The broad, long-term objective of this basic research proposal is to determine how inhalation of particulates present in smoke could initiate through antigen presenting cells (APC) immune-mediated lung pathological changes such as emphysema. We have found that a major smoke-derived product that accumulates in lung APCs is amorphous, elemental carbon (carbon black (CB)). We have further found that CB-laden APCs from the lung of smokers with emphysema manifest a distinct microRNA (miRNA) signature and that functionally they induce activation of T helper type 1 (Th1) and Th17 cells. Moreover, specific Th1 and Th17 cytokines promote lung destruction in emphysema by inducing the secretion of matrix metalloproteinase (MMP) 12 that degrades elastin and inhibits alpha 1 anti-trypsin, an inhibitor of neutrophil elastase. The resulting vicious cycle of elastolysis weakens lung parenchymal integrity that over time manifests as upper lobe-predominant emphysema. miRNAs potentially contribute to the activation of APC and therefore emphysema by controlling expression of key co-stimulatory molecules and pro-inflammatory cytokines. Because CB is intrinsic to all forms of smoke arising from the combustion of organic material (e.g., tobacco) and constitutes an important form of pollution (e.g., through coal mining, the wearing of rubber tires, diesel exhaust, etc.) we hypothesize that inhaled CB could induce maturation of lung APCs and promote differentiation of T cells into Th1 and Th17 subsets that are linked to diseases such as emphysema and lung cancer. We propose using a unique CB- based experimental model of lung inflammation to 1) Determine the immune phenotype of lung and the function of mouse lung APCs in response to CB inhalation;and 2) Determine the role of miRNAs in CB- induced activation of lung APC.
Inhalation of smoke through tobacco smoking and other smoke exposures is known to cause lung disease, but why smoke causes such injury is not known. We have discovered that a common substance in smoke, termed carbon black, causes lung diseases such as emphysema. This application is important because it will reveal how carbon black causes harmful lung inflammation and suggest new ways to treat smoke-related lung disease.
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