Exposure to particulate matter air pollution (PM) remains a major public health concern. In experiments supported by the first cycle of this award, 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. Our report provided a novel and innovative mechanistic framework to explain how PM exposure might result in excess ischemic cardiovascular events, which are the major drivers of PM-related mortality. Several groups of investigators have subsequently confirmed the importance of our findings in humans. In this revised proposal, we present new preliminary data supporting the significance of our findings for human health. We exposed mice to concentrated ambient particulate matter <2.5 5m in diameter (CAPs) via inhalation at concentrations frequently observed in major cities. These mice developed a prothrombotic state, which was absent in IL-6-/- mice. Accordingly, we have focused this proposal on the in vitro and in vivo mechanisms by which exposure to PM causes the release of IL-6 from alveolar macrophages and the molecular pathways that modulate this response. We present preliminary data suggesting for the first time that the opening of Ca2+ release-activated Ca2+ channels (CRAC) are required for the PM-induced release of IL-6 from alveolar macrophages. Our results suggest a novel role for the Bcl-2 protein NOXA in the regulation of inflammation, which is independent of its known role in apoptosis. Furthermore our data suggest that engagement of the macrophage CXCR2 receptor by KC (the murine analogue of IL-8), which is released by the alveolar epithelium in response to PM, attenuates IL-6 release. In three interrelated specific aims, we will test the hypothesis 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 NOXA and engagement of the CXCR2 receptor inhibit this response.
In Specific Aim 1, we will determine whether CRAC channel-mediated calcium influx and the generation of ROS from the mitochondria are required for the PM-induced activation of kinases that result in IL-6 release from alveolar macrophages.
In Specific Aim 2, we will determine whether NOXA prevents the PM-induced release of IL-6 from macrophages by inhibiting CRAC channel-mediated calcium influx, mitochondrial ROS generation or activation of their target kinases and in Specific Aim 3, we will determine the mechanisms by which the PM-induced release of KC from the alveolar epithelium acts through the CXCR2 receptor to prevent the release of IL-6 from alveolar macrophages. The pharmaceutical industry has identified many of the pathways we have found to be important in the response to PM as targets for drug development. Our studies will allow us to predict whether these agents are likely to modulate the cardiovascular response to inhaled particles.
Exposure to particulate matter air pollution (PM) remains a major public health concern and is linked with significant increases in cardiopulmonary morbidity and mortality. In this proposal, we will use sophisticated cell and mouse models to examine the mechanisms by which PM contributes to these adverse health outcomes. Understanding these mechanisms will allow for the development of biomarkers of PM exposure and will assist engineers and public health officials in the development of effective pollution control policies.
| Sala, Marc A; Balderas-Martínez, Yalbi Itzel; Buendía-Roldan, Ivette et al. (2018) Inflammatory pathways are upregulated in the nasal epithelium in patients with idiopathic pulmonary fibrosis. Respir Res 19:233 |
| Soberanes, Saul; Misharin, Alexander V; Jairaman, Amit et al. (2018) Metformin Targets Mitochondrial Electron Transport to Reduce Air-Pollution-Induced Thrombosis. Cell Metab : |
| Misharin, Alexander V; Morales-Nebreda, Luisa; Reyfman, Paul A et al. (2017) Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med 214:2387-2404 |
| Bharat, Ankit; Bhorade, Sangeeta M; Morales-Nebreda, Luisa et al. (2016) Flow Cytometry Reveals Similarities Between Lung Macrophages in Humans and Mice. Am J Respir Cell Mol Biol 54:147-9 |
| Cheresh, Paul; Morales-Nebreda, Luisa; Kim, Seok-Jo et al. (2015) Asbestos-induced pulmonary fibrosis is augmented in 8-oxoguanine DNA glycosylase knockout mice. Am J Respir Cell Mol Biol 52:25-36 |
| Thannickal, Victor J; Murthy, Mahadev; Balch, William E et al. (2015) Blue journal conference. Aging and susceptibility to lung disease. Am J Respir Crit Care Med 191:261-9 |
| Bharat, Ankit; Cunningham, Scott A; Scott Budinger, G R et al. (2015) Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans. Sci Transl Med 7:284re3 |
| Barreiro, Esther; Sznajder, Jacob I; Nader, Gustavo A et al. (2015) Muscle dysfunction in patients with lung diseases: a growing epidemic. Am J Respir Crit Care Med 191:616-9 |
| Morales-Nebreda, Luisa I; Rogel, Micah R; Eisenberg, Jessica L et al. (2015) Lung-specific loss of ?3 laminin worsens bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 52:503-12 |
| Chiarella, Sergio E; Budinger, G R Scott; Mutlu, Gökhan M (2015) ??-Agonist therapy may contribute to the air pollution and IL-6-associated risk of developing severe asthma with dual-positive TH2/TH17 cells. J Allergy Clin Immunol 135:290-1 |
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