Inhibition of neutrophil apoptosis by acrolein: a mechanism of tobacco-related lung disease?

Abstract

Cigarette smoking is known to contribute to inflammatory diseases of the respiratory tract by promoting recruitment of inflammatory-immune cells such as neutrophils and perhaps by altering neutrophil functional properties. We investigated whether acrolein, a toxic unsaturated aldehyde found in cigarette smoke, could directly affect neutrophil function. Exposure of freshly isolated human neutrophils to acrolein markedly inhibited spontaneous neutrophil apoptosis as indicated by loss of membrane asymmetry and DNA fragmentation and induced increased neutrophil production of the chemokine interleukin-8 (IL-8). Acrolein (1--50 microM) was found to induce marked activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPKs), and inhibition of p38 MAPK activation by SB-203580 prevented acrolein-induced IL-8 release. However, inhibition of either ERK or p38 MAPK did not affect acrolein-dependent inhibition of apoptosis. Acrolein exposure prevented the activation of caspase-3, a crucial step in the execution of neutrophil apoptosis, presumably by direct inhibition of the enzyme. Our results indicate that acrolein may contribute to smoke-induced inflammatory processes in the lung by increasing neutrophil recruitment and reducing neutrophil clearance by apoptosis.

Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate

“…We used Annexin V, an anticoagulant protein with high affinity and selectivity for phosphatidylserine (PS), to detect PS exteriorization, and propidium iodide (PI), a membrane impermeable dye, to monitor cell membrane integrity. Consistent with previous reports (8)(9)(10)(11), CSE and nicotine significantly reduced neutrophil spontaneous death. The most significant effects were observed at 36 h and 54 h (Fig.…”

“…Some of the chemical constituents of cigarette smoke (CS), such as nicotine and acrolein, have been shown to directly delay neutrophil spontaneous death (9)(10)(11), providing a mechanism for the massive accumulation of neutrophils in the lungs of smoke-induced COPD patients. Here, we investigate the mechanism by which CS reduces neutrophil spontaneous death.…”

Acrolein: Sources, metabolism, and biomolecular interactions relevant to human health and disease

“…Acrolein can either induce apoptosis [82,125] or have an inhibitory effect on apoptotic pathways as observed for human neutrophils [126]. Acrolein induced apoptosis in human lung epithelial (HBE1) cells at 10-25-μM and in isolated human alveolar macrophages at 25-μM exposure, as indicated by DNA fragmentation after 24 h of exposure.…”

“…Tanel and Averill-Bates [125] have observed during their studies on apoptotic pathways in CHO cells that procaspase-3 was proteolytically processed but that caspase-3 was not catalytically active. Finkelstein et al [126] reported that exposure of human neutrophils to acrolein also prevented the activation of caspase-3. Why can acrolein inactive cas-pases?…”

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

“…Because most particulate matter is filtered out by the airways, volatile components of the gas phase of smoke are believed to be responsible for changes in enzymatic activity, such as oxidative inhibition of ␣ 1 -antitrypsin (43). Of these, nicotine, acrolein, and acetaldehyde seem to be key short-acting pharmacological agents (44). Interestingly, acrolein stimulates release of inflammatory cytokines and can alter cellular repair processes by impairing fibroblast function (45).…”