COVID-19 infection : Regular exercise may help prevent or reduce the severity of ARDS

Regular exercise may reduce the risk of acute respiratory distress syndrome, a major cause of death in patients with the COVID-19 virus, a top exercise researcher reports.

He is urging people to exercise based on his findings, which also suggest a potential treatment approach.

A review by Zhen Yan, PhD, of the University of Virginia School of Medicine, showed that medical research findings “strongly support” the possibility that exercise can prevent or at least reduce the severity of ARDS, which affects between 3% and 17% of all patients with COVID-19.

Based on available information, the federal Centers for Disease Control and Prevention estimates 20% to 42% of patients hospitalized for COVID-19 will develop ARDS.

The range for patients admitted to intensive care is estimated at 67% to 85%.

Research conducted prior to the pandemic suggested that approximately 45 percent of patients who develop severe ARDS will die.

“All you hear now is either social distancing or ventilator, as if all we can do is either avoiding exposure or relying on a ventilator to survive if we get infected,” Yan said.

“The flip side of the story is that approximately 80% of confirmed COVID-19 patients have mild symptoms with no need of respiratory support.

The question is why. Our findings about an endogenous antioxidant enzyme provide important clues and have intrigued us to develop a novel therapeutic for ARDS caused by COVID-19.”

Powerful Antioxidant

Yan, the director of the Center for Skeletal Muscle Research at UVA’s Robert M. Berne Cardiovascular Research Center, compiled an in-depth review of existing medical research, including his own, looking at an antioxidant known as “extracellular superoxide dismutase” (EcSOD).

This potent antioxidant hunts down harmful free radicals, protecting our tissues and helping to prevent disease.

Our muscles naturally make EcSOD, secreting it into the circulation to allow binding to other vital organs, but its production is enhanced by cardiovascular exercise.

A decrease in the antioxidant is seen in several diseases, including acute lung disease, ischemic heart disease and kidney failure, Yan’s review shows. Lab research in mice suggests that blocking its production worsens heart problems, while increasing it has a beneficial effect. A decrease in EcSOD is also associated with chronic conditions such as osteoarthritis.

Research suggests that even a single session of exercise increases production of the antioxidant, prompting Yan to urge people to find ways to exercise even while maintaining social distancing.

“We cannot live in isolation forever,” he said. “Regular exercise has far more health benefits than we know. The protection against this severe respiratory disease condition is just one of the many examples.”

Potential Treatments

Yan’s review also suggests EcSOD as a potential treatment for ARDS and many other health conditions.

Gene therapy, for example, might one day be used to increase production of the antioxidant so that its protective presence in the lungs is enhanced in patients battling COVID-19.

Research has also shown that lab rats with chronic kidney disease had less kidney damage when treated with human EcSOD.

The antioxidant is already being proposed as a potential therapeutic for diabetic retinopathy, a complication of diabetes that can lead to blindness.

Further, EcSOD also may prove beneficial against multi-organ dysfunction syndrome, in which multiple organs begin to fail. Efforts to treat the condition with general antioxidants have been unsuccessful, but Yan suggests that understanding EcSOD’s workings may let doctors use it in a more targeted – and hopefully more effective – fashion.

“We often say that exercise is medicine. EcSOD set a perfect example that we can learn from the biological process of exercise to advance medicine,” Yan said.

“While we strive to learn more about the mysteries about the superb benefits of regular exercise, we do not have to wait until we know everything.”

Funding: The research was supported by the National Institutes of Health, grants R01-GM109473 and T32 HL007284-43.

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Oxygen is indispensable for life; however, under certain situations it has deleterious effects due to the formation and activity of a number of chemical compounds, known as free radicals or reactive oxygen species (ROS) [46]. Fortunately, cellular enzymatic and nonenzymatic mechanisms are in place to neutralize ROS.

Among the members of the enzymatic defense system, superoxide dismutases (SODs) are an ubiquitous family of enzymes that catalyze the dismutation of superoxide anions (O2 .-) as the first line of defense against ROS [117].

SODs reduce O2 .- to oxygen and hydrogen peroxide (H2O2), and H2O2 is further neutralized to water through enzymatic reactions by catalase (CAT) or glutathione peroxidase (GPX).

