Particulate matter induced cell death: Current understanding of molecular drivers that lead to lung damage

Particulate matter (PM), ubiquitous in indoor and outdoor air parcels, is an environmental hazard and poses a risk to human health. The proclivity for PM to be continuously inhaled is what leads to adverse human outcomes. This is because often if not always, PM is chemically laden with toxins. The scientific literature is impressively growing with studies in vitro and in vivo that probe PM-induced cellular deaths, resulting in improved knowledge of disease onset. New cell death mechanisms are being proposed, including revisions of canonical definitions (e.g., necrosis). It is helpful in our view if the current knowledge of the processes within a cell initiated by PM insults and leading to cell death are summarized and supplemented to the literature. Such a summary should highlight proteins that act as death activators or gatekeepers in a given affected transduction pathway. Additionally, this summary should discern how PM dose can promote cell death versus lead to signaling that restores cell function. The result should underscore cell resiliency and provide insight on therapeutic strategies. To this end, the objective of this review is to present reception, transduction, and the response of a cell to PM exposure. We emphasize cellular transduction pathways that have been reported by the literature as impacted significantly by PM uptake (that would otherwise occur during homeostasis in a well-regulated manner) and the resulting defined cell deaths: autophagy, apoptosis, necrosis, and cuproptosis. We find that while reactive oxygen species (ROS) and subsequent inflammatory cytokine release are commonly studied and subject to therapeutic research, damage to organelles such as the mitochondrion (and leading to mitophagy) is receiving equivalent attention as attractive research targets. We conclude the review by scaling cell death to organ or organism pathophysiology and the importance of a genetic mutations for burden of PM-induced disease. That is, while air pollution or PM might not directly cause mutations, it can be a driver by creating an environment within the cell that favors the growth and progression of cells with these mutations.