Acute Decreases in Proteasome Pathway Activity after Inhalation of Fresh Diesel Exhaust or Secondary Organic Aerosol

Abstract

BackgroundEpidemiologic studies consistently demonstrate an association between acute cardiopulmonary events and changes in air pollution; however, the mechanisms that underlie these associations are not completely understood. Oxidative stress and inflammation have been suggested to play a role in human responses to air pollution. The proteasome is an intracellular protein degradation system linked to both of these processes and may help mediate air pollution effects.ObjectivesIn these studies, we determined whether acute experimental exposure to two different aerosols altered white blood cell (WBC) or red blood cell (RBC) proteasome activity in human subjects. One aerosol was fresh diesel exhaust (DE), and the other freshly generated secondary organic aerosol (SOA).MethodsThirty-eight healthy subjects underwent 2-hr resting inhalation exposures to DE and separate exposures to clean air (CA); 26 subjects were exposed to DE, CA, and SOA. CA responses were subtracted from DE or SOA responses, and mixed linear models with F-tests were used to test the effect of exposure to each aerosol on WBC and RBC proteasome activity.ResultsWBC proteasome activity was reduced 8% (p = 0.04) after exposure to either DE or SOA and decreased by 11.5% (p = 0.03) when SOA was analyzed alone. RBCs showed similar 8–10% declines in proteasome activity (p = 0.05 for DE alone).ConclusionsAir pollution produces oxidative stress and inflammation in many experimental models, including humans. Two experimental aerosols caused rapid declines in proteasome activity in peripheral blood cells, supporting a key role for the proteasome in acute human responses to air pollution.

Hallmarks of the ageing lung

“…of cystic fibrosis transmembrane conductance regulator (CFTR), which may also contribute to COPD pathogenesis [70][71][72][73][74][75]. Of note, the proteasome itself is a direct target for environmental challenges as cigarette smoke and diesel exhaust have been shown to impair proteasome function [76,77]. In accordance with that observation, proteasome function is reduced in lungs of COPD patients and in mouse models of chronic cigarette exposure, which correlates inversely with the loss of lung function [79].…”

Mitochondrial Function in Allergic Disease

“…Proteasomal activity is normally seen to decline with age as a result of decreased expression and oxidative modification of proteasomal proteins [50]. Exposure to air pollution toxicants too has been found to result in decreased proteasomal activity, directly resulting in oxidative stress [67]. Damage to the proteasome is known to result in the accumulation of oxidatively damaged polyubiquitinated proteins, which further inhibit proteasome function either by exceeding its binding capacity or by poisoning its catalytic properties.…”

Airway Epithelium Plays a Leading Role in the Complex Framework Underlying Respiratory Allergy

“…As for the role of mitochondria in inflammation, oxidative stress may cause release to the cytosol of compounds such as damage-associated molecular pattern molecules, adenosine triphosphate, cardiolipins, and mitochondrial DNA, subsequently activating immune signalling cascades via intracellular activation of TLR agonists [85]. Mitochondrial dynamics are directly altered by the presence of airborne particles and protease allergens, leading to changes in membrane potential and proteosomal activity that ultimately leads to proapoptotic events [86,87]. However, the most important source of endogenous oxidants comes from the activation of inflammatory, immune, and structural cells by environmental components (including inhaled allergens), which in turn regulate the expression of specific genes for proinflammatory mediators and antioxidant protective enzymes via activation of redox-sensitive transcription factors such as activator protein-1 (AP-1) and NF-κB.…”