Table 1.
Cellular and molecular targets of acrolein related to its molecular mechanisms of activity in chronic lung diseases and respiratory cancer.
| Target | Experimental Approach |
Effect | References |
|---|---|---|---|
| Cytotoxic Properties of Acrolein | |||
| In Vitro Studies | |||
| Human umbilical vein endothelial cells (HUVEC) | Acrolein exposure | ↑ ROS, ↑ 8-OHdG—DNA damage, ↑ Bax, ↓ Bcl-2, ↑ caspase-3—apoptosis | [69] |
| Primary nasal epithelial cell cultures (PNECs) from healthy non-smokers | Cigarette smoke extract | ↑ caspase-3—apoptosis, | [72] |
| Bone marrow-derived GM-CSF-dependent immature macrophages (GM-IMs) | Acrolein exposure | ↑ ROS, ↑ caspase-3—apoptosis | [73] |
| Lewis lung carcinoma (LLC) cells | [73] | ||
| Human bronchial epithelial cell line (HBE1) | Acrolein exposure | ↓ GSH, ↑ ROS, phosphatidylserine (PS) externalization and DNA fragmentation—apoptosis | [74] |
| Human bronchial epithelial cell line (BEAS-2B) | Acrolein exposure | ↑ ROS, ↑ 8-OHdG, ↑ γ-H2AX—DNA damage, ↑ Bax, ↓ Bcl-2, ↑ caspase-3—apoptosis, G2/M cell cycle blockade | [75] |
| Murine FL5.12 pro B lymphoid progenitor cells | Acrolein exposure | ↓ Caspase-9, -8 and -3—apoptosis inhibition, oncotic/necrotic response | [81] |
| Human lung adenocarcinoma cells (A549) | Acrolein exposure | ↑ ROS, cytochrome c release, ↑ Bax, ↑ Bad, ↓ Bcl-2, ↑ apoptosis inducing factor AIF, ↑ caspase-9, -7, -6, -3—apoptosis | [82] |
| Human lung adenocarcinoma cells (A549), Human umbilical vein endothelial cells (HUVEC) | Cigarette smoke condensate | ↓ Caspase-9, and -3 —apoptosis inhibition, necrotic response | [83] |
| Human tracheobronchial epithelial cells (hTBE) | Cigarette smoke extract | ↓ Caspase-7, and -3 —apoptosis inhibition, necrotic response | [84] |
| Human alveolar epithelial type I-like (ATI-like) cells | Cigarette smoke extract | ↑ Caspase-7, and -3- apoptosis, necrotic response | [103] |
| In vivo studies | |||
| Lungs isolated from male albino rats | Acrolein inhalation | ↑ Proinflammatory TNF-α, ↑ Il-6 ↑ Bax, ↓ Bcl-2—apoptosis |
[70] |
| Dysregulation of mitochondrial homeostasis | |||
| In vitro studies | |||
| Normal human lung fibroblasts (MRC-5), lung adenocarcinoma cells (A549) |
Acrolein exposure | ↓ PARP-1, ↑ ROS, ↑ Caspase-9, and -3 —apoptosis, ↓ mitochondrial membrane potential, ↓ ATP, ↑ mtDNA damage, ↑ mitochondrial fission and mitophagy | [85] |
| Lung alveolar cell line RLE-6TN, Clara cell-like human bronchialepithelial cell line (H441), pAT2 cells isolated from male A/J mice (Jackson Laboratories) | Acrolein exposure | ↑ Mitochondrial metabolism of palmitate, ↑ glucose-6-phosphate dehydrogenase activity, ↑ phospholipase A2, ↓ phosphatidylcholine, inhibition of glycolysis | [87] |
