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In the lower respiratory tract, the alveolar spaces are divided from the bloodstream and the external environment by only a few microns of interstitial tissue. Alveolar macrophages (AMs) defend this delicate mucosal surface from invading infections by regularly patrolling the site. AMs have three behavior modalities to achieve this goal: extending cell protrusions to probe and sample surrounding areas, squeezing the whole cell body between alveoli, and patrolling by moving the cell body around each alveolus. In this study, we found Rho GTPase, cell division control protein 42 (CDC42) expression significantly decreased after berry-flavored e-cigarette (e-cig) exposure. This shifted AM behavior from squeezing to probing. Changes in AM behavior led to a reduction in the clearance of inhaled bacteria, Pseudomonas aeruginosa. These findings shed light on pathways involved in AM migration and highlight the harmful impact of e-cig vaping on AM function. [ABSTRACT FROM AUTHOR]

Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety 'Mode of Action' framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.

Δ9‐Tetrahydrocannabinol (Δ9‐THC) and cannabidiol (CBD) are cannabinoids found in Cannabis sativa. While research supports cannabinoids reduce inflammation, the consensus surrounding receptor(s)‐mediated effects has yet to be established. Here, we investigated the receptor‐mediated properties of Δ9‐THC and CBD on alveolar macrophages, an important pulmonary immune cell in direct contact with cannabinoids inhaled by cannabis smokers. MH‐S cells, a mouse alveolar macrophage cell line, were exposed to Δ9‐THC and CBD, with and without lipopolysaccharide (LPS). Outcomes included RNA‐sequencing and cytokine analysis. Δ9‐THC and CBD alone did not affect the basal transcriptional response of MH‐S cells. In response to LPS, Δ9‐THC and CBD significantly reduced the expression of numerous proinflammatory cytokines including tumor necrosis factor‐alpha, interleukin (IL)‐1β and IL‐6, an effect that was dependent on CB2. The anti‐inflammatory effects of CBD but not Δ9‐THC were mediated through a reduction in signaling through nuclear factor‐kappa B and extracellular signal‑regulated protein kinase 1/2. These results suggest that CBD and Δ9‐THC have potent immunomodulatory properties in alveolar macrophages, a cell type important in immune homeostasis in the lungs. Further investigation into the effects of cannabinoids on lung immune cells could lead to the identification of therapies that may ameliorate conditions characterized by inflammation. [ABSTRACT FROM AUTHOR]

Oxidative stress plays an important role in the pathogenesis of pulmonary fibrosis. Heme oxygenase-1 (HO-1) is a key antioxidant enzyme, and overexpression of HO-1 significantly decreases lung inflammation and fibrosis in animal models. Peroxisome proliferator-activated receptor-[gamma] (PPAR[gamma]) is a transcription factor that regulates adipogenesis, insulin sensitization, and inflammation. We report here that the PPAR[gamma] ligands 15d-[PGJ.sub.2] and 2-cyano-3,12-dioxoolean-l,9-dien-28-oic acid (CDDO), which have potent antifibrotic effects in vitro, also strongly induce HO-1 expression in primary human lung fibroblasts. Pharmacological and genetic approaches are used to demonstrate that induction of HO-1 is PPAR[gamma] independent. Upregulation of HO-1 coincides with decreased intracellular glutathione (GSH) levels and can be inhibited by N-acetyl cysteine (NAC), a thiol antioxidant and GSH precursor. Upregulation of HO-1 is not inhibited by Trolox, a non-thiol antioxidant, and does not involve the transcription factors AP-1 or Nrf2. CDDO and 15d-[PGJ.sub.2] contain an [alpha]/[beta] unsaturated ketone that acts as an electrophilic center that can form covalent bonds with free reduced thiols. Rosiglitazone, a PPAR[gamma], ligand that lacks an electrophilic center, does not induce HO-1. These data suggest that in human lung fibroblasts, 15d-[PGJ.sub.2] and CDDO induce HO-1 via a GSH-dependent mechanism involving the formation of covalent bonds between 15d-[PGJ.sub.2] or CDDO and GSH. Inhibiting HO-1 upregulation with NAC has only a small effect on the antifibrotic properties of 15d-[PGJ.sub.2] and CDDO in vitro. These results suggest that CDDO and similar electrophilic PPAR[gamma] ligands may have great clinical potential as antifibrotic agents, not only through direct effects on fibroblast differentiation and function, but indirectly by bolstering antioxidant defenses. 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; myofibroblast; N-acetyl cysteine doi: 10.1152/ajplung.00148.2009.