These reactions are necessary to maintain redox balance. However, excessive ROS production can exceed the capacity of the antioxidant defense system leading to oxidative stress, which causes cellular damage by oxidizing proteins, lipids, DNA/RNA, and other macromolecules.

Oxidative stress has been shown to play an important role in many disease pathologies, such as cachexia, sepsis, hypertension, myocardial infarction (MI), chronic heart failure (CHF), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and multiple organ dysfunction syndrome (MODS) [31,35].

There are three SOD isoenzymes; each resides in a distinct cellular location :

• SOD1, or CuZnSOD, is a copper and zinc-containing homodimer in cytoplasm.
• SOD2, or MnSOD, exists as a tetrameric manganese-containing enzyme in the matrix of mitochondria.
• SOD3, or EC-SOD, is a copper and zinc-containing tetrameric enzyme that is secreted from the producing cells into the extracellular space [117].

EcSOD is widely expressed in many tissues/organs with the highest levels in the lung and kidney [30,72,117]. EcSOD is so far the only known antioxidant enzyme that functions to scavenge biologically toxic O2 .- in the extracellular space.

EcSOD is produced within cells, then processed and secreted. Immature EcSOD protein has an N-terminus with targeting signal that instructs its secretion to the extracellular space. Once this targeting signal is cleaved, the mature form gains enhanced protein stability due to a glycosylation of asparagine at position 89 [80].

EcSOD contains an activity site where copper and zinc ions bind, which is essential for ROS neutralizing function. Finally, EcSOD has a heparin binding domain (HBD) on the C-terminus, consisting of six positively charged lysine and arginine residues.

This HBD is responsible for EcSOD binding to proteoglycans, such as heparin, collagen and fibulin, which allows for EcSOD localization to the cell surface and extracellular matrix. In order for EcSOD to be released into plasma and other fluids, carboxylases and furin-like proteases have to cleave EcSOD near the HBD.

In this manner, EcSOD acts not only on the cell surface and in the extracellular matrix of producing cells in a paracrine manner but can also be distributed systemically to other tissues in an endocrine manner. In vivo evidence support that EcSOD enriches at endothelial c

ells in producing cells as well as the targeted peripheral tissues [11,12,78]. Detoxification of vascular O2 .- by EcSOD preserves NO bioavailability [54], which is critical for normal vasoreactivity. Furthermore, EcSOD can be endocytosed into the targeted endothelial cells through clathrin-mediated pathway depending on HBD.

The endocytosed EcSOD does not translocate to the nucleus but may function as antioxidant intracellularly in the targeted cells [18]. Finally, a common human single nucleotide polymorphism (SNP) of EcSOD with a substitution of arginine at 213 with glycine (R213G) in HBD in about 5% of the population, which lead to impaired binding to cell surface and extracellular matrix, does not affect the enzymatic activity but lead to impaired antioxidant function in various model systems [2,16,18,56,79].

The functional importance of EcSOD in humans has been deduced from reduced EcSOD expression a variety of chronic diseases [15,22,63,95,102]. Genetic evidence also supports a causal role of reduced EcSOD activity in chronic disease pathologies [25].

For example, EcSOD R213G SNP has been associated with increased risk or poor prognosis of oxidative stress-related diseases, such as acute lung injury, ischemic heart diseases, and kidney failure [7,56,59,111].

The role of HBD in EcSOD distribution in the tissue reveals the importance of targeting specificity for EcSOD to be an effective extracellular antioxidant. For example, a T-allele of rs2284659 variant in the promoter of the EcSOD gene is associated with higher plasma EcSOD and lower plasma advanced oxidation protein products.

This gene variant is inversely associated with incidence of MI and all-cause of mortality in people with type 1 and type 2 diabetes [74], suggesting that EcSOD plays an important role in protection against diabetes-related oxidative stress.

Experimental studies in animal models show that genetic manipulation with deletion or overexpression of the EcSOD gene exacerbates or prevents chronic disease states, providing evidence for a causal role of reduced ectopic expression of EcSOD in disease development [13,41,50,66,69,70,89,105,114].