| Human lung fibroblast cells (IMR-90) | Acrolein exposure | ↑ β-galactosidase, ↑ p53, ↑ p21, ↓ DNA synthesis, ↓ Sirt1, ↑ ROS, ↓ mitochondrial membrane potential, ↓ mitochondrial biogenesis regulator PGC-1, of subunits of the electron transport chain complexes | [88] |
| In vivo studies | |||
| Lung tissue isolated from male Wistar rats | Acrolein inhalation | ↓ Transcript abundance of subunits of the electron transport chain complexes, ↓ PPARGC1A regulators associated with mitochondrial biogenesis | [77] |
| SM/J (sensitive) and 129 × 1/SvJ (resistant) inbred mouse strains | Acrolein inhalation | ↓ Transcript abundance of subunits of the electron transport chain complexes, ↑ activity of glycolytic enzymes | [86] |
| Redox homeostasis imbalance, carbonylation of antioxidant enzymes | |||
| In vitro studies | |||
| Human gingival fibroblasts cells (HGFs) | Cigarette smoke | ↑ ROS, ↑ protein carbonylation, ↑ GSH-acrolein adducts, ↓ -SH groups | [91] |
| Lung adenocarcinoma cells (A549) | Cigarette smoke extract | ↑ protein carbonylation, ↑ GSH-acrolein adducts, ↓ -SH groups | [92,93] |
| Human ALI airway tissue models | Acrolein exposure | ↑ protein carbonylation, ↑ GSH-acrolein adducts, ↑ HMOX-1 | [14] |
| Normal human primary bronchial epithelial cells (NHBE), human mucoepidermoid pulmonary carcinoma cells (NCI-H292) | Acrolein exposure | ↑ protein carbonylation, ↑ GSH-acrolein adducts | [94] |
| Human bronchial epithelial cell line (BEAS-2B) | Acrolein exposure | ↑ Trx1 and Trx2 oxidation, ↑ peroxidases Prx1 and Prx3 oxidation, ↓ TrxR, | [95] |
| Human bronchial epithelial cell line (HBE1) | Acrolein exposure | ↑ protein carbonylation, ↑ GSH-acrolein adducts, ↑ Trx1 oxidation, ↑ Prx1 oxidation, ↑ GSH-acrolein adducts | [97] |
| Human umbilical vein endothelial EA.hy926 cells | Cigarette smoke extract | ↓ eNOS, ↓ NO | [98] |
| Murine bone marrow-derived macrophage cells, Lewis lung carcinoma cells (LLC) |
Acrolein exposure | ↑ ROS, ↑ GADD34 | [99] |
| Bovine aortic endothelial cells (BAECs) | Acrolein exposure | ↓ GSH, ↑ ROS, ↑ Heme oxygenase-1 (HO-1), ↑ Nrf2 signaling pathway | [100] |
| Lung adenocarcinoma cells (A549) | Acrolein exposure | ↓ GSH, ↑ Nrf2 signaling pathway | [101] |
| Human alveolar epithelial type I-like (ATI-like) cells | Cigarette smoke extract | ↑ HO-1, ↑ Nrf2 signaling pathway, ↑ lipid peroxidation | [103] |
| In vivo studies | |||
| Female wild-type C57BL/6 mice | Acrolein inhalation | ↑ ROS, ↑ GADD34 | [99] |
| Mucus hypersecretion and tissue degradation in emphysema | |||
| In vitro studies | |||
| Human pulmonary mucoepidermoid carcinoma cell line NCI-H292 |
Cigarette smoke extract | ↑ MUC7, ↑ MUC5AC | [112,113] |
| Human pulmonary mucoepidermoid cells NCI-H292 | Acrolein exposure | ↑ MUC5AC, ↑ MMP-9, ↑ MMP-14 | [123,124] |
| Human ALI airway tissue models | Acrolein exposure | ↑ MUC5AC, ↑ MMP-7, -10, -12, and -13 | [14] |
| Human aortic vascular smooth muscle cells | Cigarette smoke extract | ↑ MMP-1 | [126] |
