Table 2.
Therapeutic candidates studied to treat hyperoxic injury
| Candidate | Mechanism of action | Models | Outcomes | References |
|---|---|---|---|---|
| Antioxidants | ||||
| MitoTEMPO/MitoTEMPOL | Mitochondrial O2•– scavenger | Murine BPD, various in vitro models |
↑Alveolarization ↓Right ventricular hypertrophy ↓ACE2 and TMPRSS2 expression ↓Proinflammatory cytokines ↓Cell death ↓Mitochondrial fragmentation |
(Datta et al. 2015; Forred et al. 2017; Ma et al. 2018; Yee et al. 2020) |
| Ascorbate (vitamin C) | Alkyl hydroperoxide scavenger, regenerates reduced tocopherol |
Healthy patients, congestive heart failure patients, Murine HALI, various in vitro models |
↑Left ventricular function ↓Hyperventilation ↓Oxidative biomarkers in blood ↓HMGB1 levels ↓Leukocyte infiltration ↓Lipid and protein oxidation ↓Vasoconstriction |
(Mak et al. 2002; Al-Shmgani et al. 2012; Gao et al. 2012; Patel et al. 2020; Fernandes et al. 2021) |
| Tocopherol (vitamin E) | Alkyl hydroperoxide scavenger | In vitro OIR, neonatal rabbits, other in vitro models |
↓Lipid and protein oxidation ↓Vascular cell injury ↓Surfactant system impairment |
(Tripathi and Tripathi 1984; Ward and Roberts 1984; Wispe et al. 1986; Al-Shmgani et al. 2012) |
| Retinol/retinoic acid (vitamin A) | ROS scavenger, retinoid X receptor agonist | Murine BPD |
↑Surfactant protein levels ↑Alveolar maturation ↓Lung damage ↓Growth retardation ↓MIP-2 expression |
(Zimová-Herknerová et al. 2008; James et al. 2010; Gelfand et al. 2020) |
| Coenzyme Q10 | ROS scavenger | Murine neonatal organ injury |
↑Antioxidant enzyme activity in heart, kidney, and brain ↓Oxidative stress in liver |
(Lee et al. 2022) |
| N-acetylcysteine | L-cysteine prodrug, replenishes GSH | Murine HALI, in vitro models |
↑Mitochondrial membrane potential ↓Lung damage ↓Cell death ↓Cyt c release ↓HGMB1 and RAGE expression ↓TLR2/4 and NF-κB activity ↓Proinflammatory cytokine secretion |
(Huang et al. 2016a; Qiao et al. 2019; Zou et al. 2019) |
| Curcumin and analogs | ROS scavenger, multiple molecular targets | Murine BPD |
↑Relaxation of tracheal smooth muscle ↑Lung maturation ↑Alveolarization ↑PPAR-γ activation ↑Catalase activity ↓Apoptosis ↓ERK1/2 activation ↓TNF-α expression ↓TGF-β signaling |
(Sakurai et al. 2011, 2013; Stamenkovska et al. 2020) |
| Sulforaphane | ROS scavenger, Nrf2 inducer, NF-κB inhibitor, other targets | Murine BPD and HALI |
↑Nrf2-mediated transcriptional response ↑Macrophage function ↓Inflammatory cell infiltration ↓LDH levels ↓Mucous hypersecretion |
(McGrath-Morrow et al. 2014; Cho et al. 2019; Patel et al. 2020) |
| Resveratrol | ROS scavenger, SIRT1, multiple molecular targets | Murine brain injury, murine HALI and BPD |
↑SIRT1/PGC-1α signaling ↑PGC-1α, NRF1, and TFAM expression ↑Mitochondrial biogenesis ↑SOD and GSH ↓Alveolar simplification ↓Lung fibrosis ↓Apoptosis ↓Mitochondrial dysfunction ↓p53 expression ↓Proinflammatory cytokine release ↓Wnt/β-catenin signaling |
(Özdemir et al. 2014; Xu et al. 2015; Zhu et al. 2020, 2021; Kang et al. 2021; Yang et al. 2022) |