For example, EcSOD knockout mice display cardiac fibrosis and ventricular hypertrophy, suggesting a role of normal expression of EcSOD in deterring these processes [105]. Furthermore, a novel rat strain with a missense mutation that alters a single amino acid (E124D) of EcSOD that produces a malfunctioning protein (EcSOD E124D) in the Dahl/Salt Sensitive (Dahl/SS) background developed age-dependent arterial hypertension, kidney failure and cardiac hypertrophy, suggesting that endogenous EcSOD protects multiple organ systems against extracellular oxidative stress [45].

On the contrary, ectopic overexpression of EcSOD mediated by adeno-associated virus (AAV) provided significant protection against ischemic damage in skeletal muscle and the heart [60,93], indicating enhanced EcSOD expression is sufficient for protection against oxidative damage.

Finally, reduced EcSOD abundance and vascular dysfunction in aged rats could be corrected by adenovirus-mediated gene transfer of EcSOD, which appear to be dependent on the HBD [9].

Overall, EcSOD has recently emerged as a promising therapy for protection of vital tissues/organs under various disease conditions related to oxidative stress. Recent findings suggest that endurance exercise promotes EcSOD expression in skeletal muscle, the largest organ in our body, leading to elevated levels of EcSOD in other peripheral organs. This humoral function of EcSOD induced by exercise training may become effective therapeutics for many disease conditions (Fig. 1 ).

Several landmark reviews have provided elegant overview of the regulation and function of EcSOD in health and disease [25,34,117]. In this review, we will focus on the benefits of EcSOD and how exercise may increase skeletal muscle EcSOD to protect vital tissues/organs against oxidative damage.

Exercise and EcSOD

The antioxidant capacity of mammalian organ systems matches very well with the rates of oxygen consumption and free radical production. Oxidative tissues, such as skeletal muscle, heart and kidney, have the greatest antioxidant enzyme activity.

Consistent with the fact that acute exercise, particularly intense or prolonged exercise, increases free radical production and that reactive free radicals are often counterbalanced by antioxidant defense systems under the control of signaling pathways in response to increased free radicals to maintain homoeostasis, exercise training or physical activity has been associated with reduced oxidative stress in many studies in humans. Indeed, controlled clinical trials show that regardless of intensity, volume, type of exercise, and studied population, the antioxidant indicators tend to increase, and pro-oxidant indicators tend to decrease after exercise training [23].

Reduction of oxidative stress in organ systems by exercise training is likely due to enhanced antioxidant defenses in tissues [88]. For example, slow-twitch, oxidative fibers in skeletal muscle with high oxidative capacities have higher antioxidant capacities compared with fast-twitch, glycolytic fibers with lower oxidative potential.

While majority of the effects of exercise training in the antioxidant defense system reside intracellularly, including CuZnSOD, MnSOD, and CAT, EcSOD is the only one that functions extracellularly. An acute bout of endurance exercise promotes EcSOD gene transcription, and exercise training promotes EcSOD protein expression in skeletal muscle in mice [49,78,99,112,119], which could be recapitulated in culture myotubes following electrical stimulation [99].

Endurance exercise training has also been shown to increase the abundance of EcSOD in the aorta in mice [32,49] and in plasma in humans [106]. Importantly, exercise training increases EcSOD protein abundance in peripheral tissues, such as the heart, with no evidence of increased transcription of the EcSOD gene in these peripheral tissues [11].

Exercise-induced EcSOD expression seems to be specific for endurance exercise, not induced by resistance exercise [106]. Finally, genetically engineered mice with enhanced EcSOD expression in skeletal muscle showed increased EcSOD levels in the blood and all peripheral tissues and organs, such as the kidneys, liver, heart, lung, and adipose tissue [12].

These findings support that endurance exercise promotes EcSOD expression in skeletal muscle, the largest organ of the body, leading to enhanced extracellular antioxidant defense in the circulation and peripheral tissues as the molecular transducer of the benefits of exercise to health and disease (Fig. 1).

Several studies have investigated the signaling mechanism of exercise-induced EcSOD expression. In human aortic smooth muscle cells, the nitric oxide (NO) donor diethylenetriamine-NO (DETA-NO) increased EcSOD expression in a time- and dose-dependent manner, which appears to be dependent on cyclic GMP (cGMP)/protein kinase (PKG) and p38 mitogen-activated kinase (p38 MAPK) [32].

