Table 2 Signalling pathways with overlapping effects of MAPK activity and elevated CO2 levels
From: Carbon dioxide and MAPK signalling: towards therapy for inflammation
Process | MAPKs | CO2 intervention | Identified mechanisms | References | |
|---|---|---|---|---|---|
CO2 | MAPK | ||||
Alveolar fluid resorption | ERK1/2, p38, JNK | 10% CO2 for 20 min in human AECs; 5–12% CO2 in rodent models | Regulation of ion and water flow by ENaC, Na/K-ATPase, CFTR and AQPs, regulation of intracellular cAMP levels | ||
LPS-induced lung injury | ERK1/2 | 2.5–20% CO2 (lung macrophages), prophylactic or therapeutic 5% CO2 inhalation | Cytokine responses in alveolar macrophages, downregulation of Toll-like receptor 4 expression, NF-κB signalling | ||
Mechanical ventilation-induced lung injury | ERK1/2, p38, JNK | 12–15% CO2 (AECs), 80–100 mm Hg PaCO2 (ventilated rats) | Regulation of NF-κb, ICAM-1, ADAM17, IL-6, IL-8, epidermal growth factor receptor (EGFR) activity, lung infiltration by neutrophils and AEC apoptosis | ||
Hyperoxia | ERK1/2, p38, JNK | Immersion of lower legs in CO2-enriched (1,553 mg CO2/l) water or 60–146 mm Hg PCO2 (cells, bioptates or the organism) | Hyperoxia-induced cell apoptosis; NADPH-oxidase activity; production of O2., antioxidants and proinflammatory cytokines; Nrf2, adenosine A2A receptor, protein kinase A (PKA), Src, cAMP, small mothers against decapentaplegic 3 (SMAD3), semaphorin 3A and A-kinase anchoring protein 1 (Akap1) signalling pathways | ||
Airway dilation | ERK1/2, p38 | Increased CO2 concentrations in the bath (isolated bronchial rings), an increase in EtCO2 of 1 kPa (healthy volunteers and asthma patients), inhaled 5–10% CO2 | Akt-C/EBPβ-CCL20-mediated epithelial-mesenchymal transition; NLRP3 deubiquitination and transcriptional upregulation leading to NLRP3 inflammasome activation, voltage-dependent Ca2+ channels; Ca2+ and substance P signalling | ||
Pulmonary artery hypertension | ERK1/2, p38 | EtCO2/PaCO2 measurement in patients with PAH, 5% CO2 for 10 min (isolated perfused rat lungs) | 15-Hydroxyeicosatetraenoic acid (15-HETE) and 15-lipoxygenase-2 signalling, mitosis and apoptosis of pulmonary arterial smooth muscle cells, differentiation of mesenchymal stem cells leading to vascular remodelling | ||
Vascular remodelling | ERK1/2, p38, JNK | 10% CO2 for 1–3 weeks | AngII- and thrombin-induced cell proliferation, deposition of the collagen/extracellular matrix | [82] | |
Thrombosis | ERK1/2, p38, JNK | 10% CO2, acidosis, higher CO2/HCO3− ratio | Induction of tissue factor expression and NET formation (bronchoalveolar fluid neutrophil infiltration, NF-κB activation, IL-6 and IL-8 production) | ||
Ischaemia‒reperfusion-induced injury | ERK1/2, p38, JNK | Inhaled CO2, CO2-enriched water (1–1.2 g/l, 10 min once per day), percutaneous CO2, EtCO2 measurement | Vascular endothelial growth factor (VEGF) stimulation, NO production, cGMP accumulation, cerebral vasodilation, blood‒brain barrier function, haem oxygenase-1 (HO-1) antioxidant activity, attenuation of tissue nitration, inflammation (IL-1β, IL-6 and TNF-α production) and apoptosis | ||
Insulin resistance | ERK1/2, p38, JNK | Incubation of adipocytes in 10% CO2 | IRS-1 phosphorylation | [21] | |
Obesity | ERK1/2, p38, JNK | Subcutaneous injections of CO2, bathing in neutral bicarbonate ion water | Regulation of adipogenesis, lipogenesis, thermogenesis and browning of white adipose tissue, modification of mitochondrial function | ||
Allergic reactions | ERK1/2, p38 | Noninhaled 100% CO2 (flow rate 5–10 ml/s), CO2 administered intranasally for 10–30 s | Mast cell induction, i.e., activation of NF-κB and AP-1, regulating the expression of histidine decarboxylase and production of histamine and proinflammatory factors, histamine signalling through H1, H2, H3 and H4 receptors | ||
Production of proinflammatory cytokines | ERK1/2, p38, JNK | 2–20% CO2 for 1–24 h (macrophages or venous blood samples) | Heat shock factor 1 (HSF1)- and NF-κB-dependent transcriptional activity; cytokine secretion, HO-1 antioxidant activity | ||
Breathing regulation | ERK1/2 | Perfusing spinal cord preparations with artificial cerebrospinal fluid equilibrated with 30% CO2; CO2 inhalation; elevated PaCO2 | Na+ current, Ca2+ and Akt signalling, ATP release, erythropoietin | ||
Memory | ERK1/2 | PaCO2 80–100 mm Hg; postacquisition 10% CO2 inhalation; CA activation; CA inhibition; acidification | CA activation; protons as a neurotransmitter; acid-sensing ion channel (ASIC); Na+ and Ca2+ currents | ||
Sleep and circadian rhythm | ERK1/2 | Natural fluctuations in CO2 levels | CREB-dependent transcription | ||
Sleep apnoea | ERK1/2, p38, JNK | EtCO2 raised by 2–4 mm Hg | Regulation of postsynaptic density 95 (PSD-95) expression | [162] | |
Anxiety | ERK1/2 | 5–35% CO2 inhalation | Serotonin and BDNF signalling, CREB-dependent transcription | [165] | [166] |
Neurodegeneration/neuroprotection | ERK1/2, p38, JNK | 50–100 mm Hg PaCO2 (0.5–2 h per day, rats), 20% CO2 inhalation for 2 min (mice) | Neuronal apoptosis, improvement of exploratory behaviour and total locomotor activity; downregulation of glutamate after brain injury, Ca2+ signalling | ||
Longevity, cell survival and proliferation | ERK1/2 | 2–30% CO2 (cultured cells); self-produced hypoxic-hypercapnic environment by mice (~ 7% CO2); 5 or 20% CO2 (Blastocladia) | Protein kinase C (PKC) and serotonin signalling (cultured cells), decrease in metabolic rate, body temperature, and food consumption, accelerated wound healing | ||
Apoptosis | ERK1/2, p38, JNK | CA activation; CA inhibition; acidification; PaCO2 80–108 mm Hg | Regulating pro-survival and pro-death BCL-2 proteins and mitochondrial function; p21 and Akt signalling pathways, HO-1 antioxidant activity | ||
Mitochondrial function | ERK1/2, p38, JNK | Percutaneous CO2 (rodents), 5% CO2 inhalation (humans) | Mitochondrial biogenesis, fusion, fission, fragmentation and mitophagy, suppression of cerebral metabolic rate of oxygen | ||