Particulate matter (PM) exposure and metabolic syndrome (MetSyn) are both significant global health burdens. PM exposure has been implicated in the pathogenesis of MetSyn and cardiopulmonary diseases. Individuals with pre-existing MetSyn may be more susceptible to the detrimental effects of PM exposure. Our aim was to provide a narrative review of MetSyn/PM-induced systemic inflammation in cardiopulmonary disease, with a focus on prior studies of the World Trade Center (WTC)-exposed Fire Department of New York (FDNY). We included studies (1) published within the last 16-years; (2) described the epidemiology of MetSyn, obstructive airway disease (OAD), and vascular disease in PM-exposed individuals; (3) detailed the known mechanisms of PM-induced inflammation, MetSyn and cardiopulmonary disease; and (4) focused on the effects of PM exposure in WTC-exposed FDNY firefighters. Several investigations support that inhalation of PM elicits pulmonary and systemic inflammation resulting in MetSyn and cardiopulmonary disease. Furthermore, individuals with these preexisting conditions are more sensitive to PM exposure-related inflammation, which can exacerbate their conditions and increase their risk for hospitalization and chronic disease. Mechanistic research is required to elucidate biologically plausible therapeutic targets of MetSyn- and PM-induced cardiopulmonary disease.

World Trade Center particulate matter (WTC-PM)-exposed firefighters with metabolic syndrome (MetSyn) have a higher risk of WTC lung injury (WTC-LI). Since macrophages are crucial innate pulmonary mediators, we investigated WTC-PM/lysophosphatidic acid (LPA) co-exposure in macrophages. LPA, a low-density lipoprotein metabolite, is a ligand of the advanced glycation end-products receptor (AGER or RAGE). LPA and RAGE are biomarkers of WTC-LI. Human and murine macrophages were exposed to WTC-PM, and/or LPA, and compared to controls. Supernatants were assessed for cytokines/chemokines; cell lysate immunoblots were assessed for signaling intermediates after 24 h. To explore the translatability of our in-vitro findings, we assessed serum cytokines/chemokines and metabolites of symptomatic, never-smoking WTC-exposed firefighters. Agglomerative hierarchical clustering identified phenotypes of WTC-PM-induced inflammation. WTC-PM induced GM-CSF, IL-8, IL-10, and MCP-1 in THP-1-derived macrophages and induced IL-1α, IL-10, TNF-α, and NF-κB in RAW264.7 murine macrophage-like cells. Co-exposure induced synergistic elaboration of IL-10 and MCP-1 in THP-1-derived macrophages. Similarly, co-exposure synergistically induced IL-10 in murine macrophages. Synergistic effects were seen in the context of a downregulation of NF-κB, p-Akt, -STAT3, and -STAT5b. RAGE expression after co-exposure increased in murine macrophages compared to controls. In our integrated analysis, the human cytokine/chemokine biomarker profile of WTC-LI was associated with discriminatory metabolites (fatty acids, sphingolipids, and amino acids). LPA synergistically elaborated WTC-PM’s inflammatory effects in vitro and was partly RAGE-mediated. Further research will focus on the intersection of MetSyn/PM exposure.

Emerging evidence suggests that extracellular vesicles (EVs), which represent a crucial mode of intercellular communication, play important roles in cancer progression by transferring oncogenic materials. Nickel (Ni) has been identified as a human group I carcinogen; however, the underlying mechanisms governing Ni-induced carcinogenesis are still being elucidated. Here, we present data demonstrating that Ni exposure generates EVs that contribute to Ni-mediated carcinogenesis and cancer progression. Human bronchial epithelial (BEAS-2B) cells and human embryonic kidney-293 (HEK293) cells were chronically exposed to Ni to generate Ni-treated cells (Ni-6W), Ni-transformed BEAS-2B cells (Ni-3) and Ni-transformed HEK293 cells (HNi-4). The signatures of EVs isolated from Ni-6W, Ni-3, HNi-4, BEAS-2B, and HEK293 were analyzed. Compared to their respective untreated cells, Ni-6W, Ni-3, and HNi-4 released more EVs. This change in EV release coincided with increased transcription of the EV biogenesis markers CD82, CD63, and flotillin-1 (FLOT). Additionally, EVs from Ni-transformed cells had enriched protein and RNA, a phenotype also observed in other studies characterizing EVs from cancer cells. Interestingly, both epithelial cells and human umbilical vein endothelial (HUVEC) cells showed a preference for taking up Ni-altered EVs compared to EVs released from the untreated cells. Moreover, these Ni-altered EVs induced inflammatory responses in both epithelial and endothelial cells and increased the expression of coagulation markers in endothelial cells. Prolonged treatment of Ni-alerted EVs for two weeks induced the epithelial-to-mesenchymal transition (EMT) in BEAS-2B cells. This study is the first to characterize the effect of Ni on EVs and suggests the potential role of EVs in Ni-induced cancer progression.