These findings were corroborated by treadmill exercise in vivo in mice lacking endothelial nitric oxide synthase (eNOS) [32]. The direct evidence of NO signaling in exercise-induced EcSOD expression in skeletal muscle came from the studies where DETA-NO treatment induces EcSOD mRNA and transcription in culture C2C12 myoblasts [116], and systemic administration of endogenous NO donor S-nitrosoglutathione (GSNO) results in increased EcSOD protein expression in skeletal muscle [78].

More recently, Yamada et al. presented evidence that exercise-induced EcSOD expression is dependent on nuclear factor erythroid 2-related factor 2 (Nrf2) in oxidative soleus muscle, but not glycolytic white vastus lateralis muscle [112]. The precise mechanism(s) that controls EcSOD expression in peripheral tissues in response to exercise training remain to be fully elucidated in future studies.

Pulmonary disease

Oxidative stress in the lung tissue participates in the pathogenesis of various pulmonary pathologies, including COPD and ALI/ARDS. EcSOD is highly expressed in lungs specifically located in the extracellular matrix, the junctions of airway epithelial cells, airway smooth muscle and the endothelium of vessels of the lung [58], scavenging superoxide in this tissue in our body that directly deals with oxygen in the ambient air. Accumulating evidence shows that EcSOD polymorphisms are associated with a decline in lung function in rodents and humans, and altered susceptibility to lung injury as a result of alteration of EcSOD level and function in the lung tissue [7,22,36].

ALI/ARDS
ALI/ARDS is a disease condition of respiratory failure with a mortality rate of about 40% and accounts for approximately 75,000 annual deaths in the U.S [92,109]. General antioxidants have failed in clinical trials due to lack of targeting specificity [101]. The innate immune response plays a profound role in the pathogenesis of ALI/ARDS, which involves cascades of events with neutrophils, macrophages, and dendritic cells partaking in mediating lung injury.

A key step in ALI/ARDS is the dysregulation and recruitment of activated neutrophils to the lung microvasculature, interstitial and alveolar space [85]. Excessive neutrophil activation and accumulation leads to increased reactive oxygen species (ROS) and pro-inflammatory mediators, resulting in acute lung injury [84,85]. Therefore, neutrophil adhesion and subsequent activation by activating endothelium, a condition called endothelial cell activation, is an essential, early step in the inflammatory pathogenesis of ALI/ARDS [118]. The degree of endothelial cell activation and lung injury is strongly associated with the outcomes in ALI/ARDS [108] (Fig. 2C).

In line with the notion that EcSOD plays a critical role in the first line of defense against superoxide generation in the lung tissue, acute loss of EcSOD in adult mice (inducible EcSOD −/− mice) causes a dramatic increase of mortality with ALI/ARDS even in ambient oxygen although global EcSOD −/− mice are viable and tolerate exposure to ambient oxygen levels without difficulties. This severe pathological condition could be rescued by intranasal administration of EcSOD mimetic [40]. In contrast, low mortality rates were observed in EcSOD-overexpressing animals exposed to hyperoxia [29,40].

Exercise training and therapeutic exercise has been shown to limit alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans [28,91]. In a mouse model of endotoxemia induced by LPS, enhanced EcSOD expression in skeletal muscle profoundly protected the mice from developing ALI/ARDS with reduced mortality while EcSOD R213G mice are more vulnerable [12]. Importantly, the elevated EcSOD in the blood has been shown to be sufficient to inhibit endothelial cell activation and inflammatory cell adhesion induced by endotoxemia [12] (Fig. 2C).

These findings strongly support that enhanced EcSOD expression from skeletal muscle or other tissues/organ, which can be redistributed to the lung tissue, could be a viable preventative/therapeutic measures in reducing the risk and severity of ALI/ARDS. Considering the current outbreak of the 2019 Novel Corona virus infection (COVID-19), which is an infectious disease that leads to progressive ALI/ARDS in many patients [6,103,107,113], it is conceivable that regular exercise might be effective in preventing while EcSOD gene/protein therapy might be effective in treating ALI/ARDS under the condition of COVID-19 infection.

COPD
Oxidative stress in the lung tissue is at the center of the pathogenesis of COPD [71]. In clinical studies, rs8192287 (E1) and rs8192288 (I1) SNPs are tightly coupled and associated with reduced lung function [22,100] and elevated risk of COPD [22], whereas R213G SNP is associated with resistance to COPD [57,98,115]. These findings were somewhat paradoxical at the first glance, but careful research reveal that EcSOD plays an important role in the pathogenesis of COPD with disparate effects depending on its tissue distribution.

The former two SNPs simply lead to reduced expression of EcSOD in the lungs [22], whereas R213G SNP decreases the matrix binding affinity without altering enzyme activity but lead to redistribution of active EcSOD into the plasma and epithelial lining fluid [47]. A major difference between the R213G SNP and the E1 and I1 SNPs is the increased diffusion of EcSOD into the alveolar lining fluid of the lung, which serve as an antioxidant shield that protects the lungs against oxidants.

Consistent with this notion is the finding that EcSOD R213G polymorphism is associated with reduced risk of COPD for smokers, but not for non-smoker [57,115]. Gaurav et al. have also reported that R213G SNP carriers in humans have higher EcSOD in airway lining fluid and reduced allergic airway inflammation with reduced asthma-related symptoms in allergic asthma, which were recapitulated in EcSOD R213G mice [38].

Animal studies with genetic manipulation to mimic human SNPs have shed light on the role of EcSOD in the pathogenesis of COPD. Ganguly et al. showed correlation between EcSOD polymorphisms, lung EcSOD expression, and pulmonary function in mice. JF1/Msf mice, known with decreased ventilation efficiency, were found to have 3 EcSOD promoter SNPs and decreased EcSOD transcript, protein expression, and activity in the lungs compared to C3H/HeJ mice [36].

This study illustrates correlation of pulmonary expression of EcSOD with decreased lung function and increased susceptibility to COPD. Interestingly, EcSOD R213G knock-in mice exhibited enhanced resolution of inflammation with subsequent protection against fibrosis following bleomycin treatment compared with wild type littermates [75], which was later confirmed by RNAseq analysis showing induction of inflammatory and immune response genes were suppressed in EcSOD R213G mice [37].

Similar findings were observed for models of allergic airway inflammation [38,47]. These findings suggest that the redistributed EC-SOD due to the R213G SNP attenuates the dysregulated inflammatory responses. These findings are amazingly consistent with the findings in R213G carriers in humans [57,115]. We speculate that endurance exercise may promote EcSOD expression in skeletal muscle, which could be redistributed to peripheral tissues, such as lung, providing protection against airway inflammatory disease and COPD.

Multiple Organ Dysfunction Syndrome (MODS)

MODS, a major contributor of intensive care unit (ICU) mortality, occurs when multiple organs are damaged to the point where they cannot maintain homeostatic function. Emerging evidence suggests that oxidative stress-induced endothelial cell activation (induced expression of adhesion molecules) in vital organs is a key step in the pathology as it leads to exacerbated inflammatory cell infiltration and tissue damage [4].

Endothelial cell activation in the vasculature can further stimulate immune cell-endothelial cell interaction and production of free radicals, contribute to a vicious cycle in the development of MODS. Given the role of ROS in inducing endothelial cell activation and general oxidative stress in MODS, general antioxidants have been investigated in protection against MODS in human. Unfortunately, none of the general antioxidants, which have no target specificity, have all failed in these clinical trials [101].

Through parabiosis experiments and intraperitoneal serum transfusions, we demonstrated that EcSOD protected against LPS-induced MODS by preserving lung function, reducing endothelial cell activation, and decreasing endothelial cell adhesion [12]. Similarly, in a sepsis model, administration of an exogenous SOD mimetic protected the lung by reducing oxidative damage and inflammation [20].

Together these studies suggest boosting EcSOD abundance and activity may protect against MODS, particularly by enhanced expression of EcSOD from a remote organ like skeletal muscle. Serum carrying elevated EcSOD protein from skeletal muscle was shown to be sufficient to reduced endothelial cell activation with suppressed VCAM-1 expression in vitro and in vivo [12] (Fig. 2C). Intravital imaging of inflammatory cell-endothelial cell interaction revealed reduced inflammatory adhesion conferred by EcSOD protection in peripheral tissue vasculature under the condition of endotoxemia in muscle-specific EcSOD transgenic mice [12].

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