| Quercetin | ROS scavenger, multiple molecular targets | Murine BPD, fetal airway smooth muscle cells |
↑Alveolarization ↓Inflammation ↓NF-κB levels ↓Lipid peroxidation ↓Senescence |
(Maturu et al. 2018; Parikh et al. 2019) |
| Anthocyanins | ROS scavenger | Murine OIR, HUVECs |
↑Nrf2 gene targets ↑Cell viability ↓Mitochondrial dysmorphology ↓Endothelial cell proliferation |
(Cimino et al. 2013; Ercan et al. 2019) |
| Caffeine | ROS scavenger, A2AR antagonist, multiple molecular targets | Murine BPD, neonatal murine brain injury |
↑Alveolar development ↑Weight gain ↓DNA damage ↓A2AR expression ↓Proinflammatory cytokines ↓Inflammatory infiltration ↓Apoptosis ↓ER stress ↓NLRP3 inflammasome expression ↓NF-κB activation ↓MMP2 levels |
(Endesfelder et al. 2017, 2019; Teng et al. 2017; Chen et al. 2020c) |
| Indole-3-carbinol | ROS scavenger, AhR agonist/inducer, other targets | Murine BPD |
↑AhR gene targets ↑Alveolarization ↑NF-κB target genes ↓Fibrosis |
(Guzmán-Navarro et al. 2021) |
| Tetrandrine | ROS scavenger, multiple molecular targets | Murine BPD |
↑Antioxidant enzymes ↓Apoptosis ↓Inflammation ↓Fibrotic markers ↓NF-κB and ERK1/2 signaling |
(Jiao et al. 2020) |
| Antiapoptotic | ||||
| Cyclosporin A | Cyclophilin D inhibitor; delays mPTP opening | Murine |
↓Cyt c release ↓Mitochondrial swelling ↓Lung damage |
(Pagano et al. 2004) |
| TRP601 | Caspase inhibitor | Murine brain injury |
↓Apoptosis ↓Neurodegeneration |
(Sifringer et al. 2012) |
| Anti-inflammatory | ||||
| Interleukin-10 | Anti-inflammatory cytokine | Murine HALI, fetal alveolar cells (in vitro) |
↑Survival ↑VEGF release ↑Proliferation ↑Jak1 and TYK2 phosphorylation ↓Lung injury ↓Cell death ↓NF-κB activation ↓Proinflammatory cytokines ↓iNOS and NO levels ↓MMP2 and MMP9 activities |
(Lee and Kim 2011; Li et al. 2015b; Lee and Lee 2015) |
| Interleukin-1 receptor antagonist | Anti-inflammatory cytokine | Murine BPD, murine BPD-pulmonary hypertension |
↑Pulmonary small vessels ↑Immune cell viability ↓Pulmonary vascular resistance ↓Lung structural disintegration ↓Cardiac fibrosis ↓Immune cell activation ↓Proinflammatory cytokines |
(Nold et al. 2013; Bui et al. 2019) |
| Acetylsalicylic acid | COX inhibitor | Murine HALI |
↓NF-κB activation ↓ROS ↓Proinflammatory cytokines ↓Macrophages ↓Neutrophil infiltration ↓Lung edema |
(Chen et al. 2020b; Tung et al. 2022) |
| Ibuprofen | COX inhibitor | Murine OIR |
↓Retinopathy score ↓Extra-retinal nuclei count per section |
(Sharma et al. 2003) |
| HIF-1 upregulators | ||||
| FG-4095 | PHD inhibitor | Fetal baboon lung explants, primate BPD, distinct cell lines |
↑HIF-1/2α target genes ↑Angiogenesis ↑Alveolar surface area ↑Lung compliance |
(Asikainen et al. 2006, 2005) |
| Dimethyloxalylglycine | PHD inhibitor | Murine OIR |
↑Peripheral vascularity ↓Neovascularization ↓Ischemia |
(Sears et al. 2008; Trichonas et al. 2013) |
| Roxadustat | PHD inhibitor | Murine BPD |
↑Survival ↑Alveolarization ↑eNOS expression ↑VEGF expression |
(Huang et al. 2021) |
| Others | ||||
| Memantine | NMDA receptor antagonist | Murine brain injury |
↑Neuron viability ↓Apoptosis |
(Polat et al. 2020) |
| Lacosamide | Enhances slow Na+ channel inactivation | Murine brain injury |
↑Neuron viability ↓Apoptosis |
(Polat et al. 2020) |
| Vitamin D | Vitamin D receptor agonist | Murine BPD |
↑Alveolarization ↑VEGF and VEGFR2 expression ↑HIF-1α expression ↓Alveolar simplification ↓Apoptosis ↓TLR4 expression ↓IFN‐γ and IL‐1β expression ↓Neutrophil extracellular traps ↓Proinflammatory cytokines |
(Kose et al. 2017; Yao et al. 2017; Chen et al. 2020a; Wang and Jiang 2021) |
| Metformin | AMPK activator | Murine BPD, HUVECs |
↑Radial alveolar count ↑Vascular proliferation ↑ATP levels ↑Lung capillary number ↓Mortality ↓Inflammation ↓Fibrosis |
(Chen et al. 2015; Yadav et al. 2020) |
| Rosiglitazone | PPAR-γ agonist | Murine BPD and HALI, preterm rabbits |
↑Radial alveolar count ↑Alveolar sacculation ↑Lung maturation ↑Surfactant proteins ↑VEGF expression ↓Wnt and TGF-β signaling ↓Neutrophil influx |
(Richter et al. 2016; Rehan et al. 2010; Dasgupta et al. 2009) |
| Alda-1 | ALDH2 activator | Murine HALI, HMVECs |
↑Mitochondrial membrane potential ↑Akt/mTOR signaling ↓Alveolar damage ↓Inflammation ↓Immune cell infiltration ↓Bax and cyt c levels ↓4-HNE levels |
(Sidramagowda Patil et al. 2019, 2021) |
Abbreviations: ACE2, angiotensin converting enzyme 2; AhR, aryl hydrocarbon receptor; ALDH2, aldehyde dehydrogenase 2; Alda-1, ALDH2 activator 1; AMPK, adenosine monophosphate-activated kinase; ATP, adenosine triphosphate; A2AR, A2A adenosine receptor; BPD, bronchopulmonary dysplasia; COX, cyclooxygenase; cyt c, cytochrome c; ER, endoplasmic reticulum; ERK1/2, extracellular signal-regulated kinase 1/2; GSH, reduced glutathione; HALI, hyperoxic acute lung injury; HIF-1/2, hypoxia-inducible factor 1/2; HMGB1, high mobility group box 1; HUVECs, human umbilical vein endothelial cells; Jak, Janus kinase; IFN-γ, interferon γ; IL-1β, interleukin-1β; LDH, lactate dehydrogenase; MIP-2, macrophage inflammatory protein 2; MMP2, matrix metalloproteinase 2; mPTP, mitochondrial permeability transition pore; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3, NLR family pyrin domain containing 3; NMDA, N-methyl-D-aspartate; NRF1, nuclear respiratory factor 1; Nrf2, nuclear factor erythroid 2-related factor 2; NO, nitric oxide; eNOS, endothelial NO synthase; iNOS, inducible NO synthase; OIR, oxygen-induced retinopathy; PGC-1α, peroxisome proliferator-activated receptor-gamma coactivator 1 α; PHD, prolyl hydroxylase domain; PPAR-γ, peroxisome proliferator-activated receptor γ; RAGE, receptor for advanced glycation end-products; ROS, reactive oxygen species; SIRT1, sirtuin 1; SOD, superoxide dismutase; TMPRSS2, transmembrane protease, serine 2; TGF-β, transforming growth factor β; TFAM, transcription factor a, mitochondrial; TLR2/4, toll-like receptor 2/4: TNF-α, tumor necrosis factor α; TYK2, tyrosine kinase 2; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2; 4-HNE, 4-Hydroxynoneal