Cigarette smoke is the most important environmental risk factor for developing age-related macular degeneration (AMD). Damage to the retinal pigment epithelium (RPE) caused by cigarette smoke may underlie the etiology of AMD. This study investigated the molecular and cellular effects of cigarette smoke exposure on human RPE cells. ARPE-19 or primary human RPE cells were exposed to cigarette smoke extract (CSE) or hydroquinone (HQ), a component of cigarette smoke. The effect of this exposure on key aspects of RPE vitality including viability, cell size, mitochondrial membrane potential ([DELTA][[PSI].sub.m]), superoxide production, 4-hydroxy-2-nonenal (4-HNE), vascular endothelial growth factor (VEGF), and heine oxygenase-1 (HO-1) expression was determined. Exposure of RPE cells to CSE or HQ caused oxidative damage and apoptosis, characterized by a reduction in cell size and nuclear condensation. Evidence of oxidative damage also included increased lipid peroxidation (4-HNE) and mitochondrial superoxide production, as well as a decrease in intracellular glutathione (GSH). Exogenous administration of antioxidants (GSH and N-acetyl-cysteine) prevented oxidative damage to the RPE cells caused by CSE. Cigarette smoke also induced expression of VEGF, HO-1, and the transcription factor nuclear factor erythroid-derived 2, like 2 (NRF2). However, NRF2 was only modestly involved in CSE-induced HO-1 expression, as shown by the NRF2 small interfering RNA studies. These new findings demonstrate that cigarette smoke is a potent inducer of oxidative damage and cell death in human RPE cells. These data support the hypothesis that cigarette smoke contributes to AMD pathogenesis by causing oxidative damage and cell death to RPE cells. glutathione; heme oxygenase-1; vascular endothelial growth factor; nuclear factor erythroid-derived 2, like 2; apoptosis doi: 10.1152/ajpcell.00126.2009.

Fibroblasts are key structural cells that can be damaged by cigarette smoke. Cigarette smoke contains many components capable of eliciting oxidative stress, which may induce heine oxygenase (HO)-1, a cytoprotective enzyme. There are no data on HO-1 expression in primary human lung fibroblasts after cigarette smoke extract (CSE) exposure. We hypothesized that human lung fibroblasts exposed to cigarette smoke would increase HO-I though changes in intracellular glutathione (GSH). Primary human lung fibroblasts were exposed to CSE, and changes in HO-1 expression and GSH levels were assessed. CSE induced a time- and dose-dependent increase in expression of HO-1, but not HO-2 or biliverdin reductase, in two different primary human lung fibroblast strains, a novel finding. This induction of HO-1 paralleled a decrease in intracellular GSH, and a sustained reduction in GSH resulted in a dramatic increase in HO-1. Treatment with the antioxidants N-acetyl-L-cysteine or GSH reduced the expression of HO-I induced by CSE. We also examined the signal transduction mechanism responsible for HO-1 induction. Nuclear factor erythroid-derived 2, like 2 (Nrf2) was not involved in HO-1 induction by CSE. Activator protein-1 (AP-1) is a redox-sensitive transcription factor shown in other systems to regulate HO-1 expression. CSE exposure resulted in nuclear accumulation of c-Fos and c-Jun, two key AP-1 components. Reduction of c-Fos and c-Jun nuclear translocation by SP-600125 attenuated the CSE-induced expression of HO-1. These data support the concept that changes in the cellular redox status brought on by cigarette smoke induce HO-1 in fibroblasts. This increase in HO-1 may help protect against cigarette smoke-induced inflammation and/or cell death. oxidative stress; activator protein-l; biliverdin reductase; chronic obstructive pulmonary disease; nuclear factor erythroid-derived 2, like 2

Cigarette smoke is the principal cause of emphysema. Recent attention has focused on the loss of alveolar fibroblasts in the development of emphysema. Fibroblasts may become damaged by oxidative stress and undergo apoptosis as a result of cigarette smoke exposure. Not all smokers develop lung diseases associated with tobacco smoke, a fact that may reflect individual variation among human fibroblast strains. We hypothesize that fibroblasts from different human beings vary in their ability to undergo apoptosis after cigarette smoke exposure. This could account for emphysematous changes thai occur in the lungs of some but not all smokers. Primary human lung fibroblast strains were exposed to cigarette smoke extract (CSE) and assessed for viability, morphological changes, and mitochondrial transmembrane potential as indicators of apoptosis. We also examined the generation of intracellular reactive oxygen species (ROS), 4-hydroxy-2-nonenal, and changes in glutathione (GSH) and glutathione disulfide (GSSG) levels. Each human lung fibroblast strain exhibited a differential sensitivity to CSE as judged by changes in mitochondrial membrane potential, viability, ROS generation, and glutathione production. Interestingly, the thiol antioxidants N-acetyl-L-cysteine and GSH eliminated CSE-induced changes in fibroblast morphology such as membrane blebbing, nuclear condensation, and cell size and prevented alterations in mitochondrial membrane potential and the generation of ROS. These findings support the concept that oxidative stress and apoptosis are responsible for fibroblast death associated with exposure to tobacco smoke. Variations in the sensitivity of fibroblasts to cigarette smoke may account for the fact that only some smokers develop emphysema. mitochondrial membrane potential; reactive oxygen species; glutathione; 4-hydroxy-2-nonenal