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Review
. 2022 Sep:190:247-263.
doi: 10.1016/j.freeradbiomed.2022.08.004. Epub 2022 Aug 11.

Dual effects of supplemental oxygen on pulmonary infection, inflammatory lung injury, and neuromodulation in aging and COVID-19

Mosi Lin  1 , Maleka T Stewart  1 , Sidorela Zefi  1 , Kranthi Venkat Mateti  1 , Alex Gauthier  1 , Bharti Sharma  1 , Lauren R Martinez  1 , Charles R Ashby Jr  1 , Lin L Mantell  2
Affiliations
Review

Dual effects of supplemental oxygen on pulmonary infection, inflammatory lung injury, and neuromodulation in aging and COVID-19

Mosi Lin et al. Free Radic Biol Med. 2022 Sep.

Abstract

Clinical studies have shown a significant positive correlation between age and the likelihood of being infected with SARS-CoV-2. This increased susceptibility is positively correlated with chronic inflammation and compromised neurocognitive functions. Postmortem analyses suggest that acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), with systemic and lung hyperinflammation, can cause significant morbidity and mortality in COVID-19 patients. Supraphysiological supplemental oxygen, also known as hyperoxia, is commonly used to treat decreased blood oxygen saturation in COVID-19 patients. However, prolonged exposure to hyperoxia alone can cause oxygen toxicity, due to an excessive increase in the levels of reactive oxygen species (ROS), which can overwhelm the cellular antioxidant capacity. Subsequently, this causes oxidative cellular damage and increased levels of aging biomarkers, such as telomere shortening and inflammaging. The oxidative stress in the lungs and brain can compromise innate immunity, resulting in an increased susceptibility to secondary lung infections, impaired neurocognitive functions, and dysregulated hyperinflammation, which can lead to ALI/ARDS, and even death. Studies indicate that lung inflammation is regulated by the central nervous system, notably, the cholinergic anti-inflammatory pathway (CAIP), which is innervated by the vagus nerve and α7 nicotinic acetylcholine receptors (α7nAChRs) on lung cells, particularly lung macrophages. The activation of α7nAChRs attenuates oxygen toxicity in the lungs and improves clinical outcomes by restoring hyperoxia-compromised innate immunity. Mechanistically, α7nAChR agonist (e.g., GAT 107 and GTS-21) can regulate redox signaling by 1) activating Nrf2, a master regulator of the antioxidant response and a cytoprotective defense system, which can decrease cellular damage caused by ROS and 2) inhibiting the activation of the NF-κB-mediated inflammatory response. Notably, GTS-21 has been shown to be safe and it improves neurocognitive functions in humans. Therefore, targeting the α7nAChR may represent a viable therapeutic approach for attenuating dysregulated hyperinflammation-mediated ARDS and sepsis in COVID-19 patients receiving prolonged oxygen therapy.

Keywords: Acute respiratory distress syndrome (ARDS); Aging; COVID-19; Cholinergic anti-inflammatory pathway; Inflammation; Mitochondria; Supplemental oxygen therapy; α7 nicotinic acetylcholine receptor.

