TABLE 1

Summary of the involvement of signal pathways or targets in cigarette smoke (CS)-induced lung injury or COPD from current investigations

Induction model (in vitro)Induction model (in vivo)Significant findingsRef.
CSE treatment: A549 cells
CSE treatment: BEAS-2B cells
TRP ion channels, TRPA1 and TRPV1, mediate CSE-induced damage of bronchial and alveolar epithelial cells via modulation of oxidative stress, inflammation and mitochondrial damage.[59]
CSE/LPS treatment: MDM cells
CSE/LPS treatment: THP-1 cells
Increased caspase-1 activity via an NLRP3-independent and TLR4–TRIF–caspase-8-dependent pathway.[60]
CSE treatment: 16HBE cellsCS exposure: male C57BL/6J mice, 30 days, with twice LPS (30 μg per 6 μL) intratracheal instillationCSE-induced inflammation and contributed to pyroptosis through the ROS–NLRP3–caspase-1 pathway in 16HBE cells.[52]
CSE treatment: NCI-H292, 16HBE, NHBE cells
CSE treatment: THP-1 cells, MDM cells
CSE- and eHSP70-induced ATP secretion and differential activation of NLRP3 inflammasome.[61]
CSE treatment: THP-1 cells, MDM cellsCS exposure: male C57BL/6 mice, 6 months exposureCSE decreased NLRP3 protein abundance via increased ubiquitin-mediated proteasomal processing. The release of IL-1β and IL-18 was also decreased with CSE. Provides mechanistic insights on immunosuppression in smokers.[62]
CSE treatment: THP-1 cellsCS exposure: C57BL/6 mice, 5 weeks exposureCS repressed central components of the innate immune response to inhaled asbestos.[63]
CSE treatment: THP-1 cellsMyD88 inhibition markedly attenuated the expression of NLRP3 markers (NLRP3, caspase-1, IL-1β and IL-18), IL-6, SOCS3 and NF-κB.[64]
CSE/LPS treatment: A549 cellsNLRP3 inflammasome is upregulated in COPD exacerbation and novel biomarkers for COPD exacerbation.[65]
CS exposure: male C57BL/6 mice (wild type, ASC−/–, NALP3−/–, IPAF−/–, IL-1β−/–, IL-1α−/–, IL-18−/–, IL-18R–/–, caspase-1/11–/– and caspase-11–/–), 3 days LPS (1 mg·mL–1) aerosol for 30 minA key role for the P2X7–NALP3–ASC–caspase-1/11–IL-1β–IL-18 axis in CS-induced airway inflammation.[9]
Fresh-frozen lung tissues from COPD patients and healthy
CS exposure: NLRX1−/– mutant mice and wild-type mice, exposure 3 months
CS-dependent NLRX1 inhibition facilitates MAVS/RHL activation and subsequent inflammation, remodelling, protease, cell death, and inflammasome responses.[66]
CS exposure: female BALB/c mice, exposure 6 weeks plus gestation and lactation periodsMaternal CSE had adverse impacts on the male offspring's lungs, which were partially alleviated by maternal L-carnitine supplementation. Females were less affected by the adverse effects of maternal CSE.[67]
CSE treatment: RAW264.7 cellsCS exposure: male C57BL/6J mice, exposure 15 weeksTREM-1 promoted the lung injury and inflammation in COPD mouse through activation of NLRP3 inflammasome-mediated pyroptosis. A novel mechanism of TREM-1 in COPD development.[68]
CSE treatment: RAW 264.7 cells
LPS treatment: RAW 264.7 cells
DEP treatment: RAW 264.7 cells
PPE (15 μg per 50 μL) intratracheal instillation: C57BL/6 female miceThe NLRP3 inflammasome is activated by DEPs in ex vivo tissue explants from elastase-induced emphysema animal model. NAC inhibits this activation.[69]
UFP treatment: COPD and non-COPD PBMCs
UFP treatment: smoker and non-smoker PBMCs
Combustion-generated UFPs induced the release of caspase-4-dependent inflammasome from PBMCs of COPD patients compared with healthy subjects.[70]
CS exposure: SD rats for 2 months with twice LPS (200 μg per 100 μL) intratracheal instillationSIRT1 attenuated apoptosis and ER stress in the lung tissues. A positive correlation was identified between SIRT1 and oxygen regulated protein 150.[71]

16HBE: human airway epithelial cell; A549: alveolar epithelial cell; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; BEAS-2B: human bronchial epithelial cell; CSE: cigarette smoke extract; DEP: diesel exhaust particle; ER: endoplasmic reticulum; eHSP70: extracellular heat shock protein 70kDa; IL: interleukin; IPAF: interleukin converting enzyme protease activating factor; LPS: lipopolysaccharide; MAVS: mitochondrial antiviral signalling protein; MDM: human monocyte-derived macrophage; NAC: N-acetylcysteine (an ROS scavenger); NALP3: NACHT, LRR and PYD domains-containing protein 3; NCI-H292: human lung mucoepidermoid carcinoma cell; NF-κB: nuclear factor-κB; NHBE: normal human bronchial epithelial cell; NLRP3: nucleotide-binding oligomerisation domain-like receptor family, pyrin domain containing protein-3; NLRX1: nucleotide-binding oligomerisation domain, leucine rich repeat containing X1; PBMC: human peripheral blood mononuclear cell; PPE: porcine pancreatic elastase; RAW 264.7: mouse macrophage; RHL: RIG-I-like helicase; ROS: reactive oxygen species; SD: Sprague Dawley; SIRT1: sirtuin 1; SOCS3: suppressor of cytokine signalling 3; THP-1: monocytic leukaemic cell line; TLR: Toll-like receptor; TREM-1: triggering receptor expressed on myeloid cells 1; TRIF: TIR-domain-containing adaptor-inducing interferon-β; TRP: transient receptor potential protein; TRPA1: transient receptor potential cation channel, subfamily A, member 1; TRPV1: transient receptor potential cation channel subfamily V member 1; UFP: ultrafine particulate.