<p>Necroptosis Mediates Cigarette Smoke-Induced Inflammatory Responses in Macrophages</p>

Abstract

Introduction: Cigarette smoke (CS)-induced inflammation in macrophages is involved in the pathological process of chronic obstructive pulmonary disease (COPD). Necroptosis, which is a form of programmed necrosis, has a close relationship with robust inflammation, while its roles in COPD are unclear. Materials and Methods: Necroptosis markers were measured in mouse alveolar macrophages and cultured bone marrow-derived macrophages (BMDMs). Necroptosis inhibitors were used to block necroptosis in BMDMs, and inflammatory cytokines were detected. We further explored the related signaling pathways. Results: In this study, we demonstrated the way in which necroptosis, in addition to its upstream and downstream signals, regulates CS-induced inflammatory responses in macrophages. We observed that CS exposure caused a significant increase in the levels of necroptosis markers (receptor interacting kinases [RIPK] 1 and 3) in mouse alveolar macrophages and BMDMs. Pharmacological inhibition of RIPK1 or 3 caused a significant suppression in CS extract (CSE)-induced inflammatory cytokines, chemokine ligands (CXCL) 1 and 2, and interleukin (IL)-6 in BMDMs. CSE-induced necroptosis was regulated by mitochondrial reactive oxygen species (mitoROS), which also promoted inflammation in BMDMs. Furthermore, necroptosis regulated CSE-induced inflammatory responses in BMDMs, most likely through activation of the nuclear factor-κB pathway. Conclusion: Taken together, our results demonstrate that mitoROS-dependent necroptosis is essential for CS-induced inflammation in BMDMs and suggest that inhibition of necroptosis in macrophages may represent effective therapeutic approaches for COPD patients.

Cortactin Modulates Lung Endothelial Apoptosis Induced by Cigarette Smoke

“…Mitochondrial oxidative stress plays a key role in CS-induced pulmonary disorders and is a predisposing factor in the pathogenesis of COPD [ 26 , 27 ]. Therefore, we next explored the role of CTTN in oxidative stress induced by CSC [ 28 , 29 , 30 ].…”

<p>Human Lung Macrophages Challenged to Oxidants ex vivo: Lysosomal Membrane Sensitization is Associated with Inflammation and Chronic Airflow Limitation</p>

“…Such oxidant challenge may increase LMP, which in turn may lead to impaired functions of LMs due to the cellular stress executed by increased LMP, and, if pronounced, the increase of LMP may even kill the LMs. 11,12,23,24 Unregulated death of LMs by necroptosis is associated with tobacco-smoke induced airway damage and COPD. 24 This scenario may be prevented by azithromycin, 25 a macrolide antibiotic used in the clinic to prevent COPD deterioration due to frequent exacerbations.…”

“…11,12,23,24 Unregulated death of LMs by necroptosis is associated with tobacco-smoke induced airway damage and COPD. 24 This scenario may be prevented by azithromycin, 25 a macrolide antibiotic used in the clinic to prevent COPD deterioration due to frequent exacerbations. In a series of studies of a variety of inflammatory and fibrotic lung diseases, we have previously presented observations suggesting that oxidant-induced LMP, mainly driven by a disturbed metabolism of iron and an accumulation of this metal inside lysosomes, 26 may be an important up-stream event in the cascade of events that trigger inflammation and/or fibrosis, 11,12,27,28 ultimately leading to CAL.…”

Role of necroptosis in airflow limitation in chronic obstructive pulmonary disease: focus on small-airway disease and emphysema

“…The results indicate that necroptosis promotes inflammatory responses and mucin production at the cellular level [ 9 , 27 , 28 ]. In addition, the inhibition of necroptosis of macrophages exposed to CSE can also prevent the production of inflammatory cytokines [ 29 ]. Epithelial cells were co-cultured with macrophages under CSE exposure, pre-treated with necroptosis or apoptosis inhibitors and detected for inflammation-related markers.…”

“…Mitochondrial ROS (mitoROS) modulates the occurrence of necroptosis in COPD, which leads to airflow limitation. Wang et al [ 29 ] specifically inhibited mitoROS in macrophages by mitochondria-targeted antioxidant (Mito-TEMPO) and confirmed that mitoROS mediates CSE-induced necroptosis and inflammatory responses, indicating that the necroptosis pathway is most likely dependent on mitoROS. Xu et al [ 9 ] treated PM-exposed human bronchial epithelial cells by Mito-TEMPO and found that PM exposure produces excessive mitoROS that activates the mitoROS-dependent early growth response gene-1 and therefore mediates the necroptosis of epithelial cells, whereas the mitoROS/early growth response gene-1/necroptosis pathway triggers two distinct signalling cascade responses (NF-κB and AP-1 pathways) to cause airway inflammation and mucus overproduction.…”