| Primary human lung micro-vascular endothelial cells, fusion of human umbilical vascular endothelial cells with the lung carcinoma cell line A549 |
Acrolein exposure | ↑ CLDN5 | [130] |
| The murine macrophage cell line, J774A.1 | Acrolein exposure | ↑ MMP-9, ↑ 5-lipoxygenase | [135] |
| In vivo studies | |||
| MUC7 transgenic mouse tissues | Cigarette smoke extract | ↑ MUC7 | [112] |
| Female Han Wistar rats | Cigarette smoke extract | ↑ MUC5AC | [113] |
| Gene-targeted Mmp9(-/-) mice, Mmp9(+/+) mice, | Acrolein exposure | ↑ MUC5AC, ↑ MMP-9 | [117] |
| Specific pathogen-free grade male C57BL/6 Mice |
Airway remodeling model—acrolein inhalation | ↑ MUC5AC | [118] |
| Human bronchial epithelial cells and induced sputum from e-cigarette users | E-cigarette exposure | ↑ MUC4, ↑ MUC5AC, ↑ MMP-8, ↑ MMP-9 | [119,120] |
| A/J mice (Jackson Laboratories) | E-cigarette exposure | ↑ MUC5AC | [122] |
| Pathogen-free male Kunming mice | Acrolein intraperitoneal injection | ↑ MUC5AC, ↑ MMP-9 | [125] |
| Inbred mouse strains | Acrolein exposure | ↑ CLDN5, acute lung injury (ALI) | [130] |
| C57BL/6J mice | Cigarette smoke extract | ↓ Elastin, ↑ collagen | [132] |
| Airway smooth muscle from smokers | Cigarette smoke extract | ↑ MMP-1, -3 and -10, ↑ collagen VIII alpha 1 (COL8A1) | [136] |
| Sputum from smokers | Cigarette smoke extract | ↑ MMP-12 | [137] |
| Bronchoscopies on cigarette smokers, and e-cigarette users |
Cigarette smoke extract, e-cigarette exposure | ↑ MMP-2, ↑ MMP-9 | [139] |
| Immunomodulatory properties | |||
| In vitro studies | |||
| Human ALI airway tissue models | Acrolein exposure | ↑ IL-1b, ↑ IL-6, ↑ IL-8, ↑ TNF-α, ↑ IFN-γ | [14] |
| Primary nasal epithelial cell cultures (PNECs) from healthy non-smokers | Cigarette smoke extract (CSE) containing acrolein | ↑ IL-8 | [72] |
| Bone marrow-derived GM-CSF-dependent immature macrophages (GM-IMs), Lewis lung carcinoma (LLC) cells | Acrolein exposure | ↑ NF-κB, ↑ TNF-α, ↑ IL-6, ↑ IL-12, ↑ CD11c+ F4/80 high macrophages | [73] |
| Human small airway epithelial cells (SAECs), normal human bronchial epithelial cells (NHBEs), normal human lung fibroblasts (NHLF) | Acrolein exposure | Influence on the p38MAPK/MK2 and ERK 1/2 signaling pathway, ↑ IL-8 | [76,150] |
| Rat lung epithelial cells (LE) | Acrolein exposure | Influence on the Raf-1/ERK signaling pathway, ↑ NF-κB, ↑ COX-2 | [151] |
| In vivo studies | |||
| Lungs isolated from male albino rats | Acrolein inhalation | ↑ TNF-α, ↑ Il-6 | [70] |
| Male C57BL/6J mice, peripheral blood was drawn from healthy, non-smoking adult volunteers |
Acrolein inhalation and exposure | ↓ NF-κB, ↓ IL-2, ↓ IL-10, ↓ TNF-α, ↓ INF-γ | [145,148,149] |
| Female C57BL/6 mice | Cigarette smoke extract | ↓ SP-A, ↓ SP-D | [152,153] |
The effects of acrolein are marked as follows: ↓ decreased, ↑ increased.