Innate immune stimulation contributes to or increases the severity of inflammatory lung diseases including;asthma, COPD, ARDS, and pneumonia. A mechanistic understanding of the contribution of innate immune signaling to these diseases will directly impact quality of care and outcome in the clinic. Classic genetic approaches have identified many of the innate immune signaling pathways and other genes that regulate the response to bacterial lipopolysaccharide (LPS). Now, increasing evidence suggests that common environmental exposures can modify the severity of many inflammatory lung diseases. However, the connection between environmental exposures and an altered innate immunity remains poorly understood. Our previous work showing that maternal exposure to a diet rich in methyl donors alters heritable risk of allergic airways disease through enhanced CpG methylation of key regulatory genes. It is therefore plausible that common environmental exposures during a vulnerable period of development could alter patterns of methylation thereby altering heritable risk of other immunological phenotypes. Proximity to traffic and inhalation of diesel particles are associated with detrimental human respiratory health outcomes. Diesel particle exposure in mice enhances the allergic airway response to Aspergillus fungus antigen through alteration of CpG methylation of key Th2 gene promoters. Similarly, exposure of pregnant female mice to diesel particles also enhances allergic inflammation in offspring. However, whether common environmental exposures modify innate immunity through altered CpG methylation remains to be determined. In support of this possibility, LPS responsiveness is regulated by the level of TLR4 expression and level of TLR4 expression can be altered by CpG methylation. These observations taken together suggest that environmental exposures could regulate innate immune response to LPS through specific changes in the pattern of CpG methylation in key regulatory genes. Thus the overall goal of this proposal is to identify the mechanisms by which maternal inhalation of diesel modifies heritable transmission of innate immune response to LPS. Based on prior evidence and our preliminary data, we hypothesize that gestational exposure to diesel exhaust particles increases LPS-induced lung inflammation and airway reactivity in offspring and subsequent generations by enhancing LPS-mediated responses of myeloid-derived cells in the lung. Furthermore, altered CpG methylation of myeloid cell DNA causes aberrant expression of innate immune response genes, thereby conferring enhanced sensitivity to inhaled LPS. To address this hypothesis we will address the following specific aims:
Aim 1 : Determine the role of myeloid-derived cells in the heritably enhanced response to LPS consequent to gestational exposure to diesel particles.
Aim 2 : Determine the role of CpG methylation of DNA on mRNA expression of LPS response genes in alveolar macrophages derived from subsequent generations of offspring.

Public Health Relevance

Asthma is a common disease affecting approximately 8% of the population in the US. Inhalation of ambient environmental endotoxin contributes to respiratory morbidity in human populations. We identify that maternal inhalation of diesel particles is associated with increased heritable risk of enhanced response to bacterial endotoxin. This shift in sensitivity could account for the observed increase in respiratory symptoms commonly observed in urban environments. Our studies provide an opportunity to understand the fundamental biological mechanisms, which contribute to the heritable response to inhaled endotoxin. These studies will broadly provide insight into the complex interaction between a common environmental exposure and genetic/epigenetic transmission of pulmonary innate immune responsiveness. We anticipate the proposed work will provide novel insight into mechanisms, by which, maternal inhalation of diesel particles can modify epigenetic transmission of a complex heritable trait of high clinical significance.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Innate Immunity and Inflammation Study Section (III)
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Nadadur, Srikanth
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Duke University
Internal Medicine/Medicine
Schools of Medicine
United States
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Horr, Samuel; Roberson, Russell; Hollingsworth, John W (2013) Pseudohypoxemia in a patient with chronic lymphocytic leukemia. Respir Care 58:e31-3
Murphy, Susan K; Hollingsworth, John W (2013) Stress: a possible link between genetics, epigenetics, and childhood asthma. Am J Respir Crit Care Med 187:563-4
Li, Zhuowei; Tighe, Robert M; Feng, Feifei et al. (2013) Genes of innate immunity and the biological response to inhaled ozone. J Biochem Mol Toxicol 27:3-16
Feng, Feifei; Li, Zhuowei; Potts-Kant, Erin N et al. (2012) Hyaluronan activation of the Nlrp3 inflammasome contributes to the development of airway hyperresponsiveness. Environ Health Perspect 120:1692-8
Potts-Kant, Erin N; Li, Zhuowei; Tighe, Robert M et al. (2012) RETRACTED: NAD(P)H:quinone oxidoreductase 1 protects lungs from oxidant-induced emphysema in mice. Free Radic Biol Med 52:705-715
Tighe, Robert M; Li, Zhuowei; Potts, Erin N et al. (2011) Ozone inhalation promotes CX3CR1-dependent maturation of resident lung macrophages that limit oxidative stress and inflammation. J Immunol 187:4800-8
Li, Zhuowei; Potts-Kant, Erin N; Garantziotis, Stavros et al. (2011) Hyaluronan signaling during ozone-induced lung injury requires TLR4, MyD88, and TIRAP. PLoS One 6:e27137