Cigarette smoke promotes dendritic cell accumulation in COPD; a Lung Tissue Research Consortium study

<p>Abstract</p> <p>Background</p> <p>Abnormal immune responses are believed to be highly relevant in the pathogenesis of chronic obstructive pulmonary disease (COPD). Dendritic cells provide a critical checkpoint for immunity by their capacity to both induce and suppress immunity. Although evident that cigarette smoke, the primary cause of COPD, significantly influences dendritic cell functions, little is known about the roles of dendritic cells in the pathogenesis of COPD.</p> <p>Methods</p> <p>The extent of dendritic cell infiltration in COPD tissue specimens was determined using immunohistochemical localization of CD83+ cells (marker of matured myeloid dendritic cells), and CD1a+ cells (Langerhans cells). The extent of tissue infiltration with Langerhans cells was also determined by the relative expression of the CD207 gene in COPD <it>versus </it>control tissues. To determine mechanisms by which dendritic cells accumulate in COPD, complimentary studies were conducted using monocyte-derived human dendritic cells exposed to cigarette smoke extract (CSE), and dendritic cells extracted from mice chronically exposed to cigarette smoke.</p> <p>Results</p> <p>In human COPD lung tissue, we detected a significant increase in the total number of CD83+ cells, and significantly higher amounts of CD207 mRNA when compared with control tissue. Human monocyte-derived dendritic cells exposed to CSE (0.1-2%) exhibited enhanced survival <it>in vitro </it>when compared with control dendritic cells. Murine dendritic cells extracted from mice exposed to cigarette smoke for 4 weeks, also demonstrated enhanced survival compared to dendritic cells extracted from control mice. Acute exposure of human dendritic cells to CSE induced the cellular pro-survival proteins heme-oxygenase-1 (HO-1), and B cell lymphoma leukemia-x(L) (Bcl-xL), predominantly through oxidative stress. Although activated human dendritic cells conditioned with CSE expressed diminished migratory CCR7 expression, their migration towards the CCR7 ligand CCL21 was not impaired.</p> <p>Conclusions</p> <p>These data indicate that COPD is associated with increased numbers of cells bearing markers associated with Langerhans cells and mature dendritic cells, and that cigarette smoke promotes survival signals and augments survival of dendritic cells. Although CSE suppressed dendritic cell CCR7 expression, migration towards a CCR7 ligand was not diminished, suggesting that reduced CCR7-dependent migration is unlikely to be an important mechanism for dendritic cell retention in the lungs of smokers with COPD.</p

Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage

The DNA repair capacity of human cells declines with age, in a process that is not clearly understood. Mutation of the nuclear envelope protein barrier-to-autointegration factor 1 (Banf1) has previously been shown to cause a human progeroid disorder, Néstor–Guillermo progeria syndrome (NGPS). The underlying links between Banf1, DNA repair and the ageing process are unknown. Here, we report that Banf1 controls the DNA damage response to oxidative stress via regulation of poly [ADP-ribose] polymerase 1 (PARP1). Specifically, oxidative lesions promote direct binding of Banf1 to PARP1, a critical NAD-dependent DNA repair protein, leading to inhibition of PARP1 auto-ADP-ribosylation and defective repair of oxidative lesions, in cells with increased Banf1. Consistent with this, cells from patients with NGPS have defective PARP1 activity and impaired repair of oxidative lesions. These data support a model whereby Banf1 is crucial to reset oxidative-stress-induced PARP1 activity. Together, these data offer insight into Banf1-regulated, PARP1-directed repair of oxidative lesions

Assessment of chronic low‐dose elemental and radiological exposures of biota at the Kanab North uranium mine site in the Grand Canyon watershed

High-grade U ore deposits are in various stages of exploitation across the Grand Canyon watershed, yet the effects of U mining on ecological and cultural resources are largely unknown. Wecharacterized the concentrations of Al, As, Bi, Cd, Co, Cu, Fe, Pb, Hg, Mo, Ni, Se, Ag, Tl, Th, U, and Zn, gross alpha and beta activities, and U and Th radioisotopes in soil, vegetation (Hesperostipa comata, Artemisia tridentata, Tamarix chinensis), and rodents (Peromyscus maniculatus, P. boylii) to waste material at the Kanab North mine, a mine with decades-long surficial contamination, and compared the concentrations (P\u3c0.01) to those at a premining site (Canyon Mine). Rodent tissues were also analyzed for radium-226 and microscopic lesions. Radioactivities and some elemental concentrations (e.g., Co, Pb, U) were greater in the Kanab North mine biological samples than in Canyon Mine biota, indicating a mining-related elemental signature. Mean rodent Ra-226 (111 Bq/kg dry weight [dry wt]) was 3 times greater than expected, indicating radioactive disequilibrium. Multiple soil sample U concentrations exceeded a screening benchmark, growth inhibition thresholds for sensitive plants, and an EC20 for a soil arthropod. Lesions associated with metals exposure were also observed more frequently in rodents at Kanab North than those at Canyon Mine but could not be definitively attributed to U mining. Our results indicate that Kanab North biota have taken up U mining-related elements owing to chronic exposure to surficial contamination. However, no literature-based effects thresholds for small rodents were exceeded, and only a few soil and vegetation thresholds for sensitive species were exceeded; therefore, adverse effects to biota from U mining-related elements at Kanab North are unlikely despite chronic exposure