fungi
Primary Outcomes: Asthma
Project 1: Multi-component Intervention Study of Asthma in Children from Rural Communities
There are conflicting findings about the prevalence of asthma among farm and non-farm children, and this project sought to estimate asthma prevalence and morbidity and determine differences between the two groups. The study population consisted of rural children ages 6-14 years enrolled in 10 school districts in 2 noncontiguous rural Iowa counties from 2000-2002.
Project 2: A Model to Study the Development of Persistent Environmental Airway Disease
A multicomponent intervention model was designed for the Rural Childhood Asthma Study (RCAS) reflecting the health care and environmental issues of children in rural areas. The RCAM model includes asthma counselor visits and individualized recommendations to the child’s primary care provider generated by counselor worksheets and reviewed by the study physician-pharmacist-counselor intervention team in weekly rounds.
Project 3: Mechanisms that Initiate, Promote, and Resolve Grain Dust/LPS Induced Inflammation
This project addressed a fundamental issue in childhood asthma: why only a minority of children who wheeze at an early age develop lifelong persistent airway disease. Studies at the Iowa Center have shown that mice exposed to grain dust, endotoxin or LPS can develop the classical features of asthma – airflow obstruction, reversible airway inflammation, persistent airway hyperreactivity and airway remodeling. The major strength of these studies is that they are modeled on the physiologically relevant concept that understanding grain dust-induced asthma will require understanding the effects of intact dust on the human airway. They also represent collaborative endeavors between the laboratories of Drs. Nauseef, Denning, Moreland, Weiss, and Schwartz and include parallel studies with mouse and human model systems.
Project 4: Role of RSV Infection and Endotoxin in Airway Inflammation
Airway infection with RSV is associated with worsening airway function in infants and young children with asthma. A better understanding of factors which determine successful host defense against RSV may uncover new approaches to control or prevent RSV infection and its effects on airway inflammation and function in asthma. Effective pulmonary clearance of the virus requires epithelial cell participation in type I interferon-dependent immunity. Another aim is to uncover strategies for selectively modifying damaging viral effects but not beneficial immunity.
Project 1: Multi-component Intervention Study of Asthma in Children from Rural Communities
- Children who lived on farms were less likely than those who lived in town to have ever wheezed (odds radio OR=0.71 [0.58-0.87]) or to have wheezed during the past year. However, this protective effect with farming was only observed in one of the study areas, Keokuk County. Among those who wheezed, farm and non-farm children were equally likely to have been given a diagnosis of asthma and had comparable morbidity. A major conclusion of this large, rural, population-based study is that asthma prevalence in this population rivals that in large Midwestern cities. Unmeasured risk factors might account for the apparent protective effect in Keokuk County. These findings cast doubt on a protective effect of rural life for the development of childhood asthma (Chrischilles et al. 2004).
- The 2-county Rural Childhood Asthma Study (RCAS) found the RCAM model improved asthma medical and environmental behaviors and reduced persistent symptoms in the intervention county compared with the control county. The Iowa Asthma Coalition has assisted in protocol design and recruitment and has reviewed intervention materials.
Project 2: A Model to Study the Development of Persistent Environmental Airway Disease
- Iowa Children’s Center researchers investigated the development of airway hyperreactivity (AHR) and inflammation in the lungs of nine genetically diverse inbred strains of mice. After sensitization and challenge with ovalbumin (OVA). At 24, 48, and 72 h post-OVA exposure, the severity of AHR and eosinophilic inflammation of the mouse strains ranged from relatively unresponsive to responsive. The severity of the airway eosinophilia of some strains did not clearly correlate with the development of AHR. The temporal presence of T helper type 2 cytokines in lung lavage fluid also varied markedly among the strains. The levels of IL-4 and IL-13 were generally increased in the strains with the highest airway eosinophilia at 24 and 72 h postexposure, respectively; the levels of IL-5 were significantly increased in most of the strains with airway inflammation over the 72-h time period. The differences of physiological and biological responses among the inbred mouse strains after OVA sensitization and challenge support the hypothesis that genetic factors contribute, in part, to the development of allergen-induced airway disease (Whitehead et al. 2003).
Project 3: Mechanisms that Initiate, Promote, and Resolve Grain Dust/LPS Induced Inflammation
- Iowa Center studies show that the development of chronic airway disease in mice is dependent on the recruitment of polymorphonuclear neutrophils (PMNs) and is associated with fibrin deposition and the expression of transforming growth factor (TGF- β 1) and matrix metalloprotease 9 (MMP-9), an enzyme that splits proteins. This provides a clear rationale to use this model system to identify the biological features of reversible neutrophilic airway inflammation fundamental to development of chronic environmental asthma. Investigators hypothesize that activation of neutrophils at inflammation sites disrupts extracellular matrix homeostasis, altering the balance between pro- and anti-fibrotic factors leading to pathological tissue repair of the airway.
Project 4: Role of RSV Infection
and Endotoxin in Airway Inflammation
- Iowa Children’s Center researchers have found that RSV preferentially infects lung airway epithelial cells and is a major cause of illness in young children. Findings indicate that RSV infection in the first year of life increases the risk of subsequent development of asthma. Researchers found that RSV increased lipopolysaccharide (LPS) sensitivity of airway epithelial cells by up-regulating the LPS receptor, Toll-like receptor 4 (TLR4) and possible mechanisms are being investigated. This suggests that RSV infection sensitizes bronchial epithelium to environmental exposure via effects on receptors that interact with environmental agents. The increases in TLR4 expression and receptors that interact with other environmental agents may explain why children with RSV-induced asthma are especially sensitive to their environment.
- Iowa researchers have made several observations regarding expression of antiviral genes in human airway epithelial cells after RSV infection:
- Airway epithelial cells response to both type I and type II interferons by expression of antiviral proteins
- Respiratory viruses have different capacities and often multiple mechanisms for inhibition of interferon-dependent gene expression
- RSV infection selectively inhibits type I interferon signal transduction by blocking Stat1 and Stat2 phosphorylation.
Based on these observations, investigators hypothesize that a critical mechanism for this effect is viral inhibition of the type I interferon-activated JAK-STAT signal transition cascades. The overall goal of this project is to better understand the biochemical basis of RSV effects on antiviral gene expression in human epithelial cells.
- Iowa researchers have demonstrated that C57BL/6 immune cells express Th2 but not Th1 cytokines at lower levels than DBA/2 cells. They also found that C57BL/6 splenocytes exhibit decreased mRNA stability of Th2 cytokines, relative to DBA/2 splenocytes. Stability of IL-2 and IFN-gamma were similar in the two strains of mice. Differences in Th2 cytokine mRNA stability between C57BL/6 and DBA/2 cells were not due to sequence polymorphism at specific regions of the IL-4/IL-13 locus. Furthermore, expression of Th1- and Th2-specific transcription factors T-bet and GATA-3, as well as the nuclear factor of activated T cells transcription factor, NFATc, was not significantly different between the two mice. The data suggest that decreased mRNA stability of Th2 cytokines in C57BL/6 splenocytes may underlie the differential susceptibility to hypersensitivity pneumonitis between C57BL/6 and DBA/2 mice. Moreover, the results indicate that regulation of mRNA stability may serve as an important mechanism underlying Th1/Th2 immune polarization (Butler et al. 2002).
Butler NS, Monick MM, Yarovinsky TO, Powers LS, Hunninghake GW 2002. Altered IL-4 mRNA stability correlates with Th1 and Th2 bias and susceptibility to hypersensitivity pneumonitis in two inbred strains of mice. J Immunol. 2002 Oct 1;169(7):3700-9.
Chrischilles
E, Ahrens R, Kuehl A, Kelly K, Thorne P, Burmeister L, Merchant J 2004. Asthma
prevalence and morbidity among rural Iowa schoolchildren. J Allergy
Clin Immunol. 2004 Jan;113(1):66-71. Erratum in: J Allergy Clin
Immunol. 2004 Mar;113(3):391.
Monick MM, Yarovinsky TO, Powers LS, Butler NS, Carter AB, Gudmundsson G, Hunninghake GW 2003. Respiratory syncytial virus up-regulates TLR4 and sensitizes airway epithelial cells to endotoxin. J Biol Chem. 2003 Dec 26;278(52):53035-44. Epub 2003 Oct 17.
Moreland JG, Fuhrman RM, Pruessner JA, Schwartz DA 2002. CD11b and intercellular adhesion molecule-1 are involved in pulmonary neutrophil recruitment in lipopolysaccharide-induced airway disease. Am J Respir Cell Mol Biol. 2002 Oct;27(4):474-80.
Whitehead GS, Walker JK, Berman KG, Foster WM, Schwartz DA 2003. Allergen-induced airway disease is mouse strain dependent. Am J Physiol Lung Cell Mol Physiol. 2003 Jul;285(1):L32-42. Epub 2003 Mar 7. Comment in: Am J Physiol Lung Cell Mol Physiol. 2003 Jul;285(1):L29-31.
Full List of Publications | Publications List from NIEHS PubMed Database
Centers Funded By: 