Genetic Mechanisms of Susceptibility to Ozone-induced Lung Inflammation

Environmental Genetics

The primary objective of this project is to utilize proven positional cloning techniques to identify the gene or genes that determine differential susceptibility to O₃-induced pulmonary inflammation and injury in inbred mice, and search for homologues in the human genome.  The group pursues this objective using a multi-disciplinary approach that applies genetic and molecular biology techniques to an in vivo animal model.  Ongoing collaboration with David Peden, M.D., of the University of North Carolina at Chapel Hill has enabled testing in O₃-exposed subjects mechanisms that the group identified in mouse models.  The group has also begun to expand the scope of this project to include pathological processes that may have etiologies in common with those found in O₃-induced inflammation (e.g. lung tumorigenesis).

Ongoing Projects in the Laboratory:

• TNF-α -mediated signaling pathways in O₃-induced inflammation (see figure below)
• Role of pro-inflammatory (IL12) and anti-inflammatory (IL10, IL18) cytokines and chemokines (Cx3CR1) in O₃-induced inflammation
• Genetic susceptibility to O₃-induced inflammation: role of MHC Class II genes
• Role of matrix metalloproteinases (MMPs) in the pathogenesis of O₃-induced inflammation and hyperpermeability
• Protection against inhaled oxidants through scavenging of oxidized lipids by macrophage receptors MARCO and SR-AI/II
• Mechanisms of ozone-induced exacerbation of allergic responses in the lung
• Association of candidate susceptibility gene polymorphisms in O₃-exposed human subjects
• Mechanisms of innate immune response-mediated protection against lung tumorigenesis

A hypothetical molecular mechanism underlying inhaled O₃-induced pulmonary inflammation and augmentation of lung disease symptoms. O₃ may cause ligand binding to tumor necrosis factor receptor (TNF-R) on pulmonary cells to elicit trimerization of TNF-R and receptor complex formation by recruitment of accessory proteins including TNF-R1-associated death domain protein (TRADD) and TNF-R associated factor (TRAF2). This event will trigger phosphorylation of downstream signal transducers including mitogen activated protein kinase (MAPK) kinase (MEK) and inhibitor of κB (IκB) kinase (IKK), which in turn would induce phosphorylation of MKK including c-Jun-NH2 terminal kinase (JNK) and phosphorylational degradation of IκB, respectively. AP-1 proteins activated by phosphorylated MAPK and NF-κB subunits (e.g., p50, p65) liberated from IκB-NF-κB complex would be subsequently translocalized into nuclei for DNA binding to modulate inflammatory effector gene expression. These signaling pathways and possibly feedback regulation by TNF-α (dotted arrow) and/or by other cytokines and receptors (dashed arrows) may be essential to propagate airway inflammation and injury caused by O₃, and exacerbate symptoms in subjects with pre-existing respiratory disease (e.g. asthma). (From Cho et al., Am J Respir Crit Care Med, 2007).

 Back to top