Functional and metabolic impairment in cigarette smoke-exposed macrophages is tied to oxidative stress.
Daniel S AridgidesDiane L MellingerDavid A ArmstrongHaley F HazlettJohn A DessaintThomas H HamptonGraham T AtkinsJames L CarrollAlix AsharePublished in: Scientific reports (2019)
Cigarette smoke inhalation exposes the respiratory system to thousands of potentially toxic substances and causes chronic obstructive pulmonary disease (COPD). COPD is characterized by cycles of inflammation and infection with a dysregulated immune response contributing to disease progression. While smoking cessation can slow the damage in COPD, lung immunity remains impaired. Alveolar macrophages (AMΦ) are innate immune cells strategically poised at the interface between lungs, respiratory pathogens, and environmental toxins including cigarette smoke. We studied the effects of cigarette smoke on model THP-1 and peripheral blood monocyte derived macrophages, and discovered a marked inhibition of bacterial phagocytosis which was replicated in primary human AMΦ. Cigarette smoke decreased AMΦ cystic fibrosis transmembrane conductance regulator (CFTR) expression, previously shown to be integral to phagocytosis. In contrast to cystic fibrosis macrophages, smoke-exposed THP-1 and AMΦ failed to augment phagocytosis in the presence of CFTR modulators. Cigarette smoke also inhibited THP-1 and AMΦ mitochondrial respiration while inducing glycolysis and reactive oxygen species. These effects were mitigated by the free radical scavenger N-acetylcysteine, which also reverted phagocytosis to baseline levels. Collectively these results implicate metabolic dysfunction as a key factor in the toxicity of cigarette smoke to AMΦ, and illuminate avenues of potential intervention.
Keyphrases
- cystic fibrosis
- oxidative stress
- lung function
- chronic obstructive pulmonary disease
- immune response
- smoking cessation
- peripheral blood
- pseudomonas aeruginosa
- reactive oxygen species
- ischemia reperfusion injury
- endothelial cells
- diabetic rats
- dna damage
- randomized controlled trial
- magnetic resonance
- dendritic cells
- small molecule
- induced apoptosis
- replacement therapy
- transcription factor
- inflammatory response
- computed tomography
- magnetic resonance imaging
- toll like receptor
- binding protein
- multidrug resistant
- drinking water
- antimicrobial resistance
- induced pluripotent stem cells