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Figures

Image 1
Graphical abstract
Fig. 1
Fig. 1
Aging and age-related diseases are the major risk factors that are correlated with the susceptibility and severity of COVID-19. Exacerbated symptoms of COVID-19 in patients are correlated with age and medical comorbidities, such as pneumonia, dementia, COPD, diabetes, obesity, cardiovascular diseases. Patients with increasingly severe COVID-19 symptoms are significantly more likely to have higher and sustained systemic and local levels of pro-inflammatory mediators. This pro-inflammatory phenotype increases the production of reactive oxygen species (ROS), producing oxidative stress, which contributes to chronic inflammation. The treatment of COVID-19 patients with supraphysiological supplemental oxygen therapy (≥21% O2) for prolonged periods of time induces oxidative stress, which alters immune cell functions and the inflammatory response that further exacerbates unresolved chronic inflammation. SARS-CoV-2-related viral pathology and the presence of oxidative stress associated with chronic inflammation make the biologically elderly more susceptible to severe COVID-19 and mortality. The size of the box indicates the magnitude of the inflammatory responses.
Fig. 2
Fig. 2
Hyperoxia exacerbates the production of aging biomarkers that increase inflammaging and decrease health span. Prolonged exposure to hyperoxia (≥21% O2) increases the levels of reactive oxygen species (ROS). Subsequently, the increased ROS production can directly result in 1) increased expression of angiotensin-converting enzyme-2 (ACE2); 2) increased activation of NF-κB; 3) inflammation of the lungs; 4) accumulation of lipofuscin; 5) decreased length of telomeres; 6) accumulation of senescent cells, and 7) disrupted mitochondrial integrity. These effects can increase the susceptibility to other disease and disease severity. For example, the increased expression of ACE2 in the lungs may result in an increased susceptibility to SARS-CoV-2 infection. If oxygen therapy needed, neurological injury and lung inflammation can together contribute to systemic inflammation that triggers in a vicious cycle of inflammation and tissue injury, thereby increasing lung and brain dysfunction. An increase in the aging phenotype negatively affects inflammaging and health span, a measure of the length of a life without disease or injury, resulting in increased morbidity and mortality.
Fig. 3
Fig. 3
Proposed mechanisms by which α7nAChR agonists protect patients from hyperoxia-induced neurocognitive dysfunction and compromised innate immunity by activating the cholinergic anti-inflammatory pathway. Under normoxic conditions, lung inflammation in response to infections or injuries in healthy subjects is at least partially modulated by the activation of the cholinergic anti-inflammatory pathway (CAIP). The CAIP aids in the homeostatic maintenance of lung and brain inflammation, which influences healthy lung and cognitive functions. Under hyperoxic conditions and as a consequence of aging and neurodegenerative diseases, increased levels of reactive oxygen species (ROS) can impair macrophage functions in the lung and the neurons in the brain. ROS-induced damage to the cells in the central nervous system (CNS), peripheral nervous system (PNS), and blood-brain barrier (BBB) can result in cognitive dysfunction, which can cause impairment of the CAIP. The compromised CAIP can establish a pathological inflammatory cycle, resulting in dysregulated hyperinflammatory responses in the lung and the development of the acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Increased levels of ROS in the lung also activate NF-κB, which further increase the release of proinflammatory cytokines, exacerbating lung inflammation. Hyperinflammatory responses can then contribute to systemic inflammation and neuroinflammation and produce a further deterioration in cognitive function, thus establishing a vicious cycle of compromised neuro-immune modulation. α7 nicotinic acetylcholine receptor (α7nAChR) agonists, such as GTS-21 or GAT107, help re-establish the homeostatic inflammatory balance. The activation of α7nAChR by GTS-21 or GAT107 can down-regulate the excessive production/secretion of proinflammatory cytokines (including HMGB1), which is correlated with the attenuation of hyperoxia-compromised innate immunity and neurocognitive function. Therefore, α7nAChR agonists may have a protective role in hyperoxia-induced neurocognitive dysfunction and inflammatory lung diseases.
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References

    1. Han H., Ma Q., Li C., Liu R., Zhao L., Wang W., Zhang P., Liu X., Gao G., Liu F., Jiang Y., Cheng X., Zhu C., Xia Y. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg. Microb. Infect. 2020;9:1123–1130. doi: 10.1080/22221751.2020.1770129. - DOI - PMC - PubMed
    1. Lai X., Wang M., Qin C., Tan L., Ran L., Chen D., Zhang H., Shang K., Xia C., Wang S., Xu S., Wang W. Coronavirus disease 2019 (COVID-2019) infection among health care workers and implications for prevention measures in a tertiary hospital in wuhan, China. JAMA netw. Open. 2020;3:e209666. doi: 10.1001/jamanetworkopen.2020.9666. - DOI - PMC - PubMed
    1. Anderson E.J., Rouphael N.G., Widge A.T., Jackson L.A., Roberts P.C., Makhene M., Chappell J.D., Denison M.R., Stevens L.J., Pruijssers A.J., McDermott A.B., Flach B., Lin B.C., Doria-Rose N.A., O'Dell S., Schmidt S.D., Corbett K.S., Swanson P.A., Padilla M., Neuzil K.M., Bennett H., Leav B., Makowski M., Albert J., Cross K., Edara V.V., Floyd K., Suthar M.S., Martinez D.R., Baric R., Buchanan W., Luke C.J., Phadke V.K., Rostad C.A., Ledgerwood J.E., Graham B.S., Beigel J.H. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med. 2020;383:2427–2438. doi: 10.1056/NEJMoa2028436. - DOI - PMC - PubMed
    1. Jackson L.A., Anderson E.J., Rouphael N.G., Roberts P.C., Makhene M., Coler R.N., McCullough M.P., Chappell J.D., Denison M.R., Stevens L.J., Pruijssers A.J., McDermott A., Flach B., Doria-Rose N.A., Corbett K.S., Morabito K.M., O'Dell S., Schmidt S.D., Swanson P.A., Padilla M., Mascola J.R., Neuzil K.M., Bennett H., Sun W., Peters E., Makowski M., Albert J., Cross K., Buchanan W., Pikaart-Tautges R., Ledgerwood J.E., Graham B.S., Beigel J.H. An mRNA vaccine against SARS-CoV-2 — preliminary report. N. Engl. J. Med. 2020;383:1920–1931. doi: 10.1056/NEJMoa2022483. - DOI - PMC - PubMed
    1. Wang F., Kream R.M., Stefano G.B. An evidence based perspective on mRNA-SARS-CoV-2 vaccine development. Med. Sci. Mon. Int. Med. J. Exp. Clin. Res. 2020;26 doi: 10.12659/MSM.924700. - DOI - PMC - PubMed