Northwestern University Feinberg School of Medicine

GR Scott Budinger Lab

Signaling in the lung induced by particular matter air pollution

Exposure to particulate matter air pollution (PM) remains a major public health concern. There is strong evidence that links the levels of air pollution, particularly the levels of particulate matter, to human disease. On days when pollution levels are high, there are more hospitalizations for heart and lung conditions and more people die when compared to days when pollution is low.  We understand very little, however, about the biologic mechanisms by which exposure to air pollution causes illness. None of these studies provide a mechanism linking PM exposure with these adverse outcomes.

We have developed a mechanistic framework to explain how PM exposure might result in excess ischemic cardiovascular events, which are the major drivers of PM-related mortality. We found that the intratracheal administration of PM to mice induces lung macrophages to release IL-6, which is required for the development of an increased tendency to arterial thrombosis.

We observed that exposure to PM induces the generation of oxidants from the mitochondria, the opening of Ca2+ release-activated Ca2+ channels (CRAC) and the activation of oxidant-sensitive kinases, all of which are required for IL-6 release. We hypothesize that exposure of macrophages to PM causes the CRAC channel and mitochondrial ROS-mediated activation of oxidant sensitive kinases to induce the transcription of IL-6 and determine the mechanisms by which pro-aptotic protein NOXA and engagement of the CXCR2 macrophage receptor inhibit this response.

GR Scott Budinger, MD
Principal Investigator

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