Cigarette smoke activates the parthanatos pathway of cell death in human bronchial epithelial cells

Abstract

Tobacco smoke negatively affects human bronchial epithelial (HBE) cells and is directly implicated in the etiology of smoking related respiratory diseases. Smoke exposure causes double-stranded DNA breaks and DNA damage activates PARP-1, the key mediator of the parthanatos pathway of cell death. We hypothesize that smoke exposure activates the parthanatos pathway in HBE cells and represents a cell death mechanism that contributes to smoking related lung diseases. We exposed fully differentiated, primary HBE cells grown at the air liquid interface to cigarette smoke and evaluated them for parthanatos pathway activation. Smoke exposure induced mitochondrial to nuclear translocation of Apoptosis-Inducing Factor (AIF) and Endonuclease G (EndoG) within the first three hours characteristic of the parthanatos pathway. Exposing cells to an increasing number of cigarettes revealed that significant activation of the parthanatos pathway occurs after exposure to higher levels of smoke. Use of the specific PARP-1 inhibitor, BMN673, abrogated the effect of smoke induced activation of the parthanatos pathway. Smoke-mediated activation of the parthanatos pathway is increased in HBE cells originating from habitual smokers compared to non-smokers. This suggests that chronic smoke exposure leads to an increase in smoke-mediated activation of the parthanatos pathway and implicates its contribution in the pathogenesis of smoke-related lung diseases.

Coronavirus infection and PARP expression dysregulate the NAD metabolome: An actionable component of innate immunity

“…Morbidity and mortality data make it clear that age, smoking status, and multiple preexisting conditions greatly increase the frequency of serious illness and death ( 34 ). There is an abundance of data from model systems and humans that age and conditions of metabolic stress including obesity and type 2 diabetes ( 35 ), smoking ( 36 ), heart failure ( 29 ), nerve damage ( 37 ), and central brain injury ( 28 ) challenge the NAD system in affected tissues. Although PARP1 was known to be a significant consumer of NAD + , we showed that noncanonical PARP isozymes are consistently up-regulated by CoV infections, that PARP10 overexpression can depress the NAD metabolome, and that four noncanonical PARP isozymes that are induced by SARS-CoV-2 have MARylating activities that are limited by cellular NAD status.…”

Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity

“…Morbidity and mortality data make it clear that age, smoking status and multiple preexisting conditions greatly increase the frequency of serious illness and death (37). There is an abundance of data from model systems and humans that age and conditions of metabolic stress including obesity and type 2 diabetes (38), smoking (39), heart failure (32), nerve damage (40) and central brain injury (31) challenge the NAD system in multiple affected tissues. Though PARP1 was known to be a significant consumer of NAD + , we showed that noncanonical PARP isozymes are consistently upregulated by CoV infections, that PARP10 overexpression can depress the NAD metabolome and that three noncanonical PARP isozymes that are induced by SARS-CoV-2 have MARylating activities that are limited by cellular NAD status.…”

Increased PARP Activity and DNA Damage in NSCLC Patients: The Influence of COPD

“…These are relevant findings that suggest that chronic cigarette smoking induces DNA damage, which may be counterbalanced by PARP activity. In fact, DNA damage and PARP-1 overactivation induced the parthanatos pathway of cell death as a result of the exposure of human bronchial epithelial cells to cigarette smoke [ 26 ]. Moreover, in patients with stable COPD, systemic PARP-1 activation was also observed in the lymphocytes along with increased inflammation and oxidative stress [ 27